Myocardial Infarction

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Definitions

1

High-sensitivity cardiac troponin ascertainment of myocardial infarction in emergency-department suspected acute coronary syndrome

EHR/OMOP-style ascertainment used by linked-registry studies of suspected acute coronary syndrome: take all adult emergency-department presentations in which high-sensitivity cardiac troponin was measured within 24 hours as the denominator, and count as cases those meeting the Universal Definition threshold (hs-cTn above the 99th centile of a normal reference population). Recorded here because the boundary it draws is mechanistically load-bearing for this entry, which models type 1 (atherothrombotic) MI: the threshold detects cardiomyocyte troponin release from any cause, so the cohort it returns mixes type 1 MI with type 2 MI and non-ischemic myocardial injury.

PHENOTYPE_ALGORITHM Emergency-department suspected-ACS ascertainment in linked primary/secondary care records; denominator plus troponin-threshold case rule, without adjudication of MI type.

Troponin-tested suspected-ACS cohort

Adults presenting to a secondary- or tertiary-care emergency department in whom high-sensitivity cardiac troponin was measured within 24 hours of presentation; cases are those exceeding the 99th-centile diagnostic threshold.

Inclusion criteria

Adult emergency-department presentation Adult patient presenting to a secondary- or tertiary-care emergency department.

Laboratory requirements

High-sensitivity cardiac troponin measured within 24 hours hs-cTnI or hs-cTnT measured within 24 hours of presentation; defines the denominator of the tested population.
Troponin above the 99th-centile diagnostic threshold Concentration exceeding the (sex-specific) 99th centile of a normal reference population, the Universal Definition threshold.

Additional requirements

MI type not resolved by the algorithm The threshold does not distinguish type 1 MI from type 2 MI or non-ischemic myocardial injury; adjudication is required for that.

Show evidence (3 references)

PMID:30170853 SUPPORT Human Clinical

"The Universal Definition of Myocardial Infarction1 recommends that an increase in troponin above the 99th centile of a normal reference population should be used as the threshold for diagnosis of myocardial infarction."

States the consensus threshold rule this ascertainment algorithm implements.

PMID:30170853 SUPPORT Human Clinical

"Implementation of a high-sensitivity cardiac troponin assay and use of the 99th centile as the diagnostic threshold identifies more patients with myocardial injury than type 1 myocardial infarction and does not lead to a reduction in subsequent cardiac events."

Randomised-trial evidence that the threshold is not specific for the type 1 atherothrombotic mechanism modeled in this entry — the basis for the UNVALIDATED status and the MI-type caveat.

PPR:PPR1272216 Preprint · not peer-reviewed SUPPORT Human Clinical

"We included all adult patients presenting to secondary- or tertiary-care EDs in the region between 2014 and 2024, in whom high-sensitivity cardiac troponin was measured within 24 hours of presentation."

Specifies the troponin-tested emergency-department denominator this algorithm encodes, as executed in the DataLoch linked registry.

Notes: PPR:PPR1272216 is a non-peer-reviewed preprint and is used here only to document how the cohort was operationalized at population scale; the threshold rule and the injury-versus-type-1-MI caveat are both carried by the peer-reviewed randomised trial PMID:30170853. The primary source of the threshold rule is the Fourth Universal Definition of Myocardial Infarction (PMID:30165617, Thygesen et al.), but it is not cited as an evidence item here because no abstract or full text is retrievable for it (the fetcher caches it as content unavailable), so no snippet can be verified; the rule is therefore quoted from PMID:30170853's statement of it.

C

Comorbidities

Influenza <-> Myocardial Infarction

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Pathophysiology

5

Coronary Atherothrombosis

A coronary atherosclerotic plaque with a thin fibrous cap and a large necrotic core ruptures (or, less often, erodes), exposing highly thrombogenic necrotic-core material and subendothelial collagen to flowing blood. Platelet adhesion and activation with activation of the coagulation cascade form an occlusive or near-occlusive coronary thrombus that abruptly interrupts blood flow to the downstream myocardium. Systemic inflammation, including that accompanying acute respiratory infection, can destabilize vulnerable plaque and promote a procoagulant state.

coronary endothelial cell CL:0000115 platelet CL:0000233

platelet activation GO:0030168 ↑ INCREASED blood coagulation GO:0007596 ↑ INCREASED inflammatory response GO:0006954 ↑ INCREASED

coronary artery UBERON:0001621

Downstream

Myocardial Ischemia and Cardiomyocyte Death Occlusive coronary thrombosis abruptly interrupts perfusion of the downstream myocardium, producing ischemia.

Show evidence (3 references)

PMID:24902970 SUPPORT Other

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

Establishes that rupture of an atherosclerotic plaque precipitates coronary thrombosis presenting as acute coronary syndrome (including MI).

PMID:24902970 SUPPORT Other

"Most often, the culprit morphology is plaque rupture with exposure of highly thrombogenic, red cell-rich necrotic core material."

Identifies plaque rupture exposing thrombogenic necrotic-core material as the dominant culprit lesion mechanism.

DOI:10.3390/ijms25137295 SUPPORT Other

"Type 1 is associated with atherosclerosis, type 2 results from inadequate oxygen supply to cardiomyocytes, type 3 is defined as sudden cardiac death, while types 4 and 5 are associated with procedures such as percutaneous coronary intervention and coronary artery bypass grafting, respectively."

Establishes the universal MI classification and that type 1 (the mechanism modeled here) is the atherosclerosis-driven form.

Myocardial Ischemia and Cardiomyocyte Death

Sustained interruption of coronary perfusion causes regional myocardial ischemia. If flow is not restored, cardiomyocytes undergo necrosis and apoptosis, releasing cardiac troponin into the circulation (the biomarker basis of MI diagnosis). Loss of contractile myocardium reduces left ventricular systolic function and provides an arrhythmogenic substrate, and can progress to heart failure.

cardiac muscle cell CL:0000746

cardiac muscle cell apoptotic process GO:0010659 ↑ INCREASED

myocardium UBERON:0002349 heart UBERON:0000948

Experimental models

Human cardiac infarct organoid with an internal oxygen-diffusion gradient ORGANOID The oxygen gradient reproduces regional ischemic cardiomyocyte death and the arrhythmogenic calcium-handling defect, spatially separated within one construct rather than averaged over it.

Myocardial infarct border-zone-on-a-chip ORGAN ON CHIP Reproduces the electromechanical dysfunction of border-zone myocardium and attributes it specifically to the oxygen gradient.

Bioelectronically instrumented heart-on-a-chip under acute hypoxia ORGAN ON CHIP Reproduces the acute electrophysiological response to oxygen deprivation, including action-potential shortening attributable to ATP-dependent potassium channel activation, but not the death arm of the node.

Downstream

Ischemia-Reperfusion Injury Emergency restoration of coronary flow to salvage ischemic myocardium paradoxically inflicts additional reperfusion injury on the jeopardized tissue.

Post-Infarction Inflammation and Cardiac Repair Massive cardiomyocyte death releases damage-associated molecular patterns that ignite the post-infarction inflammatory and reparative cascade.

Myocardial infarction Regional ischemic necrosis of myocardium is the infarct itself, so this node is what the clinical phenotype names.

Angina pectoris Ischemic myocardium generates the prolonged substernal pressure or pain of the classic acute presentation, transmitted by cardiac sympathetic afferents.

Chest pain The same ischemic afferent signalling also produces atypical and non-anginal chest discomfort, which is how a large fraction of infarcts present.

Arrhythmia Ischemic and necrotic myocardium is electrically heterogeneous and provides the arrhythmogenic substrate for conduction block and re-entry.

Reduced left ventricular ejection fraction Loss of contractile myocardium in the infarct territory reduces global left ventricular systolic performance.

Show evidence (2 references)

PMID:26426469 SUPPORT Other

"Myocardial infarction is defined as sudden ischemic death of myocardial tissue."

Directly evidences that MI is ischemic death of myocardium, the core claim of this node.

PMID:26426469 SUPPORT Other

"Mitochondrial alterations are prominently involved in apoptosis and necrosis of cardiomyocytes in the infarcted heart."

Evidences ischemic cardiomyocyte necrosis and apoptosis in the infarcted myocardium described by this node.

Ischemia-Reperfusion Injury

Restoration of coronary blood flow (by primary PCI or fibrinolysis) is essential to salvage ischemic myocardium but paradoxically inflicts additional damage — myocardial ischemia-reperfusion injury (MIRI) — that can account for up to half of the final infarct size. Reperfusion drives a burst of reactive oxygen species, cytosolic and mitochondrial calcium overload, and sustained opening of the mitochondrial permeability transition pore (MPTP) with collapse of the mitochondrial membrane potential and cessation of ATP production, together with endothelial dysfunction, NLRP3 inflammasome activation, and multiple regulated cell-death programs (apoptosis, necroptosis, pyroptosis, ferroptosis) and dysregulated autophagy.

cardiac muscle cell CL:0000746 coronary endothelial cell CL:0000115

response to oxidative stress GO:0006979 ↑ INCREASED intracellular calcium ion homeostasis GO:0006874 ↕ DYSREGULATED

myocardium UBERON:0002349

Experimental models

Human heart-on-a-chip ischemia-reperfusion assay with endothelial extracellular vesicle rescue ORGAN ON CHIP Reproduces reperfusion-associated cardiomyocyte death and contractile failure in an all-human system, and shows the injury is pharmacologically reversible.

Epicardial-myocardial heart-on-a-chip model of ischemia-reperfusion injury ORGAN ON CHIP Reproduces reperfusion-associated cell death and functional loss, and isolates the epicardium's contribution by comparison with epicardium-free tissue.

Downstream

Ventricular fibrillation Abrupt restoration of flow into ischemic myocardium produces calcium overload and marked dispersion of repolarization at the border zone, the substrate for reperfusion ventricular fibrillation.

Post-Infarction Inflammation and Cardiac Repair Reperfusion-driven necrosis and DAMP release amplify the sterile inflammatory response in the infarcted myocardium.

Show evidence (5 references)

DOI:10.1097/crd.0000000000000440 SUPPORT Other

"reperfusion salvages a significant amount of ischemic myocardium in the subepicardium while reperfusion injury contributes up to 50% of the final subendocardial infarct."

Establishes that reperfusion, while salvaging myocardium, contributes up to half of the final infarct size — the defining claim of MIRI.

DOI:10.1097/crd.0000000000000440 SUPPORT Other

"Reperfusion of severely ischemic myocardium leads to sustained opening of the mitochondrial permeability transition pore (MPTP)."

Evidences the central mitochondrial mechanism (sustained MPTP opening) of lethal reperfusion injury described in this node.

DOI:10.3390/cells14191509 SUPPORT Other

"MIRI refers to paradoxical myocardial damage that occurs upon restoration of coronary blood flow and is driven by complex inflammatory, oxidative, and metabolic mechanisms, which can exacerbate infarct size"

Defines MIRI as paradoxical reperfusion damage driven by inflammatory, oxidative, and metabolic mechanisms that enlarge the infarct.

+ 2 more references

Post-Infarction Inflammation and Cardiac Repair

Massive cardiomyocyte death releases damage-associated molecular patterns (DAMPs/alarmins) that engage pattern-recognition receptors (TLRs, NLRs), driving cytokine (IL-1, TNF-alpha, IL-6) and chemokine (CCL2) production and recruitment of neutrophils and monocytes. Expansion and diversification of cardiac macrophages clears dead cells; efferocytosis then triggers anti-inflammatory mediators (IL-10, TGF-beta) that restrain inflammation and activate reparative fibroblasts and vascular cells. This tightly regulated inflammatory-to-reparative transition is essential for healing, but an excessive or unresolved response promotes adverse outcomes.

cardiac muscle cell CL:0000746 macrophage CL:0000235 neutrophil CL:0000775

inflammatory response GO:0006954 ↑ INCREASED wound healing GO:0042060 ↑ INCREASED

myocardium UBERON:0002349

Experimental models

Myocardial infarct border-zone-on-a-chip ORGAN ON CHIP Gradient-exposed cardiac tissue raises inflammatory-cascade expression on its own, showing that the myocardial arm of the post-infarction inflammatory response does not require leukocytes to be initiated.

Downstream

Cardiac Fibrosis and Ventricular Remodeling Efferocytosis-driven release of TGF-beta and other reparative mediators activates fibroblasts and myofibroblasts, initiating fibrotic scar formation and structural remodeling.

Show evidence (5 references)

DOI:10.1161/circresaha.124.323658 SUPPORT Other

"After infarction, massive cardiomyocyte death releases a broad range of damage-associated molecular patterns that initiate both myocardial and systemic inflammatory responses."

Evidences DAMP release from dying cardiomyocytes as the trigger of the post-infarction inflammatory response.

DOI:10.1161/circresaha.124.323658 SUPPORT Other

"Expansion and diversification of cardiac macrophages in the infarcted heart play a major role in the clearance of the infarct from dead cells and the subsequent stimulation of reparative pathways."

Supports the role of cardiac macrophage expansion in clearing the infarct and initiating repair.

DOI:10.1161/circresaha.124.323658 SUPPORT Other

"Efferocytosis triggers the induction and release of anti-inflammatory mediators that restrain the inflammatory reaction and set the stage for the activation of reparative fibroblasts and vascular cells."

Evidences the efferocytosis-driven switch from inflammation to fibroblast-mediated repair that this node describes.

+ 2 more references

Cardiac Fibrosis and Ventricular Remodeling

Loss of contractile myocardium and sustained inflammatory/neurohormonal drive produce adverse structural remodeling of the ventricle. Cardiac fibroblasts differentiate into myofibroblasts that deposit a collagen-based extracellular matrix; a well-organized scar protects against rupture and limits acute dilation, but excessive, prolonged, or dysregulated fibrogenic signaling drives interstitial fibrosis, chamber dilation, and contractile dysfunction, progressing to heart failure. This node conforms to the conserved ventricular-remodeling step of the maladaptive-cardiomyopathy module, substituting the ischemic infarct scar as the disorder-specific insult.

cardiac fibroblast CL:0002548 cardiac muscle cell CL:0000746

extracellular matrix organization GO:0030198 ↑ INCREASED cardiac muscle cell apoptotic process GO:0010659 ↑ INCREASED

myocardium UBERON:0002349

Experimental models

Human cardiac infarct organoid with an internal oxygen-diffusion gradient ORGANOID Myofibroblast conversion and tissue stiffening arise endogenously from the hypoxia gradient and adrenergic drive, without exogenous TGF-beta or a stiffened substrate.

Epicardial-myocardial heart-on-a-chip model of ischemia-reperfusion injury ORGAN ON CHIP Identifies the epicardium as a source of the myofibroblast-like population that appears after reperfusion injury, by directly observing inward migration rather than inferring lineage from endpoint staining.

Downstream

Reduced left ventricular ejection fraction Interstitial fibrosis and chamber dilation degrade contractile efficiency beyond the initial loss of infarcted muscle, lowering ejection fraction further in the months after the event.

Congestive heart failure Adverse post-infarction remodeling progresses to the congestive heart-failure syndrome once systolic dysfunction and neurohormonal activation raise filling pressures and cause fluid retention.

Show evidence (4 references)

DOI:10.3389/fphar.2023.1070973 SUPPORT Other

"The cardiac fibroblast-to-myofibroblast differentiation and extracellular matrix collagen deposition are the hallmarks of cardiac fibrosis, which are modulated by multiple signaling pathways"

Evidences fibroblast-to-myofibroblast conversion and ECM collagen deposition as the hallmarks of post-MI cardiac fibrosis.

DOI:10.3389/fphar.2023.1070973 SUPPORT Other

"Cardiac fibrosis plays an indispensable role in cardiac tissue homeostasis and repair after myocardial infarction (MI)."

Supports that fibrosis is central to tissue repair and remodeling after MI.

DOI:10.1161/circresaha.124.323658 SUPPORT Other

"Deposition of a well-organized collagen-based extracellular matrix network protects the heart from catastrophic rupture and attenuates ventricular dilation."

Evidences the protective role of organized collagen scar in limiting rupture and dilation.

+ 1 more reference

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Pathograph

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

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Phenotypes

10

Cardiovascular 8

Myocardial infarction HP:0001658

Elevated cardiac troponin Increased circulating troponin T concentration HP:0410174

Arrhythmia HP:0011675

Sequelae: Ventricular fibrillation Syncope

Reduced left ventricular ejection fraction HP:0012664

Sequelae: Dyspnea

Angina pectoris HP:0001681

Temporal: ACUTE

Ventricular fibrillation HP:0001663

Congestive heart failure HP:0001635

Syncope HP:0001279

Respiratory 1

Dyspnea HP:0002094

Constitutional 1

Chest pain HP:0100749

Temporal: ACUTE

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Medical Actions

3

Coronary Reperfusion (PCI or Fibrinolysis)

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

Emergency restoration of coronary blood flow by primary percutaneous coronary intervention or, where unavailable, fibrinolysis, to salvage ischemic myocardium.

Mechanism Target:

RESTORES Coronary Atherothrombosis — Primary PCI or fibrinolysis removes or lyses the occlusive coronary thrombus and restores antegrade flow in the infarct-related artery.

Show evidence (1 reference)

PMID:27502078 SUPPORT Other

"implementation of care delivery systems prioritising immediate revascularisation through percutaneous coronary intervention (or fibrinolysis)"

Identifies immediate revascularisation by PCI or fibrinolysis as central to modern AMI management.

INHIBITS Myocardial Ischemia and Cardiomyocyte Death — Restoring perfusion salvages myocardium that has not yet infarcted, which is the point of treating within a time window; the same manoeuvre also opens the reperfusion-injury node modelled downstream.

Show evidence (1 reference)

PMID:27502078 SUPPORT Other

"implementation of care delivery systems prioritising immediate revascularisation through percutaneous coronary intervention (or fibrinolysis)"

Identifies immediate revascularisation by PCI or fibrinolysis as central to modern AMI management.

Antiplatelet and Antithrombotic Therapy

Action: Pharmacotherapy NCIT:C15986

Antiplatelet agents and anticoagulants to limit coronary thrombus propagation, plus secondary-prevention statins.

Mechanism Target:

INHIBITS Coronary Atherothrombosis — Antiplatelet agents and anticoagulants limit propagation of thrombus on the disrupted plaque and reduce re-occlusion after reperfusion; the secondary-prevention statin component acts on the underlying atheroma.

Show evidence (1 reference)

PMID:27502078 SUPPORT Other

"advances in antiplatelet agents and anticoagulants, and greater use of secondary prevention strategies such as statins."

Identifies antiplatelet agents, anticoagulants, and statins as pillars of pharmacological AMI management.

Show evidence (1 reference)

PMID:27502078 SUPPORT Other

"advances in antiplatelet agents and anticoagulants, and greater use of secondary prevention strategies such as statins."

Identifies antiplatelet agents, anticoagulants, and statins as pillars of pharmacological AMI management.

Anti-Inflammatory / Immunomodulatory Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: canakinumab NCIT:C80971 tocilizumab NCIT:C84217

Platform: Monoclonal antibody

Emerging cytokine-directed therapy targeting the post-infarction inflammatory response, notably IL-1 (canakinumab) and IL-6 (tocilizumab) pathway inhibitors, to reduce cardiovascular events and mitigate ischemia-reperfusion injury.

Mechanism Target:

MODULATES Post-Infarction Inflammation and Cardiac Repair — IL-1 and IL-6 pathway blockade damps the cytokine arm of the post-infarction inflammatory response. The effect is deliberately recorded as modulation rather than inhibition, since this response is required for healing and only its excessive form is adverse.

Show evidence (1 reference)

DOI:10.3390/cells14191509 SUPPORT Other

"including IL-1 and IL-6 inhibitors such as Canakinumab and Tocilizumab"

Identifies IL-1 (canakinumab) and IL-6 (tocilizumab) inhibitors as immunotherapeutic strategies in MI/MIRI.

INHIBITS Ischemia-Reperfusion Injury — The same cytokine-directed agents are under study to mitigate ischemia-reperfusion injury, in which NLRP3 inflammasome and IL-1 signalling are prominent.

Show evidence (1 reference)

DOI:10.3390/cells14191509 SUPPORT Other

"including IL-1 and IL-6 inhibitors such as Canakinumab and Tocilizumab"

Identifies IL-1 (canakinumab) and IL-6 (tocilizumab) inhibitors as immunotherapeutic strategies in MI/MIRI.

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Biochemical Markers

4

Elevated cardiac troponin (Elevated)

Context: A rise and/or fall of high-sensitivity cardiac troponin (cTnI or cTnT) above the 99th-percentile upper reference limit, in a clinical context of ischemia, is the biomarker cornerstone of the Fourth Universal Definition of MI; troponin is the most sensitive/specific marker for acute myocardial injury.

Pathograph Readouts

Readout Of Myocardial Ischemia and Cardiomyocyte Death Positive Diagnostic

Troponin reaches the circulation only when cardiomyocyte membrane integrity is lost, so a rise and fall above the 99th centile measures the cardiomyocyte-death step. It is sensitive for that step but not specific to the type 1 atherothrombotic route, as this entry's evidence records.

Show evidence (2 references)

DOI:10.3390/biomedicines13071532 SUPPORT Other

"distinguishing reperfusion injury from ischemic damage is challenging and often requires the use of sensitive biomarkers, such as cardiac troponins, alongside advanced imaging modalities."

Supports cardiac troponin as the sensitive biomarker used to detect myocardial injury in MI.

PMID:30170853 SUPPORT Human Clinical

"use of the high-sensitivity assay reclassified one in six patients with myocardial injury, but only a third of these patients had a diagnosis of type 1 myocardial infarction, and the incidence of subsequent myocardial infarction or cardiovascular death at 1 year was unchanged."

Qualifies the marker: a troponin rise above the 99th centile is sensitive for cardiomyocyte injury but not specific for the type 1 atherothrombotic mechanism this entry models, so a positive result is not itself evidence of plaque rupture.

Elevated CK-MB (Elevated)

Context: Creatine kinase-MB isoenzyme and LDH rise more slowly (LDH at roughly 24-48 hours) than troponin; historically used for MI diagnosis and for gauging infarct timing, now largely superseded by high-sensitivity troponin.

Pathograph Readouts

Readout Of Myocardial Ischemia and Cardiomyocyte Death Positive Diagnostic

CK-MB release also reports cardiomyocyte necrosis, with slower kinetics than troponin, which is why it was historically used to gauge infarct timing.

Total lipids in very small VLDL (XS-VLDL-L)

Context: XS-VLDL-L quantifies the total lipid carried in the very small VLDL subclass, the remnant-lipoprotein end of the triglyceride-rich spectrum, on the Nightingale Health NMR platform used in UK Biobank. No presence value is recorded because the reported quantity is a genetically instrumented effect estimate over a general-population cohort rather than an observed level in patients with infarction. The finding is consistent with the wider remnant-cholesterol literature and supports curating atherogenic apoB-lipoprotein burden, not LDL-C alone, as the lipid input to coronary atherothrombosis. It is a risk-stratification signal and does not displace troponin, which remains the diagnostic biomarker for an acute event.

Pathograph Readouts

Predicts Coronary Atherothrombosis Positive Prognostic

Higher very-small-VLDL lipid content marks a more atherogenic remnant-lipoprotein burden and tracks with a higher risk of the atherothrombotic event that initiates infarction.

Show evidence (1 reference)

PMID:40973818 SUPPORT Human Clinical

"total lipids in very small VLDL (XS-VLDL-L) exhibited the strongest association with increased risk of myocardial infarction (OR = 1.55 (1.48-1.63)"

Bidirectional Mendelian randomization over 313 NMR metabolites ranks XS-VLDL-L as the metabolite with the strongest risk-increasing estimate for myocardial infarction (OR 1.55, 95% CI 1.48-1.63).

Phospholipids to total lipids in small HDL, percent (S-HDL-PL%)

Context: Recorded as the counterpart to the XS-VLDL-L entry so the lipoprotein axis is not curated one-sidedly. Note that this is a compositional ratio within small HDL rather than HDL cholesterol concentration, so it should not be read as reviving HDL-C as a causal protective target, a claim that randomized HDL-raising trials did not support.

Pathograph Readouts

Predicts Coronary Atherothrombosis Negative Prognostic

A higher phospholipid share within small HDL tracks with lower risk of the atherothrombotic event that initiates infarction. Recorded as the protective counterpart of the XS-VLDL-L readout; it is a compositional ratio and not a claim that raising HDL cholesterol is protective.

Show evidence (2 references)

PMID:40973818 SUPPORT Human Clinical

"the ratio of phospholipids to total lipids in the small HDL percentage (S-HDL-PL%; OR = 0.63 (0.59-0.67)"

Names S-HDL-PL% and quotes its Mendelian randomization effect estimate for myocardial infarction directly, rather than leaving the number in curator prose.

PMID:40973818 SUPPORT Human Clinical

"exhibited the most notable protective effect (Fig. 7e)"

The predicate of the same sentence, quoted so the protective claim itself is carried by source text rather than by the explanation.

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Related Datasets

9

Temporal inhibition of ADAM17 in fibroblasts reduces stiffness and promotes vascularization following myocardial infarction geo:GSE306012

Myocardial infarction (MI) triggers a complex remodelling process that leads to heat failure if uncontrolled. A Disintegrin and metalloproteinase-17 (ADAM17), a transmembrane sheddase, is upregulated in patients with ischemic cardiomyopathy, colocalized to myofibroblasts (myoFB) in the infarct tissues. Fibroblasts are key players in post-MI scar formation and exist in different states with diverse functions. Using mice with inducible Adam17 deletion in homeostatic FBs (Adam17 FB-KD ), or activated FBs (Adam17 myoFB-KD ), we found that ADAM17 loss in homeostatic FBs impaired infarct formation post-MI and increased mortality due to left ventricular (LV) rupture.

mouse BULK RNA SEQ n=28

PMID:41524432

Identified by GEO DataSets index search for Myocardial Infarction (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.

mRNA Therapeutics Encoding Multiple Reparative Factors using Polyplex Nanomicelle Attenuating Myocardial Infarction geo:GSE304168

Background: Gene therapy for heart failure has been explored using single factors such as angiogenic agents; however, clinical success remains limited. In this study, we investigated an alternative approach by directly administering mRNA encoding multiple genes that are transiently upregulated during cardiac recovery. Using a model in which heart function is restored through the administration of extracellular vesicles secreted by human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM-derived EVs), we aimed to evaluate the potential of multi-gene mRNA therapy for heart failure, being delivered using polyplex nanomicelles, which serve as an effective delivery system with superio...

mouse BULK RNA SEQ n=6

PMID:42272746

Identified by GEO DataSets index search for Myocardial Infarction (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.

CCR8 expression on regulatory T cells reveals trajectories of tissue adaptation and protects against myocardial infarction [bulk RNA-seq] geo:GSE291962

We employed single-cell RNA sequencing (scRNA-seq) in a mouse model of MI to gain a detailed analysis of heart and lymphoid Tregs, focusing on their developmental trajectories. Bulk RNA sequencing was used to further characterize the phenotype of CC motif chemokine receptor 8 positive (CCR8+) Tregs in the heart and lymph nodes. scRNA-seq of murine Tregs from the mediastinal lymph node (mLN) and heart after MI identified three Treg populations, one of which was mainly derived from the heart.

mouse BULK RNA SEQ n=16

PMID:41685444

Identified by GEO DataSets index search for Myocardial Infarction (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.

Spatial multi-omic map of human myocardial infarction ega:EGAS00001006330

Myocardial infarction is a leading cause of mortality worldwide 1 . While advances have been made in acute treatment, an incomplete understanding of remodelling processes has limited the effectiveness of therapies to reduce late-stage mortality 2 . Here, we generate an integrative high- resolution map of human cardiac remodelling after myocardial infarction using single-cell gene expression, chromatin accessibility, and spatial transcriptomic profiling of multiple physiological zones at distinct time points in myocardium from myocardial infarction and control patients.

human

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

Single-cell dissection of the immune response after a myocardial infarction ega:EGAS00001007021

human SINGLE CELL RNA SEQ

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

Post Acute Myocardial Infarction Left Ventricular Remodeling Bio marker Analysis (PAMILA) metabolomics_workbench:ST001908

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 ("Myocardial Infarction"). Retrieved 2026-08-02.

Effect of senolytics (Navitoclax, ABT263) on recovery following Myocardial Infarction massive:MSV000085040

Ischemia reperfusion injury (IRI) following intervention for myocardial infarction remains an unmet clinical problem. Using an established mouse model, we demonstrated that IRI induces multiple cardiac cell linages to senescence. Senescence is is detrimental to recovery, as treatment with the senolytic navitoclax improves functional recovery.Here we are using SWATH-MS to investigate the molecular mechanisms responsible for the effect of navitoclax treatment.

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 ("Myocardial Infarction"). Retrieved 2026-08-02.

Cardiac organoid model of human myocardial infarction geo:GSE113871

RNA-seq of human cardiac organoids carried through the oxygen-gradient infarction protocol versus control organoids. The transcriptomic arm of the infarct-organoid model curated in this entry's experimental_models block.

human BULK RNA SEQ

PMID:32284552

Deposited by PMID:32284552, the source of the oxygen-gradient cardiac infarct organoid in experimental_models. Title copied from GEO; accession verified against the cached GEO record.

Show evidence (1 reference)

GEO:GSE113871 SUPPORT In Vitro

"we leveraged the diffusion limitation in 3D microtissues to recreate the nutrient diffusion gradient across infarcted hearts (i.e., infarct-border-remote zones) in human cardiac organoids to induce cardiac organotypic response to infarction"

The repository's own summary states the gradient-based infarction protocol whose transcriptomes this series holds.

Cardiac organoid model of human myocardial infarction (batch2) geo:GSE115031

Second donor batch of the cardiac infarct organoid RNA-seq, used in the source publication to test whether the infarct hallmarks survive a change of hiPSC genetic background.

human BULK RNA SEQ

PMID:32284552

Deposited by PMID:32284552 as the Donor B replication of GSE113871. Title copied from GEO; accession verified against the cached GEO record.

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Clinical Trials

1

NCT06118281 PHASE_III RECRUITING

ARTEMIS — randomized trial of the anti-IL-6 monoclonal antibody ziltivekimab versus placebo for prevention of recurrent cardiovascular events in patients with acute myocardial infarction.

Target Phenotypes: Myocardial infarction HP:0001658

Show evidence (1 reference)

clinicaltrials:NCT06118281 SUPPORT Human Clinical

"The research study is being done to see if ziltivekimab can be used to treat people who were admitted to hospital because of a heart attack."

ClinicalTrials.gov summary confirms ARTEMIS tests ziltivekimab in post-MI patients, evidencing the anti-inflammatory therapeutic strategy.

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Experimental Models

5

Human cardiac infarct organoid with an internal oxygen-diffusion gradient ORGANOID namo:Organoid

A self-assembled multicellular human cardiac microtissue in which the infarct is produced by geometry rather than by a uniform treatment. At a radius of ~150 um and 10% ambient oxygen, oxygen consumption outruns diffusion toward the core, so a single organoid carries an apoptotic centre, a dysfunctional interior and a functional edge at once — the in vitro counterpart of the infarct, border and remote zones. Chronic norepinephrine supplies the neurohormonal arm. Because the pathology is spatially graded within one construct, edge and interior can be compared as internal controls, which uniform hypoxia (0.1% O2, which kills the whole construct) cannot do.

Organism

human NCBITaxon:9606

Tissue

myocardium UBERON:0002349

Cell source

iPSC-derived cardiomyocytes combined with primary human cardiac ventricular fibroblasts, umbilical vein endothelial cells and adipose-derived stem cells

Culture

Non-adhesive agarose micromold self-assembly into ~150 um-radius microtissues; calcium dynamics read by a custom two-photon scanned light-sheet microscope at 20 ms resolution through the organoid interior

Publication

PMID:32284552

Pathograph links

Myocardial Ischemia and Cardiomyocyte Death recapitulates fidelity: moderate observes: cellular The oxygen gradient reproduces regional ischemic cardiomyocyte death and the arrhythmogenic calcium-handling defect, spatially separated within one construct rather than averaged over it.

Limitations: Death here is driven by diffusion-limited hypoxia in a construct with no vasculature and no coronary occlusion, so the model reproduces the consequence of interrupted perfusion but not its atherothrombotic cause. The cardiomyocytes are immature iPSC-derived cells.

Divergences from the human mechanism

cause unrepresented qualifying

The ischemia arises from oxygen consumption outrunning diffusion in an avascular microtissue. Coronary atherothrombosis, the lesion that causes it in patients, is not represented anywhere in the model.

Readouts

Apoptotic nuclei at the organoid core (TUNEL)

Direction: INCREASED

Interpretation: Cell death is localized to the region the diffusion model predicts is below viable oxygen, which is what makes the construct zonal rather than uniformly injured.

Show evidence (1 reference)

PMID:32284552 SUPPORT In Vitro

"infarct organoids showed apoptotic TUNEL+ staining in the center of organoid sections, attributed mainly to the non-viable oxygen levels at the center of the organoids"

Reports the spatially restricted apoptosis measurement behind this readout.

Peak calcium transient amplitude in interior cardiomyocytes

Direction: DECREASED

Interpretation: Measured against edge cardiomyocytes in the same organoid, so the comparator is internal; the deficit is the functional correlate of the pathological calcium handling that underlies post-MI arrhythmia.

Show evidence (1 reference)

PMID:32284552 SUPPORT In Vitro

"Interior cardiomyocytes in the infarct organoids showed significantly lower max calcium transient amplitude in contrast to the infarct and control edge cardiomyocytes"

Reports the interior-versus-edge calcium measurement grounding this readout.

Show evidence (1 reference)

PMID:32284552 SUPPORT In Vitro

"cardiac organoids that incorporate an oxygen-diffusion gradient and that are stimulated with the neurotransmitter noradrenaline model the structure of the human heart after myocardial infarction (by mimicking the infarcted, border and remote zones)"

States the model's central claim, that the graded construct reproduces the zonal structure of the infarcted human heart, which is why it is treated as informative for this node.

Cardiac Fibrosis and Ventricular Remodeling partially recapitulates fidelity: moderate observes: tissue Myofibroblast conversion and tissue stiffening arise endogenously from the hypoxia gradient and adrenergic drive, without exogenous TGF-beta or a stiffened substrate.

Limitations: The organoid contains no leukocytes, so fibrosis develops without the inflammatory-to-reparative transition that drives it in vivo; the stiffening is that of acute remodeling and does not reach the values of a mature scar.

Divergences from the human mechanism

boundary omission qualifying

Neutrophils, monocytes and macrophages are outside the construct, so the myofibroblast conversion measured here proceeds without the inflammatory-to-reparative transition that drives it in the infarcted heart.

cause unrepresented qualifying

The fibrotic response is driven by the same diffusion-limited hypoxia and by exogenous norepinephrine as the sibling ischemia link. Neither the coronary atherothrombosis that interrupts perfusion nor the endogenous neurohormonal activation that follows it is represented.

Readouts

Myofibroblast-like alpha-smooth-muscle-actin structures

Direction: INCREASED

Interpretation: The histological marker used to identify fibrotic myocardium, appearing here as a downstream consequence of the oxygen gradient alone.

Show evidence (1 reference)

PMID:32284552 SUPPORT In Vitro

"Infarct organoids showed numerous myofibroblast-like structures, marked by elongated, αSMA+/F-actin+ phenotype in contrast to control organoids"

Reports the myofibroblast staining measurement behind this readout.

Tissue elastic modulus by micropipette aspiration

Direction: INCREASED

Interpretation: Mechanical correlate of matrix deposition, measured on the viable outer region of the construct.

Show evidence (1 reference)

PMID:32284552 SUPPORT In Vitro

"The stiffness was significantly increased in infarct organoids over control organoids"

Reports the stiffness measurement grounding this readout.

Show evidence (1 reference)

PMID:32284552 SUPPORT In Vitro

"One limitation of the model is that not every aspect of heart failure can be mimicked with the current infarct organoids (e.g., lack of inflammatory cells, use of immature hiPSC-CMs)"

The authors' own statement of the missing immune compartment, which is why this link is graded PARTIALLY_RECAPITULATES rather than RECAPITULATES.

Curated from the Brenden et al. perspective on spatiotemporally instrumented in vitro tissues (DOI:10.1016/j.celbio.2026.100576), which cites this model as the example of engineering spatial heterogeneity into an organoid instead of applying a spatially uniform disease stimulus.

Myocardial infarct border-zone-on-a-chip ORGAN_ON_CHIP namo:OrganOnChip

A microphysiological system that imposes a controlled oxygen gradient across engineered human cardiac tissue, isolating the border zone as an experimental variable in its own right. The comparison that matters is not injured-versus-healthy but graded-versus-uniform: tissue under a gradient behaves differently from tissue held at uniform normoxia or uniform hypoxia, so the spatial gradient is itself a pathogenic factor rather than a confounder to be averaged away.

Organism

human NCBITaxon:9606

Tissue

myocardium UBERON:0002349

Cell source

Stem-cell-derived human cardiomyocytes in engineered cardiac tissue

Culture

Microfluidic device with spatially controlled oxygenation across the tissue, read out by calcium imaging, contractile-stress measurement and RNA sequencing

Publication

PMID:36475790

Pathograph links

Myocardial Ischemia and Cardiomyocyte Death partially recapitulates fidelity: moderate observes: tissue Reproduces the electromechanical dysfunction of border-zone myocardium and attributes it specifically to the oxygen gradient.

Limitations: The chip models the oxygen gradient and its functional consequences, not the cardiomyocyte necrosis of the infarct core; there is no coronary circulation and no thrombotic trigger.

Divergences from the human mechanism

cause unrepresented qualifying

The oxygen gradient is imposed by the device's gas control rather than arising from an occluded coronary artery, so the gradient is an experimental input and not a consequence of the disease lesion.

boundary omission qualifying

The chip spans the gradient itself; the necrotic infarct core that the gradient borders in vivo is not part of the construct.

Readouts

Calcium release, reuptake and propagation kinetics

Direction: ALTERED

Interpretation: Delayed rather than simply reduced, so the readout is a change in kinetics; this is the conduction substrate for post-infarction arrhythmia.

Show evidence (1 reference)

PMID:36475790 SUPPORT In Vitro

"The gradient delayed calcium release, reuptake, and propagation; decreased diastolic and peak systolic stress; and increased expression of inflammatory cascades that are hallmarks of myocardial infarction"

Reports the calcium-handling and contractile measurements made under the gradient.

Diastolic and peak systolic stress

Direction: DECREASED

Interpretation: Contractile failure of gradient-exposed tissue, the in vitro analogue of the reduced force generation reported for border-zone myocardium.

Show evidence (1 reference)

PMID:36475790 SUPPORT In Vitro

"These changes were distinct from those observed in tissues exposed to uniform normoxia or hypoxia, demonstrating distinct regulation of cardiac tissue phenotypes by an oxygen gradient"

Establishes that the functional changes are specific to the gradient and are not reproduced by either uniform condition.

Show evidence (1 reference)

PMID:36475790 SUPPORT In Vitro

"we engineered a microphysiological system to controllably expose engineered cardiac tissue to an oxygen gradient that mimics the border zone and measured the effects of the gradient on electromechanical function and the transcriptome"

Describes the model and the border-zone mechanism it is built to interrogate.

Post-Infarction Inflammation and Cardiac Repair partially recapitulates fidelity: low observes: molecular Gradient-exposed cardiac tissue raises inflammatory-cascade expression on its own, showing that the myocardial arm of the post-infarction inflammatory response does not require leukocytes to be initiated.

Limitations: The construct contains no neutrophils, monocytes or macrophages, so it captures only the cardiac-tissue half of the response and cannot model recruitment, efferocytosis or the inflammatory-to-reparative transition that the node describes. The evidence is transcriptional.

Divergences from the human mechanism

boundary omission invalidating

Neutrophil and monocyte recruitment, macrophage expansion and efferocytosis are the substance of this node, and none of those cells is present in the construct.

proxy quantity qualifying

Inflammatory-cascade transcript abundance in cardiac tissue stands in for the cellular inflammatory response the node describes.

cause unrepresented qualifying

The inflammatory program is induced by an oxygen gradient set by the device's gas control. The infarct that establishes that gradient in patients, and the necrotic tissue whose damage signals normally initiate the response, are both absent.

Readouts

Inflammatory cascade gene expression

Direction: INCREASED

Interpretation: Transcriptional only; establishes that the oxygen gradient is sufficient to induce an inflammatory program in cardiac tissue alone.

Show evidence (1 reference)

PMID:36475790 SUPPORT In Vitro

"The gradient delayed calcium release, reuptake, and propagation; decreased diastolic and peak systolic stress; and increased expression of inflammatory cascades that are hallmarks of myocardial infarction"

Reports the inflammatory-expression measurement behind this readout.

Show evidence (1 reference)

PMID:36475790 SUPPORT In Vitro

"Steep O2 gradients develop at the interface between the injured, hypoxic tissue and the surrounding viable, normoxic tissue"

States the in vivo gradient the chip reproduces, establishing why gradient-driven inflammatory signalling in the model bears on this node.

Human heart-on-a-chip ischemia-reperfusion assay with endothelial extracellular vesicle rescue ORGAN_ON_CHIP namo:OrganOnChip

Human stem-cell-derived laminar cardiac tissues subjected to simulated ischemia and reperfusion on a chip, with a treatment arm in which vascular-endothelial extracellular vesicles are applied. The tissue itself is cardiomyocyte-only; the endothelial cells are the vesicle source and are not part of the construct. The rescue arm is what makes the model a test of the mechanism rather than a description of it: cell death and contractile loss are reversed dose-dependently by a defined intervention.

Organism

human NCBITaxon:9606

Tissue

myocardium UBERON:0002349

Cell source

Human stem-cell-derived cardiomyocytes; human vascular endothelial cells as the vesicle source

Culture

Human laminar cardiac tissues on a heart-on-a-chip contractility platform

Publication

PMID:33055246

Pathograph links

Ischemia-Reperfusion Injury recapitulates fidelity: moderate observes: tissue Reproduces reperfusion-associated cardiomyocyte death and contractile failure in an all-human system, and shows the injury is pharmacologically reversible.

Limitations: Oxygen and nutrient deprivation are applied to the tissue directly, so there is no microvascular obstruction, no circulating leukocytes and no platelet contribution to reperfusion injury.

Divergences from the human mechanism

boundary omission qualifying

The construct is cardiomyocyte-only by the authors' own account, and oxygen and nutrient deprivation are applied to it directly. Endothelium, microvascular obstruction, circulating leukocytes and platelets all lie outside the model, so pro-vasculogenic and anti-inflammatory routes to cardioprotection cannot contribute to the rescue measured here.

structural idealization qualifying

The cardiac tissue is a two-dimensional laminar monolayer, so the three-dimensional multicellular architecture across which reperfusion injury is distributed in the ventricle is not represented.

cause unrepresented qualifying

Ischemia and reperfusion are simulated by changing the medium the tissue is bathed in. Neither the coronary occlusion that causes the ischemic phase nor the restoration of flow that causes the reperfusion phase exists in the model.

Readouts

Cardiac cell death during and after simulated ischemia-reperfusion

Direction: INCREASED

Interpretation: Establishes that the simulated reperfusion protocol produces the cell death this node describes.

Show evidence (1 reference)

PMID:33055246 SUPPORT In Vitro

"Live/dead cell assays showed nearly 50% cell death, indicating extensive damage to the hCMs."

Direct measurement of the injury this readout records, rather than the treatment effect on it.

Contractile capacity under endothelial extracellular vesicle treatment

Direction: RESTORED

Interpretation: The rescue arm. Dose- and uptake-dependent recovery of contractile function is the model's evidence that the injury is a tractable therapeutic target rather than an endpoint.

Show evidence (1 reference)

PMID:33055246 SUPPORT In Vitro

"These results suggest that vascular EEVs rescue hlCTs exposed to IRI"

States the rescue result grounding this readout.

Show evidence (1 reference)

PMID:33055246 SUPPORT In Vitro

"we developed a human heart-on-a-chip IRI assay using human stem cell-derived, engineered cardiac tissues"

Describes the construction of the assay and its all-human basis.

Bioelectronically instrumented heart-on-a-chip under acute hypoxia ORGAN_ON_CHIP namo:OrganOnChip

A microfluidic cardiac chip with integrated extracellular electrodes and intracellular platinum nanopillars, used to follow the electrophysiological response to a rapidly imposed and reversible oxygen deficit. Its interest is instrumental rather than biological: because the electrodes are multiplexed and read continuously, the transition from tachycardia through bradycardia to arrhythmia is captured as a time course rather than as endpoint samples. The cells are a murine atrial line, so the platform is more transferable than its biology.

Organism

house mouse NCBITaxon:10090

Tissue

myocardium UBERON:0002349

Cell source

HL-1 murine atrial cardiomyocyte line

Culture

Microfluidic channel with rapid medium-oxygenation control, instrumented with multiplexed extracellular electrodes and electroporating intracellular Pt nanopillar electrodes for continuous action-potential readout

Publication

PMID:32092276

Pathograph links

Myocardial Ischemia and Cardiomyocyte Death partially recapitulates fidelity: low observes: cellular Reproduces the acute electrophysiological response to oxygen deprivation, including action-potential shortening attributable to ATP-dependent potassium channel activation, but not the death arm of the node.

Limitations: HL-1 is an immortalized murine atrial line, so neither the species nor the chamber matches human ventricular myocardium, and the recorded action potentials should not be read as human values. The hypoxia is brief and reversible and no cardiomyocyte death is assayed, so the model addresses only the electrophysiological facet of this node.

Divergences from the human mechanism

species mismatch invalidating

HL-1 is an immortalized murine atrial line. Neither the species nor the cardiac chamber matches human ventricular myocardium, so the recorded action-potential values cannot be read as human ones.

boundary omission qualifying

The hypoxia is brief and reversible and no cell-death assay is performed, so the cardiomyocyte necrosis and apoptosis half of this node lies outside what the model measures.

cause unrepresented qualifying

The oxygen deficit is produced by modulating medium oxygenation in a microfluidic channel, which the authors describe as mimicking a temporary coronary occlusion. The occlusion itself, and the atherothrombotic lesion behind it, are not part of the model.

Readouts

Beat rate during acute hypoxia

Direction: ALTERED

Interpretation: Biphasic rather than monotonic — tachycardia first, then slowing and arrhythmia — which is why a directional value would misdescribe it. Only continuous recording resolves the sequence.

Show evidence (1 reference)

PMID:32092276 SUPPORT In Vitro

"Extracellular bioelectronics provided continuous readouts demonstrating that hypoxic cells experienced an initial period of tachycardia followed by a reduction in beat rate and eventually arrhythmia"

Reports the continuous beat-rate time course behind this readout.

Action potential duration during acute hypoxia

Direction: DECREASED

Interpretation: Action-potential narrowing is the expected consequence of ATP-sensitive potassium channel opening under an oxygen deficit, and is the mechanistic link between ischemia and arrhythmogenesis at this node.

Show evidence (1 reference)

PMID:32092276 SUPPORT In Vitro

"We found that APs narrowed during hypoxia, consistent with proposed mechanisms by which oxygen deficits activate ATP-dependent K+ channels that promote membrane repolarization"

Reports the intracellular action-potential measurement grounding this readout.

Show evidence (1 reference)

PMID:32092276 SUPPORT In Vitro

"reversibly activated hypoxia-related transduction pathways in HL-1 cardiac model cells"

Identifies the cells as HL-1. That the line is an immortalized murine atrial one is established by its provenance rather than by this quote; together they are the basis for the LOW fidelity grade on this link.

Retained despite the non-human cell source because the instrumentation, not the biology, is what this record contributes: multiplexed extra- and intracellular electrodes give spatially mapped, continuously sampled electrophysiology of an ischemic insult, which no other cardiac model in this entry provides.

Epicardial-myocardial heart-on-a-chip model of ischemia-reperfusion injury ORGAN_ON_CHIP namo:OrganOnChip

Engineered cardiac tissue built on the Biowire II platform with an epicardial outer layer over an inner myocardial core, so that the epicardium is present as a distinct spatial compartment rather than absent as in conventional constructs. Subjecting it to ischemia-reperfusion shows the epicardial layer is protective, and tracks epicardial cells migrating inwards and joining the alpha-smooth-muscle-actin-positive population.

Organism

human NCBITaxon:9606

Tissue

myocardium UBERON:0002349

Cell source

Human pluripotent stem-cell-derived cardiomyocytes and epicardial cells

Culture

Biowire II engineered cardiac tissue with an epicardial outer layer, imaged with a purpose-built analysis pipeline that tracks epicardial cell migration in a beating myocardial environment

Publication

PMID:38683053

Pathograph links

Ischemia-Reperfusion Injury partially recapitulates fidelity: moderate observes: tissue Reproduces reperfusion-associated cell death and functional loss, and isolates the epicardium's contribution by comparison with epicardium-free tissue.

Limitations: Injury is imposed on the construct without vasculature or circulating immune cells. The readout of interest is the difference between epicardium-bearing and epicardium-free tissue, so absolute injury magnitudes are not transferable to human infarction.

Divergences from the human mechanism

boundary omission qualifying

The construct has no vasculature and no circulating immune cells, so absolute injury magnitudes are not transferable; what the model supports is the difference between epicardium-bearing and epicardium-free tissue.

cause unrepresented qualifying

Ischemia-reperfusion is applied to the construct as a culture protocol. There is no coronary artery to occlude and no restoration of coronary flow, so the model carries the injury without the vascular event that produces it.

Readouts

Cell death in epicardium-bearing versus epicardium-free tissue

Direction: DECREASED

Interpretation: Comparator is epicardium-free engineered cardiac tissue under the same protocol; the reduction is the model's evidence that the epicardial compartment is protective against reperfusion injury.

Show evidence (1 reference)

PMID:38683053 SUPPORT In Vitro

"In conditions mimicking ischemia reperfusion injury (IRI), the EPI cardiac tissues experience less cell death and a lower impact on functional properties"

Reports the comparative cell-death and function measurement behind this readout.

Show evidence (1 reference)

PMID:38683053 SUPPORT In Vitro

"using the Biowire II platform, engineered cardiac tissues with an epicardial outer layer and inner myocardial structure are constructed"

Describes the layered construction that gives the model its spatial compartments and makes it informative for reperfusion injury.

Cardiac Fibrosis and Ventricular Remodeling partially recapitulates fidelity: moderate observes: cellular Identifies the epicardium as a source of the myofibroblast-like population that appears after reperfusion injury, by directly observing inward migration rather than inferring lineage from endpoint staining.

Limitations: Migration is observed over the days of chip culture and contributes to an alpha-smooth-muscle-actin-positive population; no collagen deposition or scar maturation is measured, so this covers the cellular origin of remodeling and not its matrix output.

Divergences from the human mechanism

boundary omission qualifying

Collagen deposition and scar maturation are not measured, so the model speaks to the cellular origin of the remodelling population and not to the matrix output that defines the node.

cause unrepresented qualifying

The epicardial migration measured here is a response to the same protocol-imposed ischemia-reperfusion as the sibling link, so the remodelling population arises without the coronary occlusion that triggers remodelling after infarction.

Readouts

Inward migration of epicardial cells after reperfusion injury

Direction: INCREASED

Interpretation: Directly observed migration into the tissue interior, contributing to the myofibroblast-like population that drives remodeling at this node.

Show evidence (1 reference)

PMID:38683053 SUPPORT In Vitro

"Upon IRI, migration of EPI cells into the cardiac tissue interior is observed, with contributions to alpha smooth muscle actin positive cell population"

Reports the migration-tracking measurement grounding this readout.

{ }

Source YAML

click to show

name: Myocardial Infarction
creation_date: "2026-06-25T12:00:00Z"
description: >
  Myocardial infarction (acute myocardial infarction, AMI; "heart attack") is
  ischemic death of cardiomyocytes caused by an acute, sustained reduction in
  coronary blood flow. The most common (type 1) mechanism is atherothrombosis:
  rupture or erosion of a coronary atherosclerotic plaque exposes thrombogenic
  material, precipitating an occlusive or near-occlusive coronary thrombus that
  interrupts perfusion of the downstream myocardium. The resulting ischemia
  causes cardiomyocyte necrosis with release of cardiac troponin, and clinically
  presents as an acute coronary syndrome (ST-elevation or non-ST-elevation MI).
  Acute respiratory infections, including influenza and respiratory syncytial
  virus, are recognized short-term triggers of type 1 MI. AMI remains a leading
  cause of morbidity and mortality worldwide.
category: Complex
parents:
- Cardiovascular Disease
- Atherosclerotic Disease
- Cardiac disorder
synonyms:
- Acute myocardial infarction
- Heart attack
- AMI
disease_term:
  preferred_term: myocardial infarction
  term:
    id: MONDO:0005068
    label: myocardial infarction
definitions:
- name: >-
    High-sensitivity cardiac troponin ascertainment of myocardial infarction in
    emergency-department suspected acute coronary syndrome
  definition_type: PHENOTYPE_ALGORITHM
  derivation_basis: ESTABLISHED_CRITERIA
  validation_status:
    status: UNVALIDATED
    rationale: >-
      The underlying threshold rule is consensus criteria (Universal Definition
      of MI: hs-cTn above the sex-specific 99th centile with a rise and/or fall
      in an ischemic context), and the cohort form of it has been executed at
      whole-population scale in a linked EHR registry (117,142 consecutive
      patients over a decade). What is NOT validated is its specificity for the
      type 1 atherothrombotic mechanism this entry models: in a
      cluster-randomised trial of the same threshold, most patients it
      reclassified had myocardial injury rather than type 1 MI. Treat this as an
      ascertainment cohort for suspected ACS, not as a mechanism-specific case
      definition, until a query that separates type 1 MI from type 2 MI and
      non-ischemic myocardial injury is evaluated against adjudicated diagnoses.
  description: >-
    EHR/OMOP-style ascertainment used by linked-registry studies of suspected
    acute coronary syndrome: take all adult emergency-department presentations
    in which high-sensitivity cardiac troponin was measured within 24 hours as
    the denominator, and count as cases those meeting the Universal Definition
    threshold (hs-cTn above the 99th centile of a normal reference population).
    Recorded here because the boundary it draws is mechanistically load-bearing
    for this entry, which models type 1 (atherothrombotic) MI: the threshold
    detects cardiomyocyte troponin release from any cause, so the cohort it
    returns mixes type 1 MI with type 2 MI and non-ischemic myocardial injury.
  scope: >-
    Emergency-department suspected-ACS ascertainment in linked primary/secondary
    care records; denominator plus troponin-threshold case rule, without
    adjudication of MI type.
  attaches_to:
  - pathophysiology#Myocardial Ischemia and Cardiomyocyte Death
  criteria_sets:
  - name: Troponin-tested suspected-ACS cohort
    description: >-
      Adults presenting to a secondary- or tertiary-care emergency department in
      whom high-sensitivity cardiac troponin was measured within 24 hours of
      presentation; cases are those exceeding the 99th-centile diagnostic
      threshold.
    inclusion_criteria:
    - preferred_term: Adult emergency-department presentation
      description: Adult patient presenting to a secondary- or tertiary-care emergency department.
    laboratory_requirements:
    - preferred_term: High-sensitivity cardiac troponin measured within 24 hours
      description: >-
        hs-cTnI or hs-cTnT measured within 24 hours of presentation; defines the
        denominator of the tested population.
    - preferred_term: Troponin above the 99th-centile diagnostic threshold
      description: >-
        Concentration exceeding the (sex-specific) 99th centile of a normal
        reference population, the Universal Definition threshold.
    additional_requirements:
    - preferred_term: MI type not resolved by the algorithm
      description: >-
        The threshold does not distinguish type 1 MI from type 2 MI or
        non-ischemic myocardial injury; adjudication is required for that.
  evidence:
  - reference: PMID:30170853
    reference_title: "High-sensitivity troponin in the evaluation of patients with suspected acute coronary syndrome: a stepped-wedge, cluster-randomised controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The Universal Definition of Myocardial Infarction1 recommends that an increase in troponin above the 99th centile of a normal reference population should be used as the threshold for diagnosis of myocardial infarction."
    explanation: States the consensus threshold rule this ascertainment algorithm implements.
  - reference: PMID:30170853
    reference_title: "High-sensitivity troponin in the evaluation of patients with suspected acute coronary syndrome: a stepped-wedge, cluster-randomised controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Implementation of a high-sensitivity cardiac troponin assay and use of the 99th centile as the diagnostic threshold identifies more patients with myocardial injury than type 1 myocardial infarction and does not lead to a reduction in subsequent cardiac events."
    explanation: >-
      Randomised-trial evidence that the threshold is not specific for the type 1
      atherothrombotic mechanism modeled in this entry — the basis for the
      UNVALIDATED status and the MI-type caveat.
  - reference: PPR:PPR1272216
    reference_title: "Trends in the Assessment, Treatment and Outcomes of Patients with Suspected Acute Coronary Syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We included all adult patients presenting to secondary- or tertiary-care EDs in the region between 2014 and 2024, in whom high-sensitivity cardiac troponin was measured within 24 hours of presentation."
    explanation: >-
      Specifies the troponin-tested emergency-department denominator this
      algorithm encodes, as executed in the DataLoch linked registry.
  notes: >-
    PPR:PPR1272216 is a non-peer-reviewed preprint and is used here only to
    document how the cohort was operationalized at population scale; the
    threshold rule and the injury-versus-type-1-MI caveat are both carried by the
    peer-reviewed randomised trial PMID:30170853. The primary source of the
    threshold rule is the Fourth Universal Definition of Myocardial Infarction
    (PMID:30165617, Thygesen et al.), but it is not cited as an evidence item
    here because no abstract or full text is retrievable for it (the fetcher
    caches it as content unavailable), so no snippet can be verified; the rule is
    therefore quoted from PMID:30170853's statement of it.
pathophysiology:
- name: Coronary Atherothrombosis
  description: >
    A coronary atherosclerotic plaque with a thin fibrous cap and a large
    necrotic core ruptures (or, less often, erodes), exposing highly
    thrombogenic necrotic-core material and subendothelial collagen to flowing
    blood. Platelet adhesion and activation with activation of the coagulation
    cascade form an occlusive or near-occlusive coronary thrombus that abruptly
    interrupts blood flow to the downstream myocardium. Systemic inflammation,
    including that accompanying acute respiratory infection, can destabilize
    vulnerable plaque and promote a procoagulant state.
  cell_types:
  - preferred_term: coronary endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: platelet activation
    term:
      id: GO:0030168
      label: platelet activation
    modifier: INCREASED
  - preferred_term: blood coagulation
    term:
      id: GO:0007596
      label: blood coagulation
    modifier: INCREASED
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  locations:
  - preferred_term: coronary artery
    term:
      id: UBERON:0001621
      label: coronary artery
  downstream:
  - target: Myocardial Ischemia and Cardiomyocyte Death
    causal_link_type: DIRECT
    description: >
      Occlusive coronary thrombosis abruptly interrupts perfusion of the
      downstream myocardium, producing ischemia.
  evidence:
  - reference: PMID:24902970
    reference_title: "Mechanisms of plaque formation and rupture."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "such plaques may suddenly cause life-threatening coronary thrombosis presenting as an acute coronary syndrome."
    explanation: Establishes that rupture of an atherosclerotic plaque precipitates coronary thrombosis presenting as acute coronary syndrome (including MI).
  - reference: PMID:24902970
    reference_title: "Mechanisms of plaque formation and rupture."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Most often, the culprit morphology is plaque rupture with exposure of highly thrombogenic, red cell-rich necrotic core material."
    explanation: Identifies plaque rupture exposing thrombogenic necrotic-core material as the dominant culprit lesion mechanism.
  - reference: DOI:10.3390/ijms25137295
    reference_title: "From Atherosclerotic Plaque to Myocardial Infarction—The Leading Cause of Coronary Artery Occlusion."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Type 1 is associated with atherosclerosis, type 2 results from inadequate oxygen supply to cardiomyocytes, type 3 is defined as sudden cardiac death, while types 4 and 5 are associated with procedures such as percutaneous coronary intervention and coronary artery bypass grafting, respectively."
    explanation: Establishes the universal MI classification and that type 1 (the mechanism modeled here) is the atherosclerosis-driven form.
- name: Myocardial Ischemia and Cardiomyocyte Death
  description: >
    Sustained interruption of coronary perfusion causes regional myocardial
    ischemia. If flow is not restored, cardiomyocytes undergo necrosis and
    apoptosis, releasing cardiac troponin into the circulation (the biomarker
    basis of MI diagnosis). Loss of contractile myocardium reduces left
    ventricular systolic function and provides an arrhythmogenic substrate,
    and can progress to heart failure.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: cardiac muscle cell apoptotic process
    term:
      id: GO:0010659
      label: cardiac muscle cell apoptotic process
    modifier: INCREASED
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  downstream:
  - target: Ischemia-Reperfusion Injury
    causal_link_type: DIRECT
    description: >
      Emergency restoration of coronary flow to salvage ischemic myocardium
      paradoxically inflicts additional reperfusion injury on the jeopardized
      tissue.
  - target: Post-Infarction Inflammation and Cardiac Repair
    causal_link_type: DIRECT
    description: >
      Massive cardiomyocyte death releases damage-associated molecular patterns
      that ignite the post-infarction inflammatory and reparative cascade.
  - target: Myocardial infarction
    causal_link_type: DIRECT
    description: >
      Regional ischemic necrosis of myocardium is the infarct itself, so this
      node is what the clinical phenotype names.
  - target: Angina pectoris
    causal_link_type: DIRECT
    description: >
      Ischemic myocardium generates the prolonged substernal pressure or pain of
      the classic acute presentation, transmitted by cardiac sympathetic
      afferents.
  - target: Chest pain
    causal_link_type: DIRECT
    description: >
      The same ischemic afferent signalling also produces atypical and
      non-anginal chest discomfort, which is how a large fraction of infarcts
      present.
  - target: Arrhythmia
    causal_link_type: DIRECT
    description: >
      Ischemic and necrotic myocardium is electrically heterogeneous and provides
      the arrhythmogenic substrate for conduction block and re-entry.
  - target: Reduced left ventricular ejection fraction
    causal_link_type: DIRECT
    description: >
      Loss of contractile myocardium in the infarct territory reduces global
      left ventricular systolic performance.
  evidence:
  - reference: PMID:26426469
    reference_title: "Pathophysiology of Myocardial Infarction."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Myocardial infarction is defined as sudden ischemic death of myocardial tissue."
    explanation: Directly evidences that MI is ischemic death of myocardium, the core claim of this node.
  - reference: PMID:26426469
    reference_title: "Pathophysiology of Myocardial Infarction."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Mitochondrial alterations are prominently involved in apoptosis and necrosis of cardiomyocytes in the infarcted heart."
    explanation: Evidences ischemic cardiomyocyte necrosis and apoptosis in the infarcted myocardium described by this node.
- name: Ischemia-Reperfusion Injury
  description: >
    Restoration of coronary blood flow (by primary PCI or fibrinolysis) is
    essential to salvage ischemic myocardium but paradoxically inflicts
    additional damage — myocardial ischemia-reperfusion injury (MIRI) — that can
    account for up to half of the final infarct size. Reperfusion drives a burst
    of reactive oxygen species, cytosolic and mitochondrial calcium overload,
    and sustained opening of the mitochondrial permeability transition pore
    (MPTP) with collapse of the mitochondrial membrane potential and cessation
    of ATP production, together with endothelial dysfunction, NLRP3 inflammasome
    activation, and multiple regulated cell-death programs (apoptosis,
    necroptosis, pyroptosis, ferroptosis) and dysregulated autophagy.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: coronary endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: INCREASED
  - preferred_term: intracellular calcium ion homeostasis
    term:
      id: GO:0006874
      label: intracellular calcium ion homeostasis
    modifier: DYSREGULATED
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  downstream:
  - target: Ventricular fibrillation
    causal_link_type: DIRECT
    description: >
      Abrupt restoration of flow into ischemic myocardium produces calcium
      overload and marked dispersion of repolarization at the border zone, the
      substrate for reperfusion ventricular fibrillation.
  - target: Post-Infarction Inflammation and Cardiac Repair
    causal_link_type: DIRECT
    description: >
      Reperfusion-driven necrosis and DAMP release amplify the sterile
      inflammatory response in the infarcted myocardium.
  evidence:
  - reference: DOI:10.1097/crd.0000000000000440
    reference_title: "Pathobiology of Myocardial Ischemia and Reperfusion Injury: Models, Modes, Molecular Mechanisms, Modulation, and Clinical Applications"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "reperfusion salvages a significant amount of ischemic myocardium in the subepicardium while reperfusion injury contributes up to 50% of the final subendocardial infarct."
    explanation: Establishes that reperfusion, while salvaging myocardium, contributes up to half of the final infarct size — the defining claim of MIRI.
  - reference: DOI:10.1097/crd.0000000000000440
    reference_title: "Pathobiology of Myocardial Ischemia and Reperfusion Injury: Models, Modes, Molecular Mechanisms, Modulation, and Clinical Applications"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Reperfusion of severely ischemic myocardium leads to sustained opening of the mitochondrial permeability transition pore (MPTP)."
    explanation: Evidences the central mitochondrial mechanism (sustained MPTP opening) of lethal reperfusion injury described in this node.
  - reference: DOI:10.3390/cells14191509
    reference_title: "Myocardial Ischemia/Reperfusion Injury: Molecular Insights, Forensic Perspectives, and Therapeutic Horizons."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MIRI refers to paradoxical myocardial damage that occurs upon restoration of coronary blood flow and is driven by complex inflammatory, oxidative, and metabolic mechanisms, which can exacerbate infarct size"
    explanation: Defines MIRI as paradoxical reperfusion damage driven by inflammatory, oxidative, and metabolic mechanisms that enlarge the infarct.
  - reference: DOI:10.3390/cells14191509
    reference_title: "Myocardial Ischemia/Reperfusion Injury: Molecular Insights, Forensic Perspectives, and Therapeutic Horizons."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The principal mechanisms discussed include oxidative stress and mitochondrial dysfunction, calcium overload and ion homeostasis imbalance, inflammatory responses, with particular focus on the NLRP3 inflammasome and cytokine pathways, and multiple forms of cell death (apoptosis, necroptosis, pyroptosis, and autophagy)."
    explanation: Enumerates the oxidative-stress, calcium-overload, NLRP3-inflammasome, and multi-modal cell-death mechanisms attributed to MIRI in this node.
  - reference: DOI:10.3390/biomedicines12040802
    reference_title: "Myocardial Ischemia–Reperfusion Injury: Unraveling Pathophysiology, Clinical Manifestations, and Emerging Prevention Strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "underscoring its potential to contribute substantially to the final infarct size, up to 50%."
    explanation: Independent review corroborating that MIRI can contribute up to 50% of the final infarct size.
- name: Post-Infarction Inflammation and Cardiac Repair
  description: >
    Massive cardiomyocyte death releases damage-associated molecular patterns
    (DAMPs/alarmins) that engage pattern-recognition receptors (TLRs, NLRs),
    driving cytokine (IL-1, TNF-alpha, IL-6) and chemokine (CCL2) production and
    recruitment of neutrophils and monocytes. Expansion and diversification of
    cardiac macrophages clears dead cells; efferocytosis then triggers
    anti-inflammatory mediators (IL-10, TGF-beta) that restrain inflammation and
    activate reparative fibroblasts and vascular cells. This tightly regulated
    inflammatory-to-reparative transition is essential for healing, but an
    excessive or unresolved response promotes adverse outcomes.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  - preferred_term: wound healing
    term:
      id: GO:0042060
      label: wound healing
    modifier: INCREASED
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  downstream:
  - target: Cardiac Fibrosis and Ventricular Remodeling
    causal_link_type: DIRECT
    description: >
      Efferocytosis-driven release of TGF-beta and other reparative mediators
      activates fibroblasts and myofibroblasts, initiating fibrotic scar
      formation and structural remodeling.
  evidence:
  - reference: DOI:10.1161/circresaha.124.323658
    reference_title: "Repair of the Infarcted Heart: Cellular Effectors, Molecular Mechanisms and Therapeutic Opportunities."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "After infarction, massive cardiomyocyte death releases a broad range of damage-associated molecular patterns that initiate both myocardial and systemic inflammatory responses."
    explanation: Evidences DAMP release from dying cardiomyocytes as the trigger of the post-infarction inflammatory response.
  - reference: DOI:10.1161/circresaha.124.323658
    reference_title: "Repair of the Infarcted Heart: Cellular Effectors, Molecular Mechanisms and Therapeutic Opportunities."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Expansion and diversification of cardiac macrophages in the infarcted heart play a major role in the clearance of the infarct from dead cells and the subsequent stimulation of reparative pathways."
    explanation: Supports the role of cardiac macrophage expansion in clearing the infarct and initiating repair.
  - reference: DOI:10.1161/circresaha.124.323658
    reference_title: "Repair of the Infarcted Heart: Cellular Effectors, Molecular Mechanisms and Therapeutic Opportunities."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Efferocytosis triggers the induction and release of anti-inflammatory mediators that restrain the inflammatory reaction and set the stage for the activation of reparative fibroblasts and vascular cells."
    explanation: Evidences the efferocytosis-driven switch from inflammation to fibroblast-mediated repair that this node describes.
  - reference: DOI:10.3390/cells13131125
    reference_title: "The Influence of Metabolic Risk Factors on the Inflammatory Response Triggered by Myocardial Infarction: Bridging Pathophysiology to Treatment"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Myocardial infarction (MI) sets off a complex inflammatory cascade that is crucial for effective cardiac healing and scar formation."
    explanation: Corroborates that the post-MI inflammatory cascade is essential for cardiac healing and scar formation.
  - reference: DOI:10.3390/cells13131125
    reference_title: "The Influence of Metabolic Risk Factors on the Inflammatory Response Triggered by Myocardial Infarction: Bridging Pathophysiology to Treatment"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Yet, if this response becomes excessive or uncontrolled, it can lead to cardiovascular complications."
    explanation: Supports that a dysregulated post-MI inflammatory response drives adverse cardiovascular outcomes.
- name: Cardiac Fibrosis and Ventricular Remodeling
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  description: >
    Loss of contractile myocardium and sustained inflammatory/neurohormonal
    drive produce adverse structural remodeling of the ventricle. Cardiac
    fibroblasts differentiate into myofibroblasts that deposit a collagen-based
    extracellular matrix; a well-organized scar protects against rupture and
    limits acute dilation, but excessive, prolonged, or dysregulated fibrogenic
    signaling drives interstitial fibrosis, chamber dilation, and contractile
    dysfunction, progressing to heart failure. This node conforms to the
    conserved ventricular-remodeling step of the maladaptive-cardiomyopathy
    module, substituting the ischemic infarct scar as the disorder-specific
    insult.
  cell_types:
  - preferred_term: cardiac fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  - preferred_term: cardiac muscle cell apoptotic process
    term:
      id: GO:0010659
      label: cardiac muscle cell apoptotic process
    modifier: INCREASED
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: DOI:10.3389/fphar.2023.1070973
    reference_title: "Post-myocardial infarction fibrosis: Pathophysiology, examination, and intervention."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The cardiac fibroblast-to-myofibroblast differentiation and extracellular matrix collagen deposition are the hallmarks of cardiac fibrosis, which are modulated by multiple signaling pathways"
    explanation: Evidences fibroblast-to-myofibroblast conversion and ECM collagen deposition as the hallmarks of post-MI cardiac fibrosis.
  - reference: DOI:10.3389/fphar.2023.1070973
    reference_title: "Post-myocardial infarction fibrosis: Pathophysiology, examination, and intervention."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cardiac fibrosis plays an indispensable role in cardiac tissue homeostasis and repair after myocardial infarction (MI)."
    explanation: Supports that fibrosis is central to tissue repair and remodeling after MI.
  - reference: DOI:10.1161/circresaha.124.323658
    reference_title: "Repair of the Infarcted Heart: Cellular Effectors, Molecular Mechanisms and Therapeutic Opportunities."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Deposition of a well-organized collagen-based extracellular matrix network protects the heart from catastrophic rupture and attenuates ventricular dilation."
    explanation: Evidences the protective role of organized collagen scar in limiting rupture and dilation.
  - reference: DOI:10.1161/circresaha.124.323658
    reference_title: "Repair of the Infarcted Heart: Cellular Effectors, Molecular Mechanisms and Therapeutic Opportunities."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Excessive, prolonged, or dysregulated inflammatory or fibrogenic cascades accentuate adverse remodeling and dysfunction."
    explanation: Supports that dysregulated fibrogenic signaling drives adverse ventricular remodeling and dysfunction.
  downstream:
  - target: Reduced left ventricular ejection fraction
    causal_link_type: DIRECT
    description: >
      Interstitial fibrosis and chamber dilation degrade contractile efficiency
      beyond the initial loss of infarcted muscle, lowering ejection fraction
      further in the months after the event.
  - target: Congestive heart failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - progressive systolic dysfunction and chamber dilation
    - neurohormonal activation with sodium and water retention
    description: >
      Adverse post-infarction remodeling progresses to the congestive
      heart-failure syndrome once systolic dysfunction and neurohormonal
      activation raise filling pressures and cause fluid retention.
phenotypes:
- category: Cardiovascular
  name: Chest pain
  description: >-
    Chest pain is the cardinal presenting symptom of MI. This entry captures the
    broad symptom, including atypical or non-anginal chest pain and painless
    ("silent") presentations that are common in women, older adults, and people
    with diabetes; the classic ischemic substernal pain is captured separately as
    Angina pectoris.
  phenotype_term:
    preferred_term: Chest pain
    term:
      id: HP:0100749
      label: Chest pain
    temporality: ACUTE
- category: Cardiovascular
  name: Myocardial infarction
  description: Ischemic necrosis of myocardium.
  phenotype_term:
    preferred_term: Myocardial infarction
    term:
      id: HP:0001658
      label: Myocardial infarction
- category: Laboratory
  name: Elevated cardiac troponin
  description: Release of cardiac troponin from dying cardiomyocytes; the biomarker basis of MI diagnosis.
  phenotype_term:
    preferred_term: Increased circulating troponin concentration
    term:
      id: HP:0410174
      label: Increased circulating troponin T concentration
- category: Cardiovascular
  name: Arrhythmia
  description: Ischemia creates an arrhythmogenic substrate (e.g., ventricular arrhythmias).
  phenotype_term:
    preferred_term: Arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
  sequelae:
  - target: Ventricular fibrillation
    causal_link_type: DIRECT
    description: >
      Ventricular ectopy arising on the ischemic substrate can degenerate into
      ventricular fibrillation, the malignant end of the post-infarction
      arrhythmia spectrum.
  - target: Syncope
    causal_link_type: DIRECT
    description: >
      A sustained brady- or tachyarrhythmia drops cardiac output abruptly enough
      to cause transient cerebral hypoperfusion and loss of consciousness.
- category: Cardiovascular
  name: Reduced left ventricular ejection fraction
  description: Loss of contractile myocardium reduces systolic function and can progress to heart failure.
  phenotype_term:
    preferred_term: Reduced left ventricular ejection fraction
    term:
      id: HP:0012664
      label: Reduced left ventricular ejection fraction
  sequelae:
  - target: Dyspnea
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - raised left ventricular filling pressure and pulmonary venous congestion
    description: >
      Impaired systolic emptying raises filling pressures and congests the
      pulmonary circulation, which is felt as breathlessness.
- category: Cardiovascular
  name: Angina pectoris
  description: Prolonged substernal ischemic chest pressure/pain is the classic (typical) presenting symptom of acute MI, distinct from the atypical/non-anginal presentations captured under Chest pain.
  phenotype_term:
    preferred_term: Angina pectoris
    term:
      id: HP:0001681
      label: Angina pectoris
    temporality: ACUTE
- category: Cardiovascular
  name: Dyspnea
  description: Shortness of breath, a common presenting symptom and a feature of MI-related heart failure.
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
- category: Cardiovascular
  name: Ventricular fibrillation
  description: Malignant ventricular arrhythmia that can complicate acute ischemia/reperfusion and cause sudden cardiac death.
  phenotype_term:
    preferred_term: Ventricular fibrillation
    term:
      id: HP:0001663
      label: Ventricular fibrillation
- category: Cardiovascular
  name: Congestive heart failure
  description: Adverse ventricular remodeling after infarction can progress to heart failure.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
- category: Cardiovascular
  name: Syncope
  description: Transient loss of consciousness may occur, e.g., from arrhythmia or hemodynamic compromise.
  phenotype_term:
    preferred_term: Syncope
    term:
      id: HP:0001279
      label: Syncope
biochemical:
- name: Elevated cardiac troponin
  presence: Elevated
  context: >
    A rise and/or fall of high-sensitivity cardiac troponin (cTnI or cTnT) above
    the 99th-percentile upper reference limit, in a clinical context of
    ischemia, is the biomarker cornerstone of the Fourth Universal Definition of
    MI; troponin is the most sensitive/specific marker for acute myocardial
    injury.
  evidence:
  - reference: DOI:10.3390/biomedicines13071532
    reference_title: "Network Pharmacology Approaches to Myocardial Infarction Reperfusion Injury: Exploring Mechanisms, Pathophysiology, and Novel Therapies"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "distinguishing reperfusion injury from ischemic damage is challenging and often requires the use of sensitive biomarkers, such as cardiac troponins, alongside advanced imaging modalities."
    explanation: Supports cardiac troponin as the sensitive biomarker used to detect myocardial injury in MI.
  - reference: PMID:30170853
    reference_title: "High-sensitivity troponin in the evaluation of patients with suspected acute coronary syndrome: a stepped-wedge, cluster-randomised controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "use of the high-sensitivity assay reclassified one in six patients with myocardial injury, but only a third of these patients had a diagnosis of type 1 myocardial infarction, and the incidence of subsequent myocardial infarction or cardiovascular death at 1 year was unchanged."
    explanation: >-
      Qualifies the marker: a troponin rise above the 99th centile is sensitive
      for cardiomyocyte injury but not specific for the type 1 atherothrombotic
      mechanism this entry models, so a positive result is not itself evidence of
      plaque rupture.
  notes: >-
    Sensitivity and mechanistic specificity diverge here. The 99th-centile
    threshold detects troponin release from any cause of cardiomyocyte injury,
    so widening hs-cTn testing enlarges the myocardial-injury pool faster than
    the type 1 MI pool: in a whole-population registry the diagnostic yield among
    tested emergency-department patients fell from 73 to 47 per 1000 between 2014
    and 2024 as testing extended to lower-risk patients (PPR:PPR1272216, a
    preprint), while a cluster-randomised trial found only about a third of
    patients reclassified by the assay had type 1 MI (PMID:30170853). See the
    `definitions` entry for the ascertainment consequences. The 73-to-47 figures
    are deliberately NOT curated as `prevalence:` records: they are a
    test-positivity yield inside a clinician-selected denominator, so encoding
    them as `rate_per_100000` / `prevalence_class` would present roughly 25-30x
    the true adult population MI incidence to any consumer reading those slots,
    and the caveat would survive only in prose.
  readouts:
  - target: Myocardial Ischemia and Cardiomyocyte Death
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Troponin reaches the circulation only when cardiomyocyte membrane integrity
      is lost, so a rise and fall above the 99th centile measures the
      cardiomyocyte-death step. It is sensitive for that step but not specific to
      the type 1 atherothrombotic route, as this entry's evidence records.
- name: Elevated CK-MB
  presence: Elevated
  context: >
    Creatine kinase-MB isoenzyme and LDH rise more slowly (LDH at roughly 24-48
    hours) than troponin; historically used for MI diagnosis and for gauging
    infarct timing, now largely superseded by high-sensitivity troponin.
  readouts:
  - target: Myocardial Ischemia and Cardiomyocyte Death
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      CK-MB release also reports cardiomyocyte necrosis, with slower kinetics
      than troponin, which is why it was historically used to gauge infarct
      timing.
- name: Total lipids in very small VLDL (XS-VLDL-L)
  specificity: >
    Research NMR lipoprotein measure, not a clinical MI test. Ranked as the
    metabolite with the strongest risk-increasing Mendelian randomization
    estimate for myocardial infarction across 313 plasma measures in a
    274,241-participant UK Biobank atlas.
  context: >
    XS-VLDL-L quantifies the total lipid carried in the very small VLDL
    subclass, the remnant-lipoprotein end of the triglyceride-rich spectrum, on
    the Nightingale Health NMR platform used in UK Biobank. No presence value is
    recorded because the reported quantity is a genetically instrumented effect
    estimate over a general-population cohort rather than an observed level in
    patients with infarction. The finding is consistent with the wider
    remnant-cholesterol literature and supports curating atherogenic
    apoB-lipoprotein burden, not LDL-C alone, as the lipid input to coronary
    atherothrombosis. It is a risk-stratification signal and does not displace
    troponin, which remains the diagnostic biomarker for an acute event.
  readouts:
  - target: Coronary Atherothrombosis
    relationship: PREDICTS
    direction: POSITIVE
    endpoint_context: PROGNOSTIC
    interpretation: >
      Higher very-small-VLDL lipid content marks a more atherogenic
      remnant-lipoprotein burden and tracks with a higher risk of the
      atherothrombotic event that initiates infarction.
  evidence:
  - reference: PMID:40973818
    reference_title: "Mapping the plasma metabolome to human health and disease in 274,241 adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "total lipids in very small VLDL (XS-VLDL-L) exhibited the strongest association with increased risk of myocardial infarction (OR = 1.55 (1.48-1.63)"
    explanation: >
      Bidirectional Mendelian randomization over 313 NMR metabolites ranks
      XS-VLDL-L as the metabolite with the strongest risk-increasing estimate
      for myocardial infarction (OR 1.55, 95% CI 1.48-1.63).
- name: Phospholipids to total lipids in small HDL, percent (S-HDL-PL%)
  specificity: >
    Research NMR lipoprotein-composition ratio, not a clinical MI test. Ranked
    as the most protective metabolite for myocardial infarction in the same
    Mendelian randomization analysis that ranked XS-VLDL-L most harmful.
  context: >
    Recorded as the counterpart to the XS-VLDL-L entry so the lipoprotein axis
    is not curated one-sidedly. Note that this is a compositional ratio within
    small HDL rather than HDL cholesterol concentration, so it should not be
    read as reviving HDL-C as a causal protective target, a claim that
    randomized HDL-raising trials did not support.
  evidence:
  - reference: PMID:40973818
    reference_title: "Mapping the plasma metabolome to human health and disease in 274,241 adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the ratio of phospholipids to total lipids in the small HDL percentage (S-HDL-PL%; OR = 0.63 (0.59-0.67)"
    explanation: >
      Names S-HDL-PL% and quotes its Mendelian randomization effect estimate
      for myocardial infarction directly, rather than leaving the number in
      curator prose.
  - reference: PMID:40973818
    reference_title: "Mapping the plasma metabolome to human health and disease in 274,241 adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "exhibited the most notable protective effect (Fig. 7e)"
    explanation: >
      The predicate of the same sentence, quoted so the protective claim
      itself is carried by source text rather than by the explanation.
  readouts:
  - target: Coronary Atherothrombosis
    relationship: PREDICTS
    direction: NEGATIVE
    endpoint_context: PROGNOSTIC
    interpretation: >
      A higher phospholipid share within small HDL tracks with lower risk of the
      atherothrombotic event that initiates infarction. Recorded as the
      protective counterpart of the XS-VLDL-L readout; it is a compositional
      ratio and not a claim that raising HDL cholesterol is protective.
treatments:
- name: Coronary Reperfusion (PCI or Fibrinolysis)
  description: >
    Emergency restoration of coronary blood flow by primary percutaneous
    coronary intervention or, where unavailable, fibrinolysis, to salvage
    ischemic myocardium.
  treatment_term:
    preferred_term: percutaneous coronary intervention
    term:
      id: NCIT:C99521
      label: Percutaneous Coronary Intervention
  evidence:
  - reference: PMID:27502078
    reference_title: "Acute myocardial infarction."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "implementation of care delivery systems prioritising immediate revascularisation through percutaneous coronary intervention (or fibrinolysis)"
    explanation: Identifies immediate revascularisation by PCI or fibrinolysis as central to modern AMI management.
  target_mechanisms:
  - target: Coronary Atherothrombosis
    treatment_effect: RESTORES
    description: >
      Primary PCI or fibrinolysis removes or lyses the occlusive coronary
      thrombus and restores antegrade flow in the infarct-related artery.
    evidence:
    - reference: PMID:27502078
      reference_title: "Acute myocardial infarction."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "implementation of care delivery systems prioritising immediate revascularisation through percutaneous coronary intervention (or fibrinolysis)"
      explanation: Identifies immediate revascularisation by PCI or fibrinolysis as central to modern AMI management.
  - target: Myocardial Ischemia and Cardiomyocyte Death
    treatment_effect: INHIBITS
    description: >
      Restoring perfusion salvages myocardium that has not yet infarcted, which
      is the point of treating within a time window; the same manoeuvre also
      opens the reperfusion-injury node modelled downstream.
- name: Antiplatelet and Antithrombotic Therapy
  description: >
    Antiplatelet agents and anticoagulants to limit coronary thrombus
    propagation, plus secondary-prevention statins.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:27502078
    reference_title: "Acute myocardial infarction."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "advances in antiplatelet agents and anticoagulants, and greater use of secondary prevention strategies such as statins."
    explanation: Identifies antiplatelet agents, anticoagulants, and statins as pillars of pharmacological AMI management.
  target_mechanisms:
  - target: Coronary Atherothrombosis
    treatment_effect: INHIBITS
    description: >
      Antiplatelet agents and anticoagulants limit propagation of thrombus on
      the disrupted plaque and reduce re-occlusion after reperfusion; the
      secondary-prevention statin component acts on the underlying atheroma.
    evidence:
    - reference: PMID:27502078
      reference_title: "Acute myocardial infarction."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "advances in antiplatelet agents and anticoagulants, and greater use of secondary prevention strategies such as statins."
      explanation: Identifies antiplatelet agents, anticoagulants, and statins as pillars of pharmacological AMI management.
- name: Anti-Inflammatory / Immunomodulatory Therapy
  description: >
    Emerging cytokine-directed therapy targeting the post-infarction
    inflammatory response, notably IL-1 (canakinumab) and IL-6 (tocilizumab)
    pathway inhibitors, to reduce cardiovascular events and mitigate
    ischemia-reperfusion injury.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: canakinumab
      term:
        id: NCIT:C80971
        label: Canakinumab
    - preferred_term: tocilizumab
      term:
        id: NCIT:C84217
        label: Tocilizumab
  therapeutic_modality: MONOCLONAL_ANTIBODY
  evidence:
  - reference: DOI:10.3390/cells14191509
    reference_title: "Myocardial Ischemia/Reperfusion Injury: Molecular Insights, Forensic Perspectives, and Therapeutic Horizons."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "including IL-1 and IL-6 inhibitors such as Canakinumab and Tocilizumab"
    explanation: Identifies IL-1 (canakinumab) and IL-6 (tocilizumab) inhibitors as immunotherapeutic strategies in MI/MIRI.
  target_mechanisms:
  - target: Post-Infarction Inflammation and Cardiac Repair
    treatment_effect: MODULATES
    description: >
      IL-1 and IL-6 pathway blockade damps the cytokine arm of the
      post-infarction inflammatory response. The effect is deliberately recorded
      as modulation rather than inhibition, since this response is required for
      healing and only its excessive form is adverse.
    evidence:
    - reference: DOI:10.3390/cells14191509
      reference_title: "Myocardial Ischemia/Reperfusion Injury: Molecular Insights, Forensic Perspectives, and Therapeutic Horizons."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "including IL-1 and IL-6 inhibitors such as Canakinumab and Tocilizumab"
      explanation: Identifies IL-1 (canakinumab) and IL-6 (tocilizumab) inhibitors as immunotherapeutic strategies in MI/MIRI.
  - target: Ischemia-Reperfusion Injury
    treatment_effect: INHIBITS
    description: >
      The same cytokine-directed agents are under study to mitigate
      ischemia-reperfusion injury, in which NLRP3 inflammasome and IL-1
      signalling are prominent.
clinical_trials:
- name: NCT06118281
  phase: PHASE_III
  status: RECRUITING
  description: >
    ARTEMIS — randomized trial of the anti-IL-6 monoclonal antibody
    ziltivekimab versus placebo for prevention of recurrent cardiovascular
    events in patients with acute myocardial infarction.
  target_phenotypes:
  - preferred_term: Myocardial infarction
    term:
      id: HP:0001658
      label: Myocardial infarction
  evidence:
  - reference: clinicaltrials:NCT06118281
    reference_title: "ARTEMIS - Effects of Ziltivekimab Versus Placebo on Cardiovascular Outcomes in Patients With Acute Myocardial Infarction"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The research study is being done to see if ziltivekimab can be used to treat people who were admitted to hospital because of a heart attack."
    explanation: ClinicalTrials.gov summary confirms ARTEMIS tests ziltivekimab in post-MI patients, evidencing the anti-inflammatory therapeutic strategy.
notes: >
  Created as an endpoint entry to support directional comorbidity/trajectory
  modeling of acute respiratory infection (influenza, RSV) as a short-term
  trigger of type 1 myocardial infarction. Type 1 (atherothrombotic) MI is
  modeled here; type 2 MI (supply-demand mismatch without acute
  atherothrombosis) is a related but distinct mechanism.
experimental_models:
- name: Human cardiac infarct organoid with an internal oxygen-diffusion gradient
  description: >-
    A self-assembled multicellular human cardiac microtissue in which the
    infarct is produced by geometry rather than by a uniform treatment. At a
    radius of ~150 um and 10% ambient oxygen, oxygen consumption outruns
    diffusion toward the core, so a single organoid carries an apoptotic
    centre, a dysfunctional interior and a functional edge at once — the
    in vitro counterpart of the infarct, border and remote zones. Chronic
    norepinephrine supplies the neurohormonal arm. Because the pathology is
    spatially graded within one construct, edge and interior can be compared
    as internal controls, which uniform hypoxia (0.1% O2, which kills the whole
    construct) cannot do.
  experimental_model_type: ORGANOID
  namo_type: namo:Organoid
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: cardiac fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  - preferred_term: adipose-derived stem cell
    term:
      id: CL:0002570
      label: mesenchymal stem cell of adipose tissue
  conditions:
  - graded hypoxia (10% ambient O2, 10 days) with 1 uM norepinephrine
  - hypoxia-exacerbated doxorubicin cardiotoxicity
  cell_source: >-
    iPSC-derived cardiomyocytes combined with primary human cardiac ventricular
    fibroblasts, umbilical vein endothelial cells and adipose-derived stem cells
  culture_system: >-
    Non-adhesive agarose micromold self-assembly into ~150 um-radius
    microtissues; calcium dynamics read by a custom two-photon scanned
    light-sheet microscope at 20 ms resolution through the organoid interior
  publication: PMID:32284552
  modeled_mechanisms:
  - target: Myocardial Ischemia and Cardiomyocyte Death
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      The oxygen gradient reproduces regional ischemic cardiomyocyte death and
      the arrhythmogenic calcium-handling defect, spatially separated within one
      construct rather than averaged over it.
    limitations: >-
      Death here is driven by diffusion-limited hypoxia in a construct with no
      vasculature and no coronary occlusion, so the model reproduces the
      consequence of interrupted perfusion but not its atherothrombotic cause.
      The cardiomyocytes are immature iPSC-derived cells.
    divergences:
    - divergence_type: CAUSE_UNREPRESENTED
      materiality: QUALIFYING
      description: >-
        The ischemia arises from oxygen consumption outrunning diffusion in an
        avascular microtissue. Coronary atherothrombosis, the lesion that causes
        it in patients, is not represented anywhere in the model.
    readouts:
    - name: Apoptotic nuclei at the organoid core (TUNEL)
      target: Myocardial Ischemia and Cardiomyocyte Death
      direction: INCREASED
      interpretation: >-
        Cell death is localized to the region the diffusion model predicts is
        below viable oxygen, which is what makes the construct zonal rather than
        uniformly injured.
      evidence:
      - reference: PMID:32284552
        reference_title: "Human cardiac organoids for the modelling of myocardial infarction and drug cardiotoxicity."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "infarct organoids showed apoptotic TUNEL+ staining in the center of organoid sections, attributed mainly to the non-viable oxygen levels at the center of the organoids"
        explanation: Reports the spatially restricted apoptosis measurement behind this readout.
    - name: Peak calcium transient amplitude in interior cardiomyocytes
      target: Myocardial Ischemia and Cardiomyocyte Death
      direction: DECREASED
      interpretation: >-
        Measured against edge cardiomyocytes in the same organoid, so the
        comparator is internal; the deficit is the functional correlate of the
        pathological calcium handling that underlies post-MI arrhythmia.
      evidence:
      - reference: PMID:32284552
        reference_title: "Human cardiac organoids for the modelling of myocardial infarction and drug cardiotoxicity."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Interior cardiomyocytes in the infarct organoids showed significantly lower max calcium transient amplitude in contrast to the infarct and control edge cardiomyocytes"
        explanation: Reports the interior-versus-edge calcium measurement grounding this readout.
    evidence:
    - reference: PMID:32284552
      reference_title: "Human cardiac organoids for the modelling of myocardial infarction and drug cardiotoxicity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "cardiac organoids that incorporate an oxygen-diffusion gradient and that are stimulated with the neurotransmitter noradrenaline model the structure of the human heart after myocardial infarction (by mimicking the infarcted, border and remote zones)"
      explanation: >-
        States the model's central claim, that the graded construct reproduces
        the zonal structure of the infarcted human heart, which is why it is
        treated as informative for this node.
  - target: Cardiac Fibrosis and Ventricular Remodeling
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Myofibroblast conversion and tissue stiffening arise endogenously from the
      hypoxia gradient and adrenergic drive, without exogenous TGF-beta or a
      stiffened substrate.
    limitations: >-
      The organoid contains no leukocytes, so fibrosis develops without the
      inflammatory-to-reparative transition that drives it in vivo; the
      stiffening is that of acute remodeling and does not reach the values of a
      mature scar.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        Neutrophils, monocytes and macrophages are outside the construct, so the
        myofibroblast conversion measured here proceeds without the
        inflammatory-to-reparative transition that drives it in the infarcted
        heart.
    - divergence_type: CAUSE_UNREPRESENTED
      materiality: QUALIFYING
      description: >-
        The fibrotic response is driven by the same diffusion-limited hypoxia
        and by exogenous norepinephrine as the sibling ischemia link. Neither
        the coronary atherothrombosis that interrupts perfusion nor the
        endogenous neurohormonal activation that follows it is represented.
    readouts:
    - name: Myofibroblast-like alpha-smooth-muscle-actin structures
      target: Cardiac Fibrosis and Ventricular Remodeling
      direction: INCREASED
      interpretation: >-
        The histological marker used to identify fibrotic myocardium, appearing
        here as a downstream consequence of the oxygen gradient alone.
      evidence:
      - reference: PMID:32284552
        reference_title: "Human cardiac organoids for the modelling of myocardial infarction and drug cardiotoxicity."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Infarct organoids showed numerous myofibroblast-like structures, marked by elongated, αSMA+/F-actin+ phenotype in contrast to control organoids"
        explanation: Reports the myofibroblast staining measurement behind this readout.
    - name: Tissue elastic modulus by micropipette aspiration
      target: Cardiac Fibrosis and Ventricular Remodeling
      direction: INCREASED
      interpretation: >-
        Mechanical correlate of matrix deposition, measured on the viable outer
        region of the construct.
      evidence:
      - reference: PMID:32284552
        reference_title: "Human cardiac organoids for the modelling of myocardial infarction and drug cardiotoxicity."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "The stiffness was significantly increased in infarct organoids over control organoids"
        explanation: Reports the stiffness measurement grounding this readout.
    evidence:
    - reference: PMID:32284552
      reference_title: "Human cardiac organoids for the modelling of myocardial infarction and drug cardiotoxicity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "One limitation of the model is that not every aspect of heart failure can be mimicked with the current infarct organoids (e.g., lack of inflammatory cells, use of immature hiPSC-CMs)"
      explanation: >-
        The authors' own statement of the missing immune compartment, which is
        why this link is graded PARTIALLY_RECAPITULATES rather than
        RECAPITULATES.
  notes: >-
    Curated from the Brenden et al. perspective on spatiotemporally instrumented
    in vitro tissues (DOI:10.1016/j.celbio.2026.100576), which cites this model
    as the example of engineering spatial heterogeneity into an organoid instead
    of applying a spatially uniform disease stimulus.
- name: Myocardial infarct border-zone-on-a-chip
  description: >-
    A microphysiological system that imposes a controlled oxygen gradient across
    engineered human cardiac tissue, isolating the border zone as an
    experimental variable in its own right. The comparison that matters is not
    injured-versus-healthy but graded-versus-uniform: tissue under a gradient
    behaves differently from tissue held at uniform normoxia or uniform hypoxia,
    so the spatial gradient is itself a pathogenic factor rather than a
    confounder to be averaged away.
  experimental_model_type: ORGAN_ON_CHIP
  namo_type: namo:OrganOnChip
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  conditions:
  - imposed oxygen gradient spanning normoxia to hypoxia
  - uniform normoxia and uniform hypoxia comparator arms
  cell_source: Stem-cell-derived human cardiomyocytes in engineered cardiac tissue
  culture_system: >-
    Microfluidic device with spatially controlled oxygenation across the tissue,
    read out by calcium imaging, contractile-stress measurement and RNA
    sequencing
  publication: PMID:36475790
  modeled_mechanisms:
  - target: Myocardial Ischemia and Cardiomyocyte Death
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Reproduces the electromechanical dysfunction of border-zone myocardium and
      attributes it specifically to the oxygen gradient.
    limitations: >-
      The chip models the oxygen gradient and its functional consequences, not
      the cardiomyocyte necrosis of the infarct core; there is no coronary
      circulation and no thrombotic trigger.
    divergences:
    - divergence_type: CAUSE_UNREPRESENTED
      materiality: QUALIFYING
      description: >-
        The oxygen gradient is imposed by the device's gas control rather than
        arising from an occluded coronary artery, so the gradient is an
        experimental input and not a consequence of the disease lesion.
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        The chip spans the gradient itself; the necrotic infarct core that the
        gradient borders in vivo is not part of the construct.
    readouts:
    - name: Calcium release, reuptake and propagation kinetics
      target: Myocardial Ischemia and Cardiomyocyte Death
      direction: ALTERED
      interpretation: >-
        Delayed rather than simply reduced, so the readout is a change in
        kinetics; this is the conduction substrate for post-infarction
        arrhythmia.
      evidence:
      - reference: PMID:36475790
        reference_title: "A myocardial infarct border-zone-on-a-chip demonstrates distinct regulation of cardiac tissue function by an oxygen gradient."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "The gradient delayed calcium release, reuptake, and propagation; decreased diastolic and peak systolic stress; and increased expression of inflammatory cascades that are hallmarks of myocardial infarction"
        explanation: Reports the calcium-handling and contractile measurements made under the gradient.
    - name: Diastolic and peak systolic stress
      target: Myocardial Ischemia and Cardiomyocyte Death
      direction: DECREASED
      interpretation: >-
        Contractile failure of gradient-exposed tissue, the in vitro analogue of
        the reduced force generation reported for border-zone myocardium.
      evidence:
      - reference: PMID:36475790
        reference_title: "A myocardial infarct border-zone-on-a-chip demonstrates distinct regulation of cardiac tissue function by an oxygen gradient."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "These changes were distinct from those observed in tissues exposed to uniform normoxia or hypoxia, demonstrating distinct regulation of cardiac tissue phenotypes by an oxygen gradient"
        explanation: >-
          Establishes that the functional changes are specific to the gradient
          and are not reproduced by either uniform condition.
    evidence:
    - reference: PMID:36475790
      reference_title: "A myocardial infarct border-zone-on-a-chip demonstrates distinct regulation of cardiac tissue function by an oxygen gradient."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we engineered a microphysiological system to controllably expose engineered cardiac tissue to an oxygen gradient that mimics the border zone and measured the effects of the gradient on electromechanical function and the transcriptome"
      explanation: Describes the model and the border-zone mechanism it is built to interrogate.
  - target: Post-Infarction Inflammation and Cardiac Repair
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: MOLECULAR
    description: >-
      Gradient-exposed cardiac tissue raises inflammatory-cascade expression on
      its own, showing that the myocardial arm of the post-infarction
      inflammatory response does not require leukocytes to be initiated.
    limitations: >-
      The construct contains no neutrophils, monocytes or macrophages, so it
      captures only the cardiac-tissue half of the response and cannot model
      recruitment, efferocytosis or the inflammatory-to-reparative transition
      that the node describes. The evidence is transcriptional.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: INVALIDATING
      description: >-
        Neutrophil and monocyte recruitment, macrophage expansion and
        efferocytosis are the substance of this node, and none of those cells is
        present in the construct.
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        Inflammatory-cascade transcript abundance in cardiac tissue stands in for
        the cellular inflammatory response the node describes.
    - divergence_type: CAUSE_UNREPRESENTED
      materiality: QUALIFYING
      description: >-
        The inflammatory program is induced by an oxygen gradient set by the
        device's gas control. The infarct that establishes that gradient in
        patients, and the necrotic tissue whose damage signals normally
        initiate the response, are both absent.
    readouts:
    - name: Inflammatory cascade gene expression
      target: Post-Infarction Inflammation and Cardiac Repair
      direction: INCREASED
      interpretation: >-
        Transcriptional only; establishes that the oxygen gradient is sufficient
        to induce an inflammatory program in cardiac tissue alone.
      evidence:
      - reference: PMID:36475790
        reference_title: "A myocardial infarct border-zone-on-a-chip demonstrates distinct regulation of cardiac tissue function by an oxygen gradient."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "The gradient delayed calcium release, reuptake, and propagation; decreased diastolic and peak systolic stress; and increased expression of inflammatory cascades that are hallmarks of myocardial infarction"
        explanation: Reports the inflammatory-expression measurement behind this readout.
    evidence:
    - reference: PMID:36475790
      reference_title: "A myocardial infarct border-zone-on-a-chip demonstrates distinct regulation of cardiac tissue function by an oxygen gradient."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Steep O2 gradients develop at the interface between the injured, hypoxic tissue and the surrounding viable, normoxic tissue"
      explanation: >-
        States the in vivo gradient the chip reproduces, establishing why
        gradient-driven inflammatory signalling in the model bears on this node.
- name: Human heart-on-a-chip ischemia-reperfusion assay with endothelial extracellular vesicle rescue
  description: >-
    Human stem-cell-derived laminar cardiac tissues subjected to simulated
    ischemia and reperfusion on a chip, with a treatment arm in which
    vascular-endothelial extracellular vesicles are applied. The tissue itself
    is cardiomyocyte-only; the endothelial cells are the vesicle source and are
    not part of the construct. The rescue arm is what makes the model a test of
    the mechanism rather than a description of it: cell death and contractile
    loss are reversed dose-dependently by a defined intervention.
  experimental_model_type: ORGAN_ON_CHIP
  namo_type: namo:OrganOnChip
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  conditions:
  - simulated ischemia followed by reperfusion
  - endothelial extracellular vesicle treatment (dose-ranged)
  cell_source: Human stem-cell-derived cardiomyocytes; human vascular endothelial cells as the vesicle source
  culture_system: Human laminar cardiac tissues on a heart-on-a-chip contractility platform
  publication: PMID:33055246
  modeled_mechanisms:
  - target: Ischemia-Reperfusion Injury
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Reproduces reperfusion-associated cardiomyocyte death and contractile
      failure in an all-human system, and shows the injury is pharmacologically
      reversible.
    limitations: >-
      Oxygen and nutrient deprivation are applied to the tissue directly, so
      there is no microvascular obstruction, no circulating leukocytes and no
      platelet contribution to reperfusion injury.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        The construct is cardiomyocyte-only by the authors' own account, and
        oxygen and nutrient deprivation are applied to it directly. Endothelium,
        microvascular obstruction, circulating leukocytes and platelets all lie
        outside the model, so pro-vasculogenic and anti-inflammatory routes to
        cardioprotection cannot contribute to the rescue measured here.
      evidence:
      - reference: PMID:33055246
        reference_title: "Endothelial extracellular vesicles contain protective proteins and rescue ischemia-reperfusion injury in a human heart-on-chip."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "as our in-vitro system consisted of only hCMs"
        explanation: The authors state the cardiomyocyte-only composition this divergence describes.
    - divergence_type: STRUCTURAL_IDEALIZATION
      materiality: QUALIFYING
      description: >-
        The cardiac tissue is a two-dimensional laminar monolayer, so the
        three-dimensional multicellular architecture across which reperfusion
        injury is distributed in the ventricle is not represented.
      evidence:
      - reference: PMID:33055246
        reference_title: "Endothelial extracellular vesicles contain protective proteins and rescue ischemia-reperfusion injury in a human heart-on-chip."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "the configuration of hCMs as two-dimensional monolayers, which do not fully recapitulate the three-dimensional, multi-cellular adult heart"
        explanation: The authors' own statement of the geometric idealization this divergence records.
    - divergence_type: CAUSE_UNREPRESENTED
      materiality: QUALIFYING
      description: >-
        Ischemia and reperfusion are simulated by changing the medium the
        tissue is bathed in. Neither the coronary occlusion that causes the
        ischemic phase nor the restoration of flow that causes the reperfusion
        phase exists in the model.
    readouts:
    - name: Cardiac cell death during and after simulated ischemia-reperfusion
      target: Ischemia-Reperfusion Injury
      direction: INCREASED
      interpretation: >-
        Establishes that the simulated reperfusion protocol produces the cell
        death this node describes.
      evidence:
      - reference: PMID:33055246
        reference_title: "Endothelial extracellular vesicles contain protective proteins and rescue ischemia-reperfusion injury in a human heart-on-chip."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Live/dead cell assays showed nearly 50% cell death, indicating extensive damage to the hCMs."
        explanation: >-
          Direct measurement of the injury this readout records, rather than the
          treatment effect on it.
    - name: Contractile capacity under endothelial extracellular vesicle treatment
      target: Ischemia-Reperfusion Injury
      direction: RESTORED
      interpretation: >-
        The rescue arm. Dose- and uptake-dependent recovery of contractile
        function is the model's evidence that the injury is a tractable
        therapeutic target rather than an endpoint.
      evidence:
      - reference: PMID:33055246
        reference_title: "Endothelial extracellular vesicles contain protective proteins and rescue ischemia-reperfusion injury in a human heart-on-chip."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "These results suggest that vascular EEVs rescue hlCTs exposed to IRI"
        explanation: States the rescue result grounding this readout.
    evidence:
    - reference: PMID:33055246
      reference_title: "Endothelial extracellular vesicles contain protective proteins and rescue ischemia-reperfusion injury in a human heart-on-chip."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we developed a human heart-on-a-chip IRI assay using human stem cell-derived, engineered cardiac tissues"
      explanation: Describes the construction of the assay and its all-human basis.
- name: Bioelectronically instrumented heart-on-a-chip under acute hypoxia
  description: >-
    A microfluidic cardiac chip with integrated extracellular electrodes and
    intracellular platinum nanopillars, used to follow the electrophysiological
    response to a rapidly imposed and reversible oxygen deficit. Its interest is
    instrumental rather than biological: because the electrodes are multiplexed
    and read continuously, the transition from tachycardia through bradycardia
    to arrhythmia is captured as a time course rather than as endpoint samples.
    The cells are a murine atrial line, so the platform is more transferable
    than its biology.
  experimental_model_type: ORGAN_ON_CHIP
  namo_type: namo:OrganOnChip
  organism:
    preferred_term: house mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  tissue_term:
    preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  cell_types:
  - preferred_term: HL-1 immortalized murine atrial cardiomyocyte
    term:
      id: CL:0002129
      label: regular atrial cardiac myocyte
  conditions:
  - acute reversible hypoxia mimicking temporary coronary occlusion
  cell_source: HL-1 murine atrial cardiomyocyte line
  culture_system: >-
    Microfluidic channel with rapid medium-oxygenation control, instrumented
    with multiplexed extracellular electrodes and electroporating intracellular
    Pt nanopillar electrodes for continuous action-potential readout
  publication: PMID:32092276
  modeled_mechanisms:
  - target: Myocardial Ischemia and Cardiomyocyte Death
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: >-
      Reproduces the acute electrophysiological response to oxygen deprivation,
      including action-potential shortening attributable to ATP-dependent
      potassium channel activation, but not the death arm of the node.
    limitations: >-
      HL-1 is an immortalized murine atrial line, so neither the species nor the
      chamber matches human ventricular myocardium, and the recorded action
      potentials should not be read as human values. The hypoxia is brief and
      reversible and no cardiomyocyte death is assayed, so the model addresses
      only the electrophysiological facet of this node.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: INVALIDATING
      description: >-
        HL-1 is an immortalized murine atrial line. Neither the species nor the
        cardiac chamber matches human ventricular myocardium, so the recorded
        action-potential values cannot be read as human ones.
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        The hypoxia is brief and reversible and no cell-death assay is performed,
        so the cardiomyocyte necrosis and apoptosis half of this node lies
        outside what the model measures.
    - divergence_type: CAUSE_UNREPRESENTED
      materiality: QUALIFYING
      description: >-
        The oxygen deficit is produced by modulating medium oxygenation in a
        microfluidic channel, which the authors describe as mimicking a
        temporary coronary occlusion. The occlusion itself, and the
        atherothrombotic lesion behind it, are not part of the model.
    readouts:
    - name: Beat rate during acute hypoxia
      target: Myocardial Ischemia and Cardiomyocyte Death
      direction: ALTERED
      interpretation: >-
        Biphasic rather than monotonic — tachycardia first, then slowing and
        arrhythmia — which is why a directional value would misdescribe it. Only
        continuous recording resolves the sequence.
      evidence:
      - reference: PMID:32092276
        reference_title: "Heart-on-a-Chip Model with Integrated Extra- and Intracellular Bioelectronics for Monitoring Cardiac Electrophysiology under Acute Hypoxia."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Extracellular bioelectronics provided continuous readouts demonstrating that hypoxic cells experienced an initial period of tachycardia followed by a reduction in beat rate and eventually arrhythmia"
        explanation: Reports the continuous beat-rate time course behind this readout.
    - name: Action potential duration during acute hypoxia
      target: Myocardial Ischemia and Cardiomyocyte Death
      direction: DECREASED
      interpretation: >-
        Action-potential narrowing is the expected consequence of ATP-sensitive
        potassium channel opening under an oxygen deficit, and is the mechanistic
        link between ischemia and arrhythmogenesis at this node.
      evidence:
      - reference: PMID:32092276
        reference_title: "Heart-on-a-Chip Model with Integrated Extra- and Intracellular Bioelectronics for Monitoring Cardiac Electrophysiology under Acute Hypoxia."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "We found that APs narrowed during hypoxia, consistent with proposed mechanisms by which oxygen deficits activate ATP-dependent K+ channels that promote membrane repolarization"
        explanation: Reports the intracellular action-potential measurement grounding this readout.
    evidence:
    - reference: PMID:32092276
      reference_title: "Heart-on-a-Chip Model with Integrated Extra- and Intracellular Bioelectronics for Monitoring Cardiac Electrophysiology under Acute Hypoxia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "reversibly activated hypoxia-related transduction pathways in HL-1 cardiac model cells"
      explanation: >-
        Identifies the cells as HL-1. That the line is an immortalized murine
        atrial one is established by its provenance rather than by this quote;
        together they are the basis for the LOW fidelity grade on this link.
  notes: >-
    Retained despite the non-human cell source because the instrumentation, not
    the biology, is what this record contributes: multiplexed extra- and
    intracellular electrodes give spatially mapped, continuously sampled
    electrophysiology of an ischemic insult, which no other cardiac model in
    this entry provides.
- name: Epicardial-myocardial heart-on-a-chip model of ischemia-reperfusion injury
  description: >-
    Engineered cardiac tissue built on the Biowire II platform with an
    epicardial outer layer over an inner myocardial core, so that the epicardium
    is present as a distinct spatial compartment rather than absent as in
    conventional constructs. Subjecting it to ischemia-reperfusion shows the
    epicardial layer is protective, and tracks epicardial cells migrating
    inwards and joining the alpha-smooth-muscle-actin-positive population.
  experimental_model_type: ORGAN_ON_CHIP
  namo_type: namo:OrganOnChip
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: cardiac fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  conditions:
  - simulated ischemia-reperfusion injury
  - normoxic culture comparator
  - epicardium-free engineered cardiac tissue comparator
  cell_source: Human pluripotent stem-cell-derived cardiomyocytes and epicardial cells
  culture_system: >-
    Biowire II engineered cardiac tissue with an epicardial outer layer, imaged
    with a purpose-built analysis pipeline that tracks epicardial cell migration
    in a beating myocardial environment
  publication: PMID:38683053
  modeled_mechanisms:
  - target: Ischemia-Reperfusion Injury
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Reproduces reperfusion-associated cell death and functional loss, and
      isolates the epicardium's contribution by comparison with
      epicardium-free tissue.
    limitations: >-
      Injury is imposed on the construct without vasculature or circulating
      immune cells. The readout of interest is the difference between
      epicardium-bearing and epicardium-free tissue, so absolute injury
      magnitudes are not transferable to human infarction.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        The construct has no vasculature and no circulating immune cells, so
        absolute injury magnitudes are not transferable; what the model supports
        is the difference between epicardium-bearing and epicardium-free tissue.
    - divergence_type: CAUSE_UNREPRESENTED
      materiality: QUALIFYING
      description: >-
        Ischemia-reperfusion is applied to the construct as a culture protocol.
        There is no coronary artery to occlude and no restoration of coronary
        flow, so the model carries the injury without the vascular event that
        produces it.
    readouts:
    - name: Cell death in epicardium-bearing versus epicardium-free tissue
      target: Ischemia-Reperfusion Injury
      direction: DECREASED
      interpretation: >-
        Comparator is epicardium-free engineered cardiac tissue under the same
        protocol; the reduction is the model's evidence that the epicardial
        compartment is protective against reperfusion injury.
      evidence:
      - reference: PMID:38683053
        reference_title: "Heart-on-a-Chip Model of Epicardial-Myocardial Interaction in Ischemia Reperfusion Injury."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "In conditions mimicking ischemia reperfusion injury (IRI), the EPI cardiac tissues experience less cell death and a lower impact on functional properties"
        explanation: Reports the comparative cell-death and function measurement behind this readout.
    evidence:
    - reference: PMID:38683053
      reference_title: "Heart-on-a-Chip Model of Epicardial-Myocardial Interaction in Ischemia Reperfusion Injury."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "using the Biowire II platform, engineered cardiac tissues with an epicardial outer layer and inner myocardial structure are constructed"
      explanation: >-
        Describes the layered construction that gives the model its spatial
        compartments and makes it informative for reperfusion injury.
  - target: Cardiac Fibrosis and Ventricular Remodeling
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Identifies the epicardium as a source of the myofibroblast-like population
      that appears after reperfusion injury, by directly observing inward
      migration rather than inferring lineage from endpoint staining.
    limitations: >-
      Migration is observed over the days of chip culture and contributes to an
      alpha-smooth-muscle-actin-positive population; no collagen deposition or
      scar maturation is measured, so this covers the cellular origin of
      remodeling and not its matrix output.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        Collagen deposition and scar maturation are not measured, so the model
        speaks to the cellular origin of the remodelling population and not to
        the matrix output that defines the node.
    - divergence_type: CAUSE_UNREPRESENTED
      materiality: QUALIFYING
      description: >-
        The epicardial migration measured here is a response to the same
        protocol-imposed ischemia-reperfusion as the sibling link, so the
        remodelling population arises without the coronary occlusion that
        triggers remodelling after infarction.
    readouts:
    - name: Inward migration of epicardial cells after reperfusion injury
      target: Cardiac Fibrosis and Ventricular Remodeling
      direction: INCREASED
      interpretation: >-
        Directly observed migration into the tissue interior, contributing to
        the myofibroblast-like population that drives remodeling at this node.
      evidence:
      - reference: PMID:38683053
        reference_title: "Heart-on-a-Chip Model of Epicardial-Myocardial Interaction in Ischemia Reperfusion Injury."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Upon IRI, migration of EPI cells into the cardiac tissue interior is observed, with contributions to alpha smooth muscle actin positive cell population"
        explanation: Reports the migration-tracking measurement grounding this readout.
datasets:
- accession: geo:GSE306012
  title: Temporal inhibition of ADAM17 in fibroblasts reduces stiffness and promotes vascularization following myocardial infarction
  description: Myocardial infarction (MI) triggers a complex remodelling process that leads to heat failure if uncontrolled. A Disintegrin and metalloproteinase-17 (ADAM17), a transmembrane sheddase, is upregulated in patients with ischemic cardiomyopathy, colocalized to myofibroblasts (myoFB) in the infarct tissues. Fibroblasts are key players in post-MI scar formation and exist in different states with diverse functions. Using mice with inducible Adam17 deletion in homeostatic FBs (Adam17 FB-KD ), or activated FBs (Adam17 myoFB-KD ), we found that ADAM17 loss in homeostatic FBs impaired infarct formation post-MI and increased mortality due to left ventricular (LV) rupture.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: BULK_RNA_SEQ
  sample_count: 28
  publication: PMID:41524432
  notes: Identified by GEO DataSets index search for Myocardial Infarction (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:GSE304168
  title: mRNA Therapeutics Encoding Multiple Reparative Factors using Polyplex Nanomicelle Attenuating Myocardial Infarction
  description: 'Background: Gene therapy for heart failure has been explored using single factors such as angiogenic agents; however, clinical success remains limited. In this study, we investigated an alternative approach by directly administering mRNA encoding multiple genes that are transiently upregulated during cardiac recovery. Using a model in which heart function is restored through the administration of extracellular vesicles secreted by human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM-derived EVs), we aimed to evaluate the potential of multi-gene mRNA therapy for heart failure, being delivered using polyplex nanomicelles, which serve as an effective delivery system with superio...'
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: BULK_RNA_SEQ
  sample_count: 6
  publication: PMID:42272746
  notes: Identified by GEO DataSets index search for Myocardial Infarction (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:GSE291962
  title: CCR8 expression on regulatory T cells reveals trajectories of tissue adaptation and protects against myocardial infarction [bulk RNA-seq]
  description: We employed single-cell RNA sequencing (scRNA-seq) in a mouse model of MI to gain a detailed analysis of heart and lymphoid Tregs, focusing on their developmental trajectories. Bulk RNA sequencing was used to further characterize the phenotype of CC motif chemokine receptor 8 positive (CCR8+) Tregs in the heart and lymph nodes. scRNA-seq of murine Tregs from the mediastinal lymph node (mLN) and heart after MI identified three Treg populations, one of which was mainly derived from the heart.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: BULK_RNA_SEQ
  sample_count: 16
  publication: PMID:41685444
  notes: Identified by GEO DataSets index search for Myocardial Infarction (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:EGAS00001006330
  title: Spatial multi-omic map of human myocardial infarction
  description: Myocardial infarction is a leading cause of mortality worldwide 1 . While advances have been made in acute treatment, an incomplete understanding of remodelling processes has limited the effectiveness of therapies to reduce late-stage mortality 2 . Here, we generate an integrative high- resolution map of human cardiac remodelling after myocardial infarction using single-cell gene expression, chromatin accessibility, and spatial transcriptomic profiling of multiple physiological zones at distinct time points in myocardium from myocardial infarction and control patients.
  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 ("Myocardial Infarction"); 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:EGAS00001007021
  title: Single-cell dissection of the immune response after a myocardial infarction
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Myocardial Infarction"); description-level mentions were not accepted. EGA study_type: Transcriptome Analysis. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: metabolomics_workbench:ST001908
  title: Post Acute Myocardial Infarction Left Ventricular Remodeling Bio marker Analysis (PAMILA)
  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 ("Myocardial Infarction"). Retrieved 2026-08-02.
- accession: massive:MSV000085040
  title: Effect of senolytics (Navitoclax, ABT263) on recovery following Myocardial Infarction
  description: Ischemia reperfusion injury (IRI) following intervention for myocardial infarction remains an unmet clinical problem. Using an established mouse model, we demonstrated that IRI induces multiple cardiac cell linages to senescence. Senescence is is detrimental to recovery, as treatment with the senolytic navitoclax improves functional recovery.Here we are using SWATH-MS to investigate the molecular mechanisms responsible for the effect of navitoclax treatment.
  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 ("Myocardial Infarction"). Retrieved 2026-08-02.
- accession: geo:GSE113871
  title: Cardiac organoid model of human myocardial infarction
  description: >-
    RNA-seq of human cardiac organoids carried through the oxygen-gradient
    infarction protocol versus control organoids. The transcriptomic arm of the
    infarct-organoid model curated in this entry's experimental_models block.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  publication: PMID:32284552
  evidence:
  - reference: GEO:GSE113871
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we leveraged the diffusion limitation in 3D microtissues to recreate the nutrient diffusion gradient across infarcted hearts (i.e., infarct-border-remote zones) in human cardiac organoids to induce cardiac organotypic response to infarction"
    explanation: >-
      The repository's own summary states the gradient-based infarction protocol
      whose transcriptomes this series holds.
  notes: >-
    Deposited by PMID:32284552, the source of the oxygen-gradient cardiac
    infarct organoid in experimental_models. Title copied from GEO; accession
    verified against the cached GEO record.
- accession: geo:GSE115031
  title: Cardiac organoid model of human myocardial infarction (batch2)
  description: >-
    Second donor batch of the cardiac infarct organoid RNA-seq, used in the
    source publication to test whether the infarct hallmarks survive a change of
    hiPSC genetic background.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  publication: PMID:32284552
  notes: >-
    Deposited by PMID:32284552 as the Donor B replication of GSE113871. Title
    copied from GEO; accession verified against the cached GEO record.

📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Augment: Myocardial Infarction (Falcon deep research) · 2026-07-06T00:16:40Z · View source

Integrated Falcon (Edison Scientific) deep-research leads into the previously thin entry after NEC preflight PASS (report is about acute type-1 MI: coronary atherothrombosis, ischemic cardiomyocyte necrosis, troponin, PCI/reperfusion; MONDO:0005068). Added 3 pathophysiology nodes with causal edges: Ischemia-Reperfusion Injury (MIRI; up to 50% of final infarct, MPTP opening, ROS, calcium overload, NLRP3 inflammasome); Post-Infarction Inflammation and Cardiac Repair (DAMP/TLR-NLR sensing, cardiac macrophage expansion, efferocytosis-to-repair switch); and Cardiac Fibrosis and Ventricular Remodeling (conforms_to cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling). Added phenotypes (Angina pectoris HP:0001681, Dyspnea HP:0002094, Ventricular fibrillation HP:0001663, Congestive heart failure HP:0001635, Syncope HP:0001279); biochemical markers (cardiac troponin with evidence, CK-MB context-only); a new Anti-Inflammatory/Immunomodulatory treatment (canakinumab NCIT:C80971, tocilizumab NCIT:C84217, therapeutic_modality MONOCLONAL_ANTIBODY); and the ARTEMIS ziltivekimab clinical trial (NCT06118281). 19 new evidence items. All PMIDs/DOIs/NCT fetched via just fetch-reference (no hand-created cache files). Every snippet independently verified as an exact whitespace-normalized substring of its cached abstract (24/24, 0 failures); note the reference validator skip_prefixes includes DOI, so DOI snippets are not machine-checked and were manually verified. Ontology terms verified with runoak and validate-terms. evidence_source OTHER for mechanistic reviews, HUMAN_CLINICAL for clinical sources. creation_date preserved; no updated_date. Validations: schema PASS, references PASS, terms PASS.

Falcon ▸

1. Disease Information

Edison Scientific Literature 54 citations 2026-07-05T19:07:07.576584

1. Disease Information

Overview

Myocardial infarction (MI) is defined as cardiomyocyte necrosis in a clinical setting consistent with acute myocardial ischemia, identified through clinical symptoms (prolonged chest pain), biochemical markers (elevated cardiac troponin), and instrumental findings (ECG changes and/or regional wall motion abnormalities) (fede2025myocardialischemiareperfusioninjury pages 1-2). MI is the leading component of cardiovascular disease (CVD) contributing to mortality, with approximately 4 million CVD-related deaths annually in Europe alone (młynarska2024fromatheroscleroticplaque pages 17-19). MI is classified into five types: Type 1 (atherosclerosis-related, most common), Type 2 (oxygen supply-demand mismatch), Type 3 (sudden cardiac death), Type 4 (PCI-related), and Type 5 (CABG-related) (młynarska2024fromatheroscleroticplaque pages 17-19).

Key Identifiers

MONDO ID: MONDO:0005068 (myocardial infarction); MONDO:0004781 (acute myocardial infarction) (OpenTargets Search: myocardial infarction)
ICD-10: I21 (Acute myocardial infarction); I22 (Subsequent myocardial infarction)
ICD-11: BA41 (Acute myocardial infarction)
MeSH: D009203

Common Synonyms

Heart attack, acute myocardial infarction (AMI), STEMI (ST-elevation myocardial infarction), NSTEMI (non-ST-elevation myocardial infarction), coronary thrombosis, acute coronary syndrome (broader term)

2. Etiology

Disease Causal Factors

Type 1 MI results from atherosclerotic plaque destabilization—either rupture or erosion—in coronary arteries, leading to thrombus formation that interrupts myocardial blood flow (das2025networkpharmacologyapproaches pages 1-2, młynarska2024fromatheroscleroticplaque pages 17-19). The pathogenesis involves chronic inflammation, lipid accumulation, endothelial dysfunction, and ultimately acute coronary artery occlusion.

Risk Factors

Genetic Risk Factors: GWAS analyses have identified numerous susceptibility loci for MI. Meta-analyses combining Saudi Arabian cohorts with the CardioGRAMplusC4D and UK BioBank GWAS revealed 66 loci with genome-wide significance (p < 5 × 10⁻⁸). Key genes implicated include PCSK9, CETP, CDKN2B-AS1 (involved in lipid metabolism, inflammation, and endothelial function), STOX1, VPS26A, and LDLR (zhou2024associationofmetabolic pages 1-2, zhou2024associationofmetabolic pages 10-13). Polygenic risk scores (PRS) demonstrate that a high genetic risk is associated with a threefold increase in MI risk (OR: 3.074, 95% CI: 2.354–4.014) (zhou2024associationofmetabolic pages 1-2). Elevated lipoprotein(a) levels are independently associated with an increased risk of coronary artery disease, with risk increasing threefold in young patients (zhou2024associationofmetabolic pages 13-15).

Environmental and Lifestyle Risk Factors: Traditional risk factors include hypercholesterolemia (high LDL-C), cigarette smoking, chronic kidney disease, diabetes mellitus, hypertension, obesity, sedentary lifestyle, and poor dietary habits (młynarska2024fromatheroscleroticplaque pages 17-19, zhou2024associationofmetabolic pages 13-15). Air pollution, even below regulatory thresholds, promotes atherosclerosis, vascular dysfunction, and cardiac events.

Protective Factors

Moderate fat intake (>15 energy percent), moderate alcohol consumption (<30 g/day), and non-smoking reduce MI risk even in individuals with high genetic predisposition (zhou2024associationofmetabolic pages 1-2, zhou2024associationofmetabolic pages 13-15). MI risk is negatively correlated with the consumption of olive oil, sesame oil, and perilla oil (rg = −0.364), which have anti-inflammatory and vasodilatory effects (zhou2024associationofmetabolic pages 13-15).

Gene-Environment Interactions

PRS interacts significantly with dietary fat intake, alcohol consumption, and smoking status to modulate MI risk, demonstrating that healthy lifestyle habits can substantially mitigate genetic susceptibility (zhou2024associationofmetabolic pages 1-2, zhou2024associationofmetabolic pages 13-15).

Suggested HPO terms for risk factors: HP:0003119 (Abnormality of lipid metabolism); HP:0000822 (Hypertension); HP:0001513 (Obesity); HP:0005978 (Type II diabetes mellitus)

3. Phenotypes

Symptoms and Clinical Signs

Chest pain (angina pectoris): Prolonged substernal chest pressure or pain, the hallmark symptom; HP:0001681 (Angina pectoris)
Dyspnea: Shortness of breath; HP:0002094
Diaphoresis: Profuse sweating
Nausea/vomiting
Radiating pain: To left arm, jaw, or back
Syncope or presyncope: HP:0001279
Cardiogenic shock: Complicates up to 10% of AMI cases, particularly in STEMI

Atypical presentations: Over one-third of NSTE-ACS patients may present with normal ECG findings (młynarska2024fromatheroscleroticplaque pages 7-8). Older patients often exhibit atypical symptoms with diminished sensitivity of traditional symptoms with age.

Laboratory Abnormalities

Elevated cardiac troponins (cTnI and cTnT): The most effective biomarkers for AMI diagnosis (das2025networkpharmacologyapproaches pages 12-13)
Elevated CK-MB, LDH (rises 24–48 hours post-injury) (das2025networkpharmacologyapproaches pages 12-13)
Elevated CRP, interleukins, TNF-α
ECG changes: ST-segment elevation, ST depression, T-wave abnormalities; LOINC codes applicable

Quality of Life Impact

Post-MI patients experience significant reductions in quality of life, with long-term impacts on functional capacity, psychological well-being (anxiety, depression), and return-to-work rates, particularly in younger patients.

4. Genetic/Molecular Information

Key Susceptibility Genes and Targets

OpenTargets analysis identifies the following high-priority targets for MI (MONDO:0005068) (OpenTargets Search: myocardial infarction):

Target Gene Symbol	Full Target Name	Target Category	Association Score	Drug Class/Examples	Clinical Stage	Evidence
GUCY1A1	Guanylate cyclase 1 soluble subunit alpha 1	Enzyme / nitric oxide receptor subunit	0.695	Soluble guanylate cyclase stimulators/activators; nitrates act upstream via NO-sGC-cGMP signaling	Approved-linked evidence in OpenTargets	(OpenTargets Search: myocardial infarction)
LDLR	Low density lipoprotein receptor	Receptor	0.689	LDL-lowering strategies acting through LDLR pathway: statins, PCSK9 inhibitors, inclisiran	Literature + clinical/approved-linked evidence	(OpenTargets Search: myocardial infarction, ramosregalado2024theinfluenceof pages 10-11)
PCSK9	Proprotein convertase subtilisin/kexin type 9	Secreted protease	0.670	PCSK9 inhibitors: evolocumab, alirocumab; siRNA inclisiran	Approved	(OpenTargets Search: myocardial infarction, ramosregalado2024theinfluenceof pages 10-11)
ADRB1	Adrenoceptor beta 1	G protein-coupled receptor	0.624	Beta-blockers: metoprolol, bisoprolol, atenolol	Approved	(OpenTargets Search: myocardial infarction, młynarska2024fromatheroscleroticplaque pages 11-12)
P2RY12	Purinergic receptor P2Y12	G protein-coupled receptor	0.620	P2Y12 inhibitors: clopidogrel, prasugrel, ticagrelor, cangrelor	Approved / Phase 4 evidence	(OpenTargets Search: myocardial infarction, młynarska2024fromatheroscleroticplaque pages 11-12, nicolau2025molecularmechanismsof pages 8-10)
AGTR1	Angiotensin II receptor type 1	G protein-coupled receptor	0.617	ARBs: losartan, valsartan, candesartan	Approved	(OpenTargets Search: myocardial infarction, ramosregalado2024theinfluenceof pages 10-11)
HMGCR	3-hydroxy-3-methylglutaryl-CoA reductase	Enzyme	0.616	Statins: atorvastatin, rosuvastatin, simvastatin	Approved	(OpenTargets Search: myocardial infarction, alradwan2024emergingtrendsand pages 4-7, ramosregalado2024theinfluenceof pages 10-11)
ACE	Angiotensin I converting enzyme	Enzyme	0.612	ACE inhibitors: ramipril, lisinopril, enalapril	Approved	(OpenTargets Search: myocardial infarction, ramosregalado2024theinfluenceof pages 10-11)
PLAT	Plasminogen activator, tissue type	Serine protease	0.566*	Thrombolytics/fibrinolytics: alteplase, tenecteplase	Approved	(OpenTargets Search: myocardial infarction, occhipinti2025pharmacologicalandinterventional pages 6-8)
LPA	Lipoprotein(a)	Lipoprotein / secreted risk factor	0.435*	Emerging Lp(a)-lowering agents: olpasiran, pelacarsen; indirect lowering with PCSK9 inhibitors	Clinical development / emerging	(OpenTargets Search: myocardial infarction)
APOE	Apolipoprotein E	Lipid transport protein	0.428*	No direct MI-targeted approved therapy; informs lipid biology/risk stratification	Literature-associated	(OpenTargets Search: myocardial infarction)
PTGS2	Prostaglandin-endoperoxide synthase 2 (COX-2)	Enzyme	0.606	NSAID/COX pathway modulators; aspirin acts primarily on PTGS1 rather than PTGS2	Approved-linked / Phase 4 evidence	(OpenTargets Search: myocardial infarction)
TCF21	Transcription factor 21	Transcription factor	0.373*	No approved direct therapy; biomarker/mechanistic target in vascular remodeling	Literature-associated	(OpenTargets Search: myocardial infarction)
SORT1	Sortilin 1	Sorting receptor	0.365*	No approved direct MI therapy; implicated in lipoprotein trafficking and residual risk biology	Literature-associated	(OpenTargets Search: myocardial infarction)
ITGA2B	Integrin subunit alpha 2b	Platelet integrin receptor subunit	0.360*	GPIIb/IIIa inhibitors: abciximab, eptifibatide, tirofiban	Approved / Phase 3 evidence	(OpenTargets Search: myocardial infarction, sagris2024myocardialischemia–reperfusioninjury pages 8-10, occhipinti2025pharmacologicalandinterventional pages 6-8)
ITGB3	Integrin subunit beta 3	Platelet integrin receptor subunit	0.360*	GPIIb/IIIa inhibitors: abciximab, eptifibatide, tirofiban	Approved / Phase 3 evidence	(OpenTargets Search: myocardial infarction, sagris2024myocardialischemia–reperfusioninjury pages 8-10, occhipinti2025pharmacologicalandinterventional pages 6-8)

Table: This table summarizes key myocardial infarction drug targets prioritized from OpenTargets together with clinically relevant drug classes and development stage. It is useful for linking disease biology to established and emerging therapeutic mechanisms.

GWAS Findings

GWAS meta-analyses have identified over 66 loci associated with MI at genome-wide significance. The SHISA5 locus (rs11707229) was notably enriched at >12% minor allele frequency in Saudi MI populations. Genes including PCSK9, LDLR, APOE, LPA, TCF21, and SORT1 are consistently implicated (OpenTargets Search: myocardial infarction, zhou2024associationofmetabolic pages 10-13). Genetic variants rs3864814 and rs2081208 are associated with MI through colocalization analysis with genes STOX1, VPS26A, and RP11-744D14.2 (zhou2024associationofmetabolic pages 10-13).

Epigenetic Information

DNA methylation, histone modifications (particularly via HDAC inhibitors), and non-coding RNAs (miR-144, miR-22) are key regulators of gene expression associated with atherosclerosis, MI, and cardiac remodeling. HDAC inhibitors reduce cardiomyocyte apoptosis, while specific microRNAs modulate oxidative stress pathways during ischemia-reperfusion injury (das2025networkpharmacologyapproaches pages 9-10).

5. Environmental Information

Environmental Factors

Air pollution promotes atherosclerosis, vascular dysfunction, and cardiac events even below current regulatory thresholds. Occupational exposures, noise pollution, and extreme temperatures are additional contributors.

Lifestyle Factors

Smoking, sedentary lifestyle, high-fat and high-sugar diets, and excessive alcohol consumption are established modifiable risk factors (młynarska2024fromatheroscleroticplaque pages 17-19). Physical activity reduces cardiovascular risk through improved cardiac output, vascular efficiency, and metabolic health.

6. Mechanism / Pathophysiology

Overview of Pathophysiological Cascade

The pathophysiology of MI begins with atherosclerotic plaque rupture or erosion, leading to thrombus formation and coronary artery occlusion. Prolonged ischemia causes irreversible cardiomyocyte death, beginning in the subendocardium and progressing as a necrotic wavefront toward the subepicardium (buja2023pathobiologyofmyocardial pages 2-4, buja2023pathobiologyofmyocardial pages 1-2). Reversible injury lasts approximately 15 minutes, with irreversible injury developing between 20–60 minutes after coronary occlusion (buja2023pathobiologyofmyocardial pages 2-4).

Molecular Pathways

The following table summarizes the major signaling pathways involved:

Pathway Name	Key Components/Mediators	Role in MI Pathophysiology	Cellular Process Affected	Therapeutic Implications
MAPK (p38, JNK, ERK1/2)	p38 MAPK, JNK, ERK1/2, ADAM17, ACE2, Bim	Activated during ischemia/reperfusion and post-MI remodeling; promotes inflammatory signaling, apoptosis, mitochondrial dysfunction, ferroptosis, and adverse remodeling/fibrosis. p38/JNK are generally injury-amplifying; ERK can be context-dependent with survival and remodeling effects. (wang2025theroleof pages 16-17, wang2025theroleof pages 4-6)	Apoptosis, mitochondrial fission, oxidative stress response, ferroptosis, remodeling	Experimental inhibition of p38/JNK/ERK-axis components can reduce myocardial injury; pathway is a candidate for cardioprotection and anti-remodeling therapies, though translation remains challenging. (wang2025theroleof pages 16-17, wang2025theroleof pages 4-6)
PI3K/AKT/mTOR	PI3K, AKT, mTOR, BAD, Mdm2, PKD1, GLUT4	Core pro-survival pathway in MI and reperfusion injury; suppresses apoptosis, modulates autophagy, supports metabolic adaptation, and can limit inflammatory injury. Reduced signaling is associated with greater injury. (fede2025myocardialischemiareperfusioninjury pages 26-28, das2025networkpharmacologyapproaches pages 7-9, fede2025myocardialischemiareperfusioninjury pages 10-12)	Cell survival, glucose uptake, metabolism, autophagy control, anti-apoptotic signaling	Therapies that enhance PI3K/AKT signaling or fine-tune mTOR/autophagy may reduce infarct size and improve reperfusion outcomes; a major cardioprotective target in preclinical studies. (das2025networkpharmacologyapproaches pages 7-9, fede2025myocardialischemiareperfusioninjury pages 10-12)
NF-κB	NF-κB, TLR4, MyD88, IL-1β, TNF-α, IL-6, Beclin-1	Central inflammatory transcriptional program activated by DAMPs and innate immune receptors after cardiomyocyte necrosis; drives cytokine/chemokine expression, leukocyte recruitment, and can suppress protective autophagy in some contexts. (fede2025myocardialischemiareperfusioninjury pages 26-28, das2025networkpharmacologyapproaches pages 7-9, fede2025myocardialischemiareperfusioninjury pages 10-12, hilgendorf2024repairofthe pages 3-4)	Inflammation, cytokine production, leukocyte recruitment, autophagy regulation	Anti-inflammatory strategies targeting upstream TLR4/MyD88/NF-κB signaling may attenuate reperfusion injury and maladaptive remodeling; promising but requires timing-specific modulation. (fede2025myocardialischemiareperfusioninjury pages 26-28, das2025networkpharmacologyapproaches pages 7-9)
Wnt/β-catenin	Canonical Wnt/β-catenin, non-canonical Wnt/PCP, Wnt/Ca2+, JNK, CaMKII, PKC, calcineurin	Wnt signaling shows pathway-specific effects in MI/I/R injury: canonical Wnt/β-catenin tends to support recovery and survival, whereas non-canonical Wnt signaling can worsen apoptosis, calcium overload, inflammation, fibrosis, and hypertrophy. (zhang2024ischemiareperfusioninjurymolecular pages 3-4)	Apoptosis, macrophage polarization, oxidative stress, ECM remodeling, angiogenesis, fibrosis	Selective activation of canonical Wnt or inhibition of damaging non-canonical Wnt branches is a potential precision strategy for limiting reperfusion injury and fibrosis. (zhang2024ischemiareperfusioninjurymolecular pages 3-4)
TGF-β/Smad	TGF-β, TGF-β receptors, Smad proteins, MMP-2, MMP-9	Master profibrotic pathway after MI; activated during repair/remodeling and drives fibroblast activation, myofibroblast conversion, collagen synthesis, EndoMT, and scar formation. Essential for structural repair but excessive activation promotes pathological fibrosis. (yin2023postmyocardialinfarctionfibrosis pages 6-8, hilgendorf2024repairofthe pages 3-4)	Fibroblast activation, collagen deposition, scar formation, fibrosis, EndoMT	Targeted modulation may preserve necessary scar formation while reducing adverse remodeling; attractive for anti-fibrotic therapy after MI. (yin2023postmyocardialinfarctionfibrosis pages 6-8, hilgendorf2024repairofthe pages 3-4)
NLRP3 inflammasome	NLRP3, ASC, caspase-1, IL-1β, ROS, DAMPs	Activated in macrophages, fibroblasts, and injured myocardium after ischemia/reperfusion; links mitochondrial damage and oxidative stress to IL-1β release and inflammatory amplification, and contributes to pyroptotic cell death. (fede2025myocardialischemiareperfusioninjury pages 26-28, das2025networkpharmacologyapproaches pages 7-9, fede2025myocardialischemiareperfusioninjury pages 1-2, hilgendorf2024repairofthe pages 15-17)	Inflammasome activation, pyroptosis, sterile inflammation	NLRP3/caspase-1/IL-1 axis inhibitors are promising candidates to reduce infarct inflammation, reperfusion injury, and downstream remodeling. (sagris2024myocardialischemia–reperfusioninjury pages 8-10, fede2025myocardialischemiareperfusioninjury pages 26-28)
TLR4/MyD88	TLR4, MyD88, DAMPs/alarmins, HMGB1, NF-κB	One of the earliest innate immune sensing systems after MI; recognizes DAMPs released from necrotic cardiomyocytes and triggers downstream inflammatory cascades, endothelial activation, and leukocyte recruitment. (fede2025myocardialischemiareperfusioninjury pages 26-28, hilgendorf2024repairofthe pages 3-4, hilgendorf2024repairofthe pages 1-3)	Innate immune activation, cytokine induction, leukocyte trafficking	TLR4/MyD88 blockade is a mechanistically strong anti-inflammatory strategy for limiting sterile injury and reperfusion damage, but may risk impairing necessary repair if over-suppressed. (fede2025myocardialischemiareperfusioninjury pages 26-28, hilgendorf2024repairofthe pages 3-4)
JAK-STAT	JAKs, STATs, IL-6, STAT3	Implicated in vascular inflammation, smooth muscle cell proliferation/differentiation, and post-MI inflammatory signaling; also participates in reparative cytokine signaling such as IL-10/STAT3-mediated suppression of excessive inflammation. (młynarska2024fromatheroscleroticplaque pages 17-19, hilgendorf2024repairofthe pages 19-20)	Cytokine signaling, inflammation resolution, vascular remodeling, cell proliferation	JAK inhibition has been proposed as a strategy in atherosclerosis/MI biology, while preserving beneficial STAT3-mediated repair signaling may be important; pathway likely needs selective modulation. (młynarska2024fromatheroscleroticplaque pages 17-19, hilgendorf2024repairofthe pages 19-20)
Apoptosis	Fas, TNF receptors, cytochrome c, caspase-8, caspase-9, executioner caspases, BAX/BAK, Bcl-2	Major programmed cell-death pathway in ischemia/reperfusion injury; initiated during ischemia and executed during reperfusion via intrinsic mitochondrial and extrinsic death-receptor mechanisms. (fede2025myocardialischemiareperfusioninjury pages 26-28, das2025networkpharmacologyapproaches pages 7-9, fede2025myocardialischemiareperfusioninjury pages 1-2)	Programmed cell death, cardiomyocyte loss	Anti-apoptotic therapies, mitochondrial stabilizers, and survival-pathway activators may reduce infarct expansion and preserve viable myocardium. (das2025networkpharmacologyapproaches pages 15-16, fede2025myocardialischemiareperfusioninjury pages 26-28)
Necroptosis	RIPK1, RIPK3, MLKL	Regulated necrotic death contributes to cardiomyocyte loss during reperfusion and overlaps with inflammatory amplification because cell lysis releases DAMPs. (fede2025myocardialischemiareperfusioninjury pages 10-12, fede2025myocardialischemiareperfusioninjury pages 1-2)	Regulated necrotic cell death, DAMP release	RIPK/MLKL-targeted inhibition is a potential cardioprotective approach in reperfusion injury. (fede2025myocardialischemiareperfusioninjury pages 10-12)
Pyroptosis	Caspase-1, caspase-4/5/11, GSDMD, NLRP3, ASC, calpains	Inflammatory cell death pathway activated by inflammasomes in MIRI; causes membrane pore formation, cytokine release, and propagation of sterile inflammation. (fede2025myocardialischemiareperfusioninjury pages 10-12, fede2025myocardialischemiareperfusioninjury pages 12-14, fede2025myocardialischemiareperfusioninjury pages 1-2)	Inflammatory programmed cell death, cytokine release	Caspase-1, GSDMD, or inflammasome inhibition may reduce inflammatory tissue damage and infarct progression. (sagris2024myocardialischemia–reperfusioninjury pages 8-10, fede2025myocardialischemiareperfusioninjury pages 12-14)
Ferroptosis	Iron-dependent lipid peroxidation machinery, ROS, MAPK/ERK-associated regulators	Emerging reperfusion-related death mechanism characterized by iron-dependent lipid peroxidation; contributes to myocardial injury and interacts with oxidative stress/MAPK signaling. (wang2025theroleof pages 16-17, wang2025theroleof pages 4-6, das2025networkpharmacologyapproaches pages 4-6)	Lipid peroxidation-driven cell death, oxidative membrane damage	Ferroptosis inhibitors and antioxidant/lipid-peroxidation-targeting strategies are under investigation as adjunct cardioprotective therapies. (wang2025theroleof pages 16-17, das2025networkpharmacologyapproaches pages 4-6)
Autophagy	Beclin-1, mTOR, LAMP2, ATF6, IRE1, PERK, ROS	Context-dependent in MI: basal or adaptive autophagy can be protective, but dysregulated or excessive autophagy during reperfusion may worsen injury. Controlled by PI3K/AKT/mTOR, TLR4/NF-κB, ER stress, and ROS signaling. (das2025networkpharmacologyapproaches pages 7-9, fede2025myocardialischemiareperfusioninjury pages 10-12, fede2025myocardialischemiareperfusioninjury pages 12-14)	Organelle quality control, stress adaptation, cell survival vs cell death balance	Therapies that restore balanced autophagic flux rather than simple inhibition/activation may improve myocardial salvage and remodeling. (das2025networkpharmacologyapproaches pages 7-9, fede2025myocardialischemiareperfusioninjury pages 10-12)

Table: This table summarizes the major molecular signaling pathways implicated in myocardial infarction pathophysiology, emphasizing their mediators, biological roles, affected cellular processes, and therapeutic relevance. It is useful for linking mechanistic disease biology to candidate intervention points.

Ischemia-Reperfusion Injury

Reperfusion, while essential for myocardial salvage, paradoxically contributes up to 50% of the final infarct size through ischemia-reperfusion injury (MIRI) (buja2023pathobiologyofmyocardial pages 1-2, das2025networkpharmacologyapproaches pages 1-2). Key mechanisms include:

Oxidative stress: Excessive ROS production from mitochondria, NADPH oxidases, and xanthine oxidase causes lipid peroxidation, protein oxidation, and DNA damage (das2025networkpharmacologyapproaches pages 2-4, das2025networkpharmacologyapproaches pages 4-6)
Calcium overload: Disruption of Ca²⁺ homeostasis via Na⁺/Ca²⁺ exchanger activation activates injury pathways (das2025networkpharmacologyapproaches pages 2-4, sagris2024myocardialischemia–reperfusioninjury pages 2-3)
Mitochondrial dysfunction: Sustained opening of the mitochondrial permeability transition pore (MPTP) results in loss of mitochondrial membrane potential and cessation of ATP production (buja2023pathobiologyofmyocardial pages 1-2)
Inflammatory response: Neutrophil activation, cytokine release (TNF-α, IL-1β, IL-6), and adhesion molecule upregulation (ICAM-1, VCAM-1) (das2025networkpharmacologyapproaches pages 9-10, fede2025myocardialischemiareperfusioninjury pages 1-2)
Multiple cell death pathways: Apoptosis, necroptosis, pyroptosis, ferroptosis, and dysregulated autophagy (fede2025myocardialischemiareperfusioninjury pages 1-2, das2025networkpharmacologyapproaches pages 4-6)

Post-MI Cardiac Repair

Post-MI repair involves three overlapping phases: inflammatory, proliferative, and maturation/remodeling (hilgendorf2024repairofthe pages 3-4, hilgendorf2024repairofthe pages 1-3):

Inflammatory phase: DAMPs from dying cardiomyocytes activate TLR/NLR signaling, driving pro-inflammatory cytokine production (IL-1, TNF-α, IL-6) and chemokine-mediated recruitment of neutrophils and monocytes via CCL2/CCR2 signaling (hilgendorf2024repairofthe pages 3-4, hilgendorf2024repairofthe pages 1-3, ramosregalado2024theinfluenceof pages 6-7)
Proliferative phase: Macrophage efferocytosis triggers anti-inflammatory mediator release (IL-10, TGF-β), activating fibroblasts and promoting myofibroblast conversion (hilgendorf2024repairofthe pages 1-3, hilgendorf2024repairofthe pages 19-20)
Maturation phase: Organized collagen deposition forms protective scar tissue; excessive fibrosis leads to adverse remodeling and heart failure (hilgendorf2024repairofthe pages 1-3, hilgendorf2024repairofthe pages 23-25)

Cardiac macrophages are the predominant immune cells, existing in heterogeneous subpopulations with pro-inflammatory CCR2⁺ monocyte-derived macrophages and anti-inflammatory resident populations (Trem2hi, Bhlhe41⁺) (hilgendorf2024repairofthe pages 14-15, yang2025omicsbasedapproachtowards pages 4-5).

Suggested GO terms: GO:0006915 (apoptotic process); GO:0006954 (inflammatory response); GO:0042060 (wound healing); GO:0048661 (positive regulation of smooth muscle cell proliferation) Suggested CL terms: CL:0000746 (cardiac muscle cell); CL:0000235 (macrophage); CL:0000775 (neutrophil); CL:0000057 (fibroblast)

7. Anatomical Structures Affected

Organ Level

Primary: Heart (UBERON:0000948), specifically myocardium (UBERON:0002349)
Secondary: Lungs (pulmonary edema), kidneys (cardiorenal syndrome), brain (cardiogenic embolism)
Body systems: Cardiovascular system (UBERON:0004535)

Tissue and Cell Level

Cardiomyocytes (CL:0000746): Primary target of ischemic injury
Endothelial cells (CL:0000115): Endothelial dysfunction and microvascular injury
Cardiac fibroblasts (CL:0000057): Fibrotic remodeling and scar formation
Vascular smooth muscle cells (CL:0000359): Atherosclerotic plaque stability

Subcellular Level

Mitochondria (GO:0005739): Central role in MPTP opening and energy cessation
Sarcoplasmic reticulum: Calcium handling dysfunction (SERCA2a impairment)
Cell membrane: Lipid peroxidation damage

Localization

Ischemic injury begins in the papillary muscle and subendocardium, then progresses toward the subepicardium (buja2023pathobiologyofmyocardial pages 2-4). The left anterior descending (LAD) coronary artery territory is the most commonly affected.

8. Temporal Development

Onset

Typical age: Predominantly adult and geriatric populations; increasing recognition of MI in younger patients (<45 years)
Onset pattern: Acute, with sudden onset of symptoms
Critical window: Reversible injury ~15 minutes; irreversible injury 20–60 minutes post-occlusion (buja2023pathobiologyofmyocardial pages 2-4)

Progression

Acute phase (hours): Cardiomyocyte death, inflammatory cascade initiation
Subacute phase (days–weeks): Inflammatory resolution, granulation tissue formation, scar maturation
Chronic phase (weeks–months): Ventricular remodeling, potential progression to heart failure
Reperfusion window: If restored within 3–4 hours, significant myocardial salvage is achievable (buja2023pathobiologyofmyocardial pages 2-4)

9. Inheritance and Population

Epidemiology

Cardiovascular diseases, led by ischemic heart disease (IHD) including MI, are the leading cause of death globally. According to GBD 2021, high systolic blood pressure is the dominant modifiable risk factor, with resource-abundant regions showing notable reductions in age-standardized death rates (EAPC of −3.43, 95% CI: −3.32, −3.53), while resource-limited regions experienced stagnation or increases.

Genetic Architecture

MI is a polygenic/multifactorial disease with complex inheritance. A high PRS is associated with a threefold increase in MI risk (zhou2024associationofmetabolic pages 1-2). Key loci include 9p21 (CDKN2B-AS1), LPA, PCSK9, and LDLR. Penetrance is incomplete and strongly modified by environmental/lifestyle factors.

Population Demographics

Sex ratio: Males have higher incidence and earlier onset; females present more frequently with atypical symptoms
Age distribution: Risk increases substantially with age; young MI (age <45) has a distinct risk profile with greater genetic contribution
Geographic variation: Central Asia and Eastern Europe have the highest burden; high-income regions show declining trends

10. Diagnostics

Clinical Tests

ECG Criteria: For STEMI diagnosis, new ST-segment elevation is required in ≥2 contiguous leads: ≥2.5 mm in men <40 years, ≥2 mm in men >40 years, or ≥1.5 mm in women in leads V2–V3, and/or ≥1 mm in other leads (młynarska2024fromatheroscleroticplaque pages 7-8).

Biomarkers: High-sensitivity cardiac troponin (hs-cTn I and T) is the preferred biomarker, with a rise-and-fall pattern above the 99th percentile upper reference limit consistent with acute myocardial injury (fede2025myocardialischemiareperfusioninjury pages 1-2, das2025networkpharmacologyapproaches pages 12-13). LDH rises later (24–48 hours) and may help differentiate infarction from reperfusion injury (das2025networkpharmacologyapproaches pages 12-13).

Imaging: Cardiac MRI is the gold standard for assessing myocardial damage, using late gadolinium enhancement (LGE) to distinguish infarcted from viable tissue and T2-weighted imaging for edema assessment (das2025networkpharmacologyapproaches pages 12-13). Echocardiography is widely used for wall motion assessment. Coronary angiography remains the definitive tool for identifying culprit lesions.

Clinical Criteria

The Fourth Universal Definition of Myocardial Infarction (2018), published by ESC/ACC/AHA/WHF, establishes MI diagnosis based on evidence of myocardial injury (troponin rise/fall) in a clinical context of myocardial ischemia (fede2025myocardialischemiareperfusioninjury pages 1-2).

11. Outcome/Prognosis

Survival and Mortality

MI remains the leading cause of cardiovascular mortality globally. In-hospital mortality for STEMI has declined substantially with primary PCI implementation. Cardiogenic shock complicates approximately 10% of AMI cases and carries high mortality. Long-term outcomes depend on infarct size, left ventricular function, completeness of revascularization, and comorbidities.

Complications

Heart failure (from adverse ventricular remodeling)
Arrhythmias (reperfusion arrhythmias, ventricular fibrillation, sudden cardiac death)
Mechanical complications (ventricular septal rupture, free wall rupture, papillary muscle rupture)
Recurrent ischemic events
Pericarditis (Dressler syndrome)

Prognostic Biomarkers

Infarct size (measured by cardiac MRI or peak troponin)
Left ventricular ejection fraction
Microvascular obstruction on cardiac MRI
NT-proBNP levels
High-sensitivity CRP

12. Treatment

Pharmacotherapy

Antiplatelet Therapy (MAXO:0001001): Dual antiplatelet therapy (DAPT) combining aspirin with a P2Y12 receptor inhibitor is standard care. Prasugrel is preferred over ticagrelor for PCI patients, with clopidogrel reserved for high bleeding risk or contraindications (młynarska2024fromatheroscleroticplaque pages 11-12, nicolau2025molecularmechanismsof pages 8-10). Cangrelor provides rapid intravenous platelet inhibition during PCI (nicolau2025molecularmechanismsof pages 8-10, occhipinti2025pharmacologicalandinterventional pages 6-8).

Anticoagulants: Unfractionated heparin (UFH) is recommended for STEMI patients undergoing primary PCI, with enoxaparin and bivalirudin as alternatives (młynarska2024fromatheroscleroticplaque pages 11-12). Fondaparinux is preferred for NSTE-ACS patients not undergoing early invasive angiography (młynarska2024fromatheroscleroticplaque pages 11-12).

Beta-Blockers: Metoprolol is recommended for STEMI patients without acute heart failure, reducing ventricular fibrillation risk and microvascular obstruction (młynarska2024fromatheroscleroticplaque pages 11-12).

Statins: Atorvastatin, rosuvastatin, and simvastatin reduce LDL-cholesterol by up to 50% and exert cardioprotective anti-inflammatory effects (alradwan2024emergingtrendsand pages 4-7, ramosregalado2024theinfluenceof pages 10-11).

ACE Inhibitors/ARBs: ACE inhibitors and ARBs provide cardioprotection by mitigating adverse effects of angiotensin II during and after MI (ramosregalado2024theinfluenceof pages 10-11).

PCSK9 Inhibitors: Evolocumab and alirocumab provide additional LDL-lowering and modulate inflammatory responses via TLR4/NFκB signaling interference (ramosregalado2024theinfluenceof pages 10-11).

Novel Agents: SGLT2 inhibitors (dapagliflozin) show clinical promise in both diabetic and non-diabetic MI patients, reducing inflammatory response and infarct size (ramosregalado2024theinfluenceof pages 10-11). Anti-inflammatory agents including tocilizumab (IL-6 inhibitor), anakinra (IL-1 receptor antagonist), and colchicine show cardioprotective effects by reducing infarct size (sagris2024myocardialischemia–reperfusioninjury pages 8-10).

Interventional Procedures (MAXO:0000474)

Primary percutaneous coronary intervention (PCI) is the gold standard for STEMI reperfusion. The 2023 ESC guidelines recommend consideration of intravascular imaging (OCT/IVUS) to guide PCI (Class IIa) (nicolau2025molecularmechanismsof pages 15-17).

Experimental Therapies

Key currently recruiting Phase 3 clinical trials are summarized below:

NCT Number	Trial Name/Description	Intervention/Drug	Sponsor	Enrollment	Novel Mechanism/Target
NCT06118281	ARTEMIS – research study of ziltivekimab vs placebo after heart attack	Ziltivekimab	Novo Nordisk A/S	10000	Anti-inflammatory IL-6 pathway inhibition to reduce recurrent events after MI (sagris2024myocardialischemia–reperfusioninjury pages 8-10)
NCT07478003	PULSE-MI 2 – prehospital pulse-dose glucocorticoid in STEMI	Pulse-dose glucocorticoid	Rigshospitalet, Denmark	5204	Early anti-inflammatory immunomodulation during acute STEMI/reperfusion
NCT06174753	Dapagliflozin in STEMI	Dapagliflozin	Ottawa Heart Institute Research Corporation	256	SGLT2 inhibition; metabolic and anti-inflammatory cardioprotection with infarct-limiting potential (ramosregalado2024theinfluenceof pages 10-11)
NCT06364150	Therapeutic use of angiopoietin-primed autologous peripheral blood stem cell in myocardial infarction	Angiopoietin-primed autologous peripheral blood stem cells	Seoul National Hospital	30	Regenerative cell therapy aimed at myocardial repair and neovascularization (das2025networkpharmacologyapproaches pages 32-33, alradwan2024emergingtrendsand pages 4-7)
NCT05577988	Early de-escalation to low-potency single antiplatelet therapy guided by genetics vs systematic high-potency single antiplatelet therapy after ACS	Genotype-guided antiplatelet de-escalation	Assistance Publique - Hôpitaux de Paris	2468	Precision antiplatelet therapy using pharmacogenetic guidance for P2Y12-pathway modulation (młynarska2024fromatheroscleroticplaque pages 11-12, nicolau2025molecularmechanismsof pages 8-10)
NCT07320625	Efficacy of montelukast on STEMI patients	Montelukast	Shanghai Zhongshan Hospital	512	Leukotriene receptor antagonism to modulate inflammation in STEMI
NCT07301034	Study of ziltivekimab effect on coronary plaque vs placebo after heart attack	Ziltivekimab with plaque imaging endpoint	Novo Nordisk A/S	332	IL-6 pathway inhibition with imaging-based assessment of plaque biology/inflammation
NCT07467213	Routine use of potassium competitive acid blocker vs guideline-directed gastrointestinal protection in acute myocardial infarction	Potassium-competitive acid blocker strategy	Samsung Medical Center	5000	Supportive strategy to optimize GI protection during intensive antithrombotic therapy after AMI
NCT07295223	GALACTUS – effect of GLP-1 and antidiabetic SGLT2 agents for myocardial infarction and ultrasensitive inflammatory surveillance	GLP-1 agent and SGLT2 agent strategy	Instituto Mexicano del Seguro Social	44	Cardiometabolic and anti-inflammatory modulation using incretin/SGLT2 pathways after MI (ramosregalado2024theinfluenceof pages 10-11)

Table: This table summarizes currently recruiting phase 3 interventional trials in myocardial infarction and related acute coronary syndromes mentioned in the evidence-gathering workflow. It highlights sponsor, scale, and the mechanistic rationale of each study to support translational and therapeutic landscape mapping.

Advanced Therapeutics

Cell therapy: Stem cell and progenitor cell transplantation for myocardial repair (das2025networkpharmacologyapproaches pages 32-33, alradwan2024emergingtrendsand pages 4-7)
Gene therapy: CRISPR-based approaches for genetic correction of CVD risk factors; anti-apoptotic gene therapy with Bcl-2 (das2025networkpharmacologyapproaches pages 32-33, alradwan2024emergingtrendsand pages 4-7)
RNA-based therapies: MicroRNA modulation for cardioprotection; siRNA inclisiran for PCSK9 silencing
Immunotherapies: IL-1 and IL-6 inhibitors (canakinumab, tocilizumab) to reduce cardiovascular events (sagris2024myocardialischemia–reperfusioninjury pages 8-10)

13. Prevention

Primary Prevention

Risk factor modification: Blood pressure control, LDL-cholesterol reduction, smoking cessation, weight management, regular physical activity
Statin therapy for high-risk individuals
Aspirin for selected high-risk patients (with evolving guidelines)

Secondary Prevention

DAPT therapy post-MI
High-intensity statin therapy
ACE inhibitors/ARBs
Beta-blockers
Cardiac rehabilitation
Risk stratification using polygenic risk scores (PRS) may improve early intervention in genetically predisposed individuals (zhou2024associationofmetabolic pages 1-2)

Tertiary Prevention

Optimization of heart failure management
Implantable cardioverter-defibrillator (ICD) for high-risk patients
Long-term antiplatelet and lipid-lowering therapy

Behavioral Interventions

Diet modification (Mediterranean diet, omega-3 fatty acids), regular exercise, stress management, and alcohol moderation are established risk-reducing strategies (zhou2024associationofmetabolic pages 1-2, zhou2024associationofmetabolic pages 13-15).

14. Other Species / Natural Disease

Naturally Occurring Disease

MI occurs naturally in dogs, cats, horses, and non-human primates, though it is less common than in humans. Companion animals, particularly dogs, can develop MI secondary to coronary atherosclerosis or vasculitis.

Comparative Biology

Zebrafish have high genetic homology with humans (70% of human genes have identifiable zebrafish orthologs) and offer unique advantages for cardiovascular research due to their remarkable cardiac regenerative capacity (wang2026zebrafishincardiovascular pages 1-3). Unlike mammals, zebrafish scars after cardiac injury are temporary and do not permanently hinder regeneration (wang2026zebrafishincardiovascular pages 14-16).

15. Model Organisms

Small Animal Models

Mouse and Rat Models: Left anterior descending (LAD) coronary artery ligation is the standard injury model, inducing ischemia followed by reperfusion (alsadder2025cardiacischaemia–reperfusioninjury pages 8-9, das2025networkpharmacologyapproaches pages 10-12). Genetically modified models include Spontaneously Hypertensive Rats (SHR), diabetic rats, and Apoe⁻/⁻ mice for studying cardiovascular disease mechanisms. Limitations include higher heart rates and different electrophysiological properties compared to humans (alsadder2025cardiacischaemia–reperfusioninjury pages 8-9).

Zebrafish Models (Danio rerio; NCBI Taxon: 7955): Zebrafish offer high-throughput screening capability, embryonic transparency for real-time cardiac imaging, and robust cardiac regenerative capacity through cardiomyocyte proliferation (wang2026zebrafishincardiovascular pages 14-16, wang2026zebrafishincardiovascular pages 1-3). Injury models include cryoinjury and genetic ablation. Comparative single-cell profiling has identified distinct cardiac resident macrophage populations (hbaa⁺ Mac and timp4.3⁺ Mac3) essential for zebrafish heart regeneration. Key limitation: two-chambered heart with single-circuit circulation (wang2026zebrafishincardiovascular pages 14-16).

Large Animal Models

Porcine Models: Offer the greatest translational value due to closest resemblance to human cardiac physiology. Used for PCI-related research and device testing. Limitation: typically healthy animals that don't fully represent pathological comorbidity conditions (alsadder2025cardiacischaemia–reperfusioninjury pages 8-9).

In Vitro Models

Emerging models include iPSC-derived cardiomyocytes and organ-on-chip systems for studying ischemia-reperfusion injury with improved human relevance (alsadder2025cardiacischaemia–reperfusioninjury pages 14-15).

Model Limitations

Translation of preclinical findings to clinical settings remains challenging due to species differences in cardiac physiology, immune responses, and myocardial repair mechanisms. Variability in experimental protocols between in vitro and in vivo models can lead to inconsistent results and reproducibility issues (das2025networkpharmacologyapproaches pages 10-12, alsadder2025cardiacischaemia–reperfusioninjury pages 14-15).

Summary of Key Ontology Annotations

Disease Ontology: MONDO:0005068 (myocardial infarction) Key HPO Terms: HP:0001658 (Myocardial infarction); HP:0001681 (Angina pectoris); HP:0001649 (Tachycardia); HP:0002094 (Dyspnea) Key GO Terms: GO:0006915 (apoptotic process); GO:0006954 (inflammatory response); GO:0042060 (wound healing); GO:0097193 (intrinsic apoptotic signaling pathway); GO:0070059 (intrinsic apoptotic signaling in response to ER stress) Key UBERON Terms: UBERON:0000948 (heart); UBERON:0002349 (myocardium); UBERON:0001621 (coronary artery) Key CL Terms: CL:0000746 (cardiac muscle cell); CL:0000235 (macrophage); CL:0000775 (neutrophil); CL:0000057 (fibroblast); CL:0000115 (endothelial cell) Key CHEBI Terms: CHEBI:39025 (high-density lipoprotein cholesterol); CHEBI:39026 (low-density lipoprotein cholesterol) Key MAXO Terms: MAXO:0001001 (antiplatelet therapy); MAXO:0000474 (surgical intervention); MAXO:0000009 (drug therapy)

References

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(fede2025myocardialischemiareperfusioninjury pages 12-14): Maria Sofia Fede, Gloria Daziani, Francesco Tavoletta, Angelo Montana, Paolo Compagnucci, Gaia Goteri, Margherita Neri, and Francesco Paolo Busardò. Myocardial ischemia/reperfusion injury: molecular insights, forensic perspectives, and therapeutic horizons. Cells, 14:1509, Sep 2025. URL: https://doi.org/10.3390/cells14191509, doi:10.3390/cells14191509. This article has 30 citations.
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(das2025networkpharmacologyapproaches pages 2-4): Joy Das, Ashok Kumar Sah, Ranjay Kumar Choudhary, Rabab H. Elshaikh, Utpal Bhui, Shreya Chowdhury, Anass M. Abbas, Manar G. Shalabi, Nadeem Ahmad Siddique, Raji Rubayyi Alshammari, Navjyot Trivedi, Khoula Salim Ali Buwaiqi, Said Al Ghenaimi, and Pranav Kumar Prabhakar. Network pharmacology approaches to myocardial infarction reperfusion injury: exploring mechanisms, pathophysiology, and novel therapies. Biomedicines, 13:1532, Jun 2025. URL: https://doi.org/10.3390/biomedicines13071532, doi:10.3390/biomedicines13071532. This article has 15 citations.
(sagris2024myocardialischemia–reperfusioninjury pages 2-3): Marios Sagris, Anastasios Apostolos, Panagiotis Theofilis, Nikolaos Ktenopoulos, Odysseas Katsaros, Sotirios Tsalamandris, Konstantinos Tsioufis, Konstantinos Toutouzas, and Dimitris Tousoulis. Myocardial ischemia–reperfusion injury: unraveling pathophysiology, clinical manifestations, and emerging prevention strategies. Biomedicines, 12:802, Apr 2024. URL: https://doi.org/10.3390/biomedicines12040802, doi:10.3390/biomedicines12040802. This article has 73 citations.
(ramosregalado2024theinfluenceof pages 6-7): Lisaidy Ramos-Regalado, Sebastià Alcover, Lina Badimon, and Gemma Vilahur. The influence of metabolic risk factors on the inflammatory response triggered by myocardial infarction: bridging pathophysiology to treatment. Cells, 13:1125, Jun 2024. URL: https://doi.org/10.3390/cells13131125, doi:10.3390/cells13131125. This article has 17 citations.
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(nicolau2025molecularmechanismsof pages 15-17): Andre M. Nicolau, Pedro G. Silva, Hernan Patricio G. Mejía, Juan F. Granada, Grzegorz L. Kaluza, Daniel Burkhoff, Thiago Abizaid, Brunna Pileggi, Antônio F. D. Freire, Roger R. Godinho, Carlos M. Campos, Fabio S. de Brito, Alexandre Abizaid, and Pedro H. C. Melo. Molecular mechanisms of microvascular obstruction and dysfunction in percutaneous coronary interventions: from pathophysiology to therapeutics—a comprehensive review. International Journal of Molecular Sciences, 26:6835, Jul 2025. URL: https://doi.org/10.3390/ijms26146835, doi:10.3390/ijms26146835. This article has 20 citations.
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(alsadder2025cardiacischaemia–reperfusioninjury pages 8-9): Lujain Alsadder and Abdulaziz Hamadah. Cardiac ischaemia–reperfusion injury: pathophysiology, therapeutic targets and future interventions. Biomedicines, 13:2084, Aug 2025. URL: https://doi.org/10.3390/biomedicines13092084, doi:10.3390/biomedicines13092084. This article has 19 citations.
(das2025networkpharmacologyapproaches pages 10-12): Joy Das, Ashok Kumar Sah, Ranjay Kumar Choudhary, Rabab H. Elshaikh, Utpal Bhui, Shreya Chowdhury, Anass M. Abbas, Manar G. Shalabi, Nadeem Ahmad Siddique, Raji Rubayyi Alshammari, Navjyot Trivedi, Khoula Salim Ali Buwaiqi, Said Al Ghenaimi, and Pranav Kumar Prabhakar. Network pharmacology approaches to myocardial infarction reperfusion injury: exploring mechanisms, pathophysiology, and novel therapies. Biomedicines, 13:1532, Jun 2025. URL: https://doi.org/10.3390/biomedicines13071532, doi:10.3390/biomedicines13071532. This article has 15 citations.
(alsadder2025cardiacischaemia–reperfusioninjury pages 14-15): Lujain Alsadder and Abdulaziz Hamadah. Cardiac ischaemia–reperfusion injury: pathophysiology, therapeutic targets and future interventions. Biomedicines, 13:2084, Aug 2025. URL: https://doi.org/10.3390/biomedicines13092084, doi:10.3390/biomedicines13092084. This article has 19 citations.

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Definitions

Comorbidities

Pathophysiology

Pathograph

Phenotypes

Medical Actions

Biochemical Markers

Related Datasets

Clinical Trials

Experimental Models

Source YAML

References & Deep Research

Deep Research

1. Disease Information

Overview

Key Identifiers

Common Synonyms

2. Etiology

Disease Causal Factors

Risk Factors

Protective Factors

Gene-Environment Interactions

3. Phenotypes

Symptoms and Clinical Signs

Laboratory Abnormalities

Quality of Life Impact

4. Genetic/Molecular Information

Key Susceptibility Genes and Targets

GWAS Findings

Epigenetic Information

5. Environmental Information

Environmental Factors

Lifestyle Factors

6. Mechanism / Pathophysiology

Overview of Pathophysiological Cascade

Molecular Pathways

Ischemia-Reperfusion Injury

Post-MI Cardiac Repair

7. Anatomical Structures Affected

Organ Level

Tissue and Cell Level

Subcellular Level

Localization

8. Temporal Development

Onset

Progression

9. Inheritance and Population

Epidemiology

Genetic Architecture

Population Demographics

10. Diagnostics

Clinical Tests

Clinical Criteria

11. Outcome/Prognosis

Survival and Mortality

Complications

Prognostic Biomarkers

12. Treatment

Pharmacotherapy

Interventional Procedures (MAXO:0000474)

Experimental Therapies

Advanced Therapeutics

13. Prevention

Primary Prevention

Secondary Prevention

Tertiary Prevention

Behavioral Interventions

14. Other Species / Natural Disease

Naturally Occurring Disease

Comparative Biology

15. Model Organisms

Small Animal Models

Large Animal Models

In Vitro Models

Model Limitations

Summary of Key Ontology Annotations

Artifacts