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Myocardial Infarction

1. Disease Information

2026-07-05
Falcon MONDO:0005068 Model: Edison Scientific Literature 54 citations

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

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):

Table (click to expand)
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:

Table (click to expand)
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:

Post-MI Cardiac Repair

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

  1. 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)
  2. 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)
  3. 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:

Table (click to expand)
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

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)

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