Acute Myocardial Infarction: Molecular Pathogenesis, Diagnosis, and Clinical Management

Abstract

Acute myocardial infarction (AMI) is a cardiovascular disease characterized by myocardial necrosis resulting from acute coronary artery occlusion. Although standardized diagnostic and therapeutic protocols have markedly reduced its mortality, AMI remains a leading cause of death and disability worldwide. Contemporary AMI research has evolved from an initial focus on local myocardial injury to a broader perspective encompassing the entire disease course, including tissue damage, remodeling, and multi-organ interactions. This review systematically delineates the key molecular mechanisms underlying AMI and subsequent ventricular remodeling, while also exploring the complex interplay between the heart and other organs such as the gut, brain, kidney, and liver. From a clinical standpoint, we summarize the historical evolution of AMI diagnostic criteria and management strategies, highlighting current classification systems, novel diagnostic technologies, and the integration of artificial intelligence tools. Furthermore, we present recent evidence-based advances in established therapeutic approaches, along with emerging strategies ranging from cellular to genetic interventions. Future directions aim to integrate mechanistic insights with interdisciplinary clinical strategies to establish a systematic and precision-based framework for AMI prevention and management.

Keywords: acute myocardial infarction; inter‐organ crosstalk; myocardial ischemia/reperfusion infarction; pathogenesis; ventricular remodeling.

FIGURE 1

Key pathogenic mechanisms in AMI. Oxidative stress and mitochondrial dysfunction induce ROS accumulation, while DAMPs‐PRRs interaction triggers inflammatory cascades. Programmed cell death pathways and epigenetic regulation collectively constitute the core components of AMI pathogenesis. AMI, acute myocardial infarction; Breg, regulatory B cells; CAT, catalase; DAMPs, damage‐associated molecular patterns; ETC, electron transport chain; GPX, glutathione peroxidase; lncRNAs, long non‐coding RNAs; miRNAs, microRNAs; mtDNA, mitochondrial DNA; ncRNA, non‐coding RNAs; NK, natural killer; NOX, NADPH oxidase; NOS, nitric oxide synthase; PRRs, pattern recognition receptors; ROS, reactive oxygen species; SOD, superoxide dismutase; Treg, regulatory T cells; XO, Xanthine oxidase.

FIGURE 2

Cell death mechanisms in AMI. (A) Apoptosis is primarily activated by endogenous factors and can also be initiated through the binding of death ligands to their receptors. (B) Necroptosis is induced by TNF signaling upon caspase‐8 inhibition, leading to MLKL‐mediated pore formation via the RIPK1‐RIPK3 phosphorylation cascade, culminating in osmotic lysis. (C) Pyroptosis proceeds through both classical and non‐classical pathways, causing GSDMD cleavage and the release of mature IL‐18 and IL‐1β. (D) Autophagic cell death is induced under ischemic conditions via AMPK‐mediated inhibition of mTOR, promoting protective autophagy; during I/R injury, it is driven by increased expression of BECN1 and RUBCN proteins, leading to excessive autophagy. (E) Ferroptosis is marked by lipid peroxidation and dysfunction of System Xc‐, (F) whereas cuproptosis involves enhanced intracellular copper influx, resulting in the aggregation of toxic proteins. ACSL4, acyl‐CoA synthetase long‐chain family member 4; AMI, acute myocardial infarction; Apaf‐1, apoptotic protease‐activating factor 1; BECN1, beclin 1; CaMKII, calcium/calmodulin‐dependent protein kinase II; cIAP1/2, cellular inhibitor of apoptosis protein 1/2; DLAT, dihydrolipoamide S‐acetyltransferase; FDX1, ferredoxin 1; GPX, glutathione peroxidase; GSDM, gasdermin; LPCAT3, lysophosphatidylcholine acyltransferase 3; LPS, lipopolysaccharide; MLKL, mixed lineage kinase domain‐like protein; mPTP, mitochondrial permeability transition pore; PAMPs, pathogen‐associated molecular patterns; PL‐PUFA, polyunsaturated‐fatty‐acid‐containing phospholipid; PUFA, polyunsaturated fatty acids; PUFA‐CoA, PUFA‐acylated AA; RIPK1, receptor‐interacting serine/threonine‐protein kinase 1; RIPK3, receptor‐interacting serine/threonine‐protein kinase 3; ROS, reactive oxygen species; RUBCN, rubicon; TFEB, transcription factor EB; TfR1, transferrin receptor 1; TRAF, TNFR‐associated factor; TRADD, TNFR1‐associated death domain.

FIGURE 3

Key molecular mechanisms underlying ventricular remodeling after AMI. After AMI, coordinated signaling pathways regulate fibrosis, cell proliferation, angiogenesis, and cardiomyocyte hypertrophy, collectively driving structural and functional changes in the ventricle. AMI, acute myocardial infarction; ALD, aldosterone; Ang II, angiotensin II; AR, aldosterone receptor; AT1R, angiotensin II type I receptor; β1‐AR, β1‐adrenergic receptor; CA, catecholamine; ECM, extracellular matrix; EGFR, epidermal growth factor receptor; ERK, extracellular signal‐regulated kinase; FBLN7, fibulin 7; HIF‐α, hypoxia‐inducible factor 1‐α; ITGA5, integrin α5; LPA, lysophosphatidic acid; LPA₂, lysophosphatidic acid receptor 2; TNAP1, tissue nonspecific alkaline phosphatase; TREM2, triggering receptor expressed on myeloid cells 2; VEGF, vascular endothelial growth factor.

FIGURE 4

Multiorgan crosstalk in AMI pathophysiology. AMI can induce organ‐specific pathological changes such as liver inflammation, renal hemodynamic load, activation of the neuroendocrine system in the brain, and intestinal barrier disruption. These changes, in turn, exacerbate cardiac injury through mechanisms such as enhanced inflammation, oxidative stress, and metabolic dysregulation, thereby establishing a vicious cycle between the heart and multiple organs. AMI, acute myocardial infarction; ER, endoplasmic reticulum; HPA, hypothalamic–pituitary–adrenal; LPS, lipopolysaccharide; RAAS, renin‐angiotensin‐aldosterone system; SCFA, short‐chain fatty acids; TMAO, trimethylamine N‐oxide.

FIGURE 5

Evolution of diagnostic criteria and clinical management in AMI. The diagnostic criteria for AMI have progressively advanced from reliance on symptoms and ECG to the integration of troponin detection technology, with diagnostic classification becoming increasingly precise. Clinical management has transitioned from basic supportive care to the systematic adoption of comprehensive drug regimens and routine reperfusion therapy. AMI, acute myocardial infarction; AST, aspartate aminotransferase; CK, creatine kinase; CK‐MB, creatine kinase MB; DAPT, dual antiplatelet therapy; DSA, digital subtraction angiography; DES, drug‐eluting stent; hs‐cTn, high‐sensitivity cardiac troponin; IVUS, intravascular ultrasound; LDH, lactatedehydrogenase; OCT, optical coherence tomography; PCI, percutaneous coronary intervention; POC, point‐of‐care; PTCA, percutaneous transluminal coronary angioplasty; SK, streptokinase.