Acute coronary syndromes: mechanisms, challenges, and new opportunities

Abstract

Despite advances in research and patient management, atherosclerosis and its dreaded acute and chronic sequelae continue to account for one out of three deaths globally. The vast majority of acute coronary syndromes (ACS) arise from either plaque rupture or erosion, but other mechanisms, including calcific nodules, embolism, spontaneous coronary artery dissection, coronary spasm, and microvascular dysfunction, can also cause ACS. This ACS heterogeneity necessitates a paradigm shift in its management that extends beyond the binary interpretation of electrocardiographic and biomarker data. Indeed, given the evolution in the global risk factor profile, the increasing importance of previously underappreciated mechanisms, the evolving appreciation of sex-specific disease characteristics, and the advent of rapidly evolving technologies, a precision medicine approach is warranted. This review provides an update of the mechanisms of ACS, delineates the role of previously underappreciated contributors, discusses sex-specific differences, and explores novel tools for contemporary and personalized management of patients with ACS. Beyond mechanistic insights, it examines evolving imaging techniques, biomarkers, and regression- and machine learning-based approaches for the diagnosis (e.g. CoDE-ACS, MI3) and prognosis (e.g. PRAISE, GRACE, SEX-SHOCK scores) of ACS, along with their implications for future ACS management. A more individualized approach to patients with ACS is advocated, emphasizing the need for innovative studies on emerging technologies, including artificial intelligence, which may collectively facilitate clinical decision-making within a more mechanistic framework, thereby personalizing patient care and potentially improving long-term outcomes.

Keywords: Acute coronary syndromes; Acute myocardial infarction; Artificial intelligence; C-reactive protein; Clinical decision-making; Dual antiplatelet therapy; Individualized management; Inflammation; Intravascular ultrasound; Machine learning; Optical coherence tomography; Percutaneous coronary intervention; Plaque erosion; Plaque healing; Plaque rupture; Precision medicine; Sex differences.

Graphical Abstract

Figure 1

Molecular and cellular mechanisms of plaque rupture—the most common cause of acute coronary syndromes. Plaque formation in the trilaminar coronary artery begins with the subendothelial accumulation of apolipoprotein-B-containing lipid particles [e.g. LDL, lipoprotein(a)]. These lipid particles undergo oxidative and other modifications, triggering a pro-inflammatory response (with subsequent adhesion molecule upregulation) and monocyte recruitment. Classic monocytes migrate into the intima, differentiate into pro-inflammatory macrophages, and internalize modified LDL via scavenger receptors, forming foam cells. The pro-inflammatory milieu and impaired efferocytosis inhibit the polarization of macrophages towards a pro-inflammatory slant. Foam cells then release apoptotic bodies (containing tissue factor amplifying local coagulation), contributing to the accumulation of cholesterol crystals which drives the NOD-like receptor protein 3 inflammasome-mediated interleukin-1β and interleukin-18 activation. Under the influence of growth factors (e.g. platelet-derived growth factor released by activated macrophages and platelets) and certain cytokines, such as interleukin-6, smooth muscle cells then migrate towards the intima and undergo a Krüppel-like factor 4-driven phenotypic modulation. Together with T-helper cell-derived mediators, such as interferon gamma, this results in reduced collagen fibre synthesis and enhanced cathepsin-S and matrix metalloproteinase-mediated collagen breakdown. Imbalances in these pathways, combined with the progressive weakening of the fibrous cap, underpin plaque rupture, the principal driver of acute coronary syndromes. Apo-B, apolipoprotein-B; IFN-γ, interferon gamma; IL, interleukin; KLF4, Krüppel-like factor 4; Lp(a), lipoprotein(a); MMP, matrix metalloproteinase; NLRP3, NOD-like receptor protein 3; oxLDL, oxidized LDL; PDGF, platelet-derived growth factor; ROS, reactive oxygen species; Th, T-helper cell; TNF, tumour necrosis factor; T_reg, regulatory T-cell; t/u-PA, tissue- or urokinase-type plasminogen activator

Figure 2

Mechanistic insights into plaque erosion—an increasingly prevalent cause of acute coronary syndromes. (A) In regions of high oscillatory shear index (i.e. a measure of the changes in shear stress vectors over the cardiac cycle), EC activation and denudation, followed by neutrophil cell and platelet activation, are followed by NET and platelet-rich thrombus formation, resulting in plaque erosion, the second most common cause of acute coronary syndromes. (B) Toll-like receptor 2 ligation (e.g. through hyaluronan fragments) induces EC activation and intracellular reactive oxygen species synthesis, promoting type-IV collagenase activation (e.g. matrix metalloproteinase-2 or 14), endothelial desquamation, and EC apoptosis. While matrix metalloproteinases degrade basement membrane components, neutrophil-derived myeloperoxidase produces hypochlorous acid, thereby exacerbating EC death and TF expression. In parallel, certain stimuli (e.g. transforming growth factor-β) augment the endothelial loss of squamous morphology and their apical-basal polarization, driving endothelial to mesenchymal transition and their intimal penetration. (C) The exposure of subendothelial structures to circulating platelets and neutrophils leads to NET formation, with NETs acting as scaffolds for TF and coagulation cascade activation. Neutrophil extracellular trap formation may depend on PAD4, an enzyme that catalyses arginine to citrulline conversion, thereby altering the ionic interactions between DNA and proteins within the histone structure. Finally, activated platelets aggregate via fibrin cross-linking, forming a platelet-rich (‘white’) thrombus. (D) Plaque erosion typically occurs in arteries with disturbed flow dynamics, such as bifurcation sides with a high oscillatory shear index. Eroded plaques contain abundant hyaluronic acid, proteoglycans, and glycosaminoglycans, with minimal or no lipid cores. The resultant thrombi are platelet-rich, fibrin-poor, often causing subocclusive thrombosis. EC, endothelial cell; EndoMT, endothelial-to-mesenchymal transition; MMP, matrix metalloproteinase; MPO, myeloperoxidase; NETosis, neutrophil extracellular trap formation; NETs, neutrophil extracellular traps; OSI, oscillatory shear index; oxLDL, oxidized LDL; PAD4, protein arginine deiminase 4; RBC, red blood cell; ROS, reactive oxygen species; TFG-β, transforming growth factor-β; TF, tissue factor; TLR2, Toll-like receptor 2

Figure 3

Not all plaques trigger acute coronary syndromes: mechanistic insights into plaque healing. Thin-cap fibroatheromas (top left) with a lipid-rich core and macrophage accumulation represent a high-risk plaque prone to rupture. Conversely, proteoglycan- and glycosaminoglycan-rich (fibrous) plaques (bottom left) may form the basis of plaque erosion. The cellular mechanisms of plaque rupture (top right) or erosion (bottom right) (‘first hit’) causing (sub-)occlusive thrombosis in the setting of impaired healing capacity (‘second hit’) are shown in Figs. 1 and 2, respectively. Healed plaques (centre) are characterized by reparative processes that follow plaque disruption by rupture or erosion. Proliferating SMC may synthesize ECM components, such as proteoglycans and type-III collagen, forming a provisional matrix. Over time, this matrix is replaced by mature type-I collagen, stabilizing the plaque, and promoting its re-endothelialization. Effective healing capacity contains the first hit, stabilizing the plaque and promoting its evolution into a layered, less thrombogenic and disruption-prone lesion. Repeated cycles of subclinical disruption and healing may lead to progressive luminal narrowing and the development of stable but stenotic lesions without acute clinical events. ECM, extracellular matrix; SMC, vascular smooth muscle cells

Figure 4

Risk factors (top), causes (centre), and sex differences (bottom) of premature acute coronary syndromes. Risk factors for premature acute coronary syndromes include smoking (tobacco, marijuana, or vaping), a family history of premature acute coronary syndromes, dyslipidaemias [high lipoprotein(a), LDL cholesterol], systemic inflammatory diseases, hypertension, and diabetes, though the latter two are intriguingly less frequently observed in young vs old patients presenting with acute coronary syndromes. Substance abuse (particularly sympathomimetic drugs such as cocaine) remain a significant risk factor for premature acute coronary syndromes, with female sex, pregnancy, and fibromuscular dysplasia enhancing the susceptibility for spontaneous coronary artery dissection (affecting 7%–35% of female acute coronary syndrome patients ≤50 years and representing the most frequent cause of acute coronary syndrome during pregnancy). Most common causes of premature acute coronary syndrome include obstructive coronary artery disease (80%–90%), myocardial infarction with non-obstructive coronary arteries (10%–20%), and spontaneous coronary artery dissection. Plaque erosion, non-obstructive coronary artery disease, spontaneous coronary artery dissection, single-vessel disease, and congenital coronary anomalies dominate in women. Young women who survived hospitalization due to acute coronary syndromes have higher all-cause mortality risk as compared to young men. CAD, coronary artery disease; FHx, family history; FMD, fibromuscular dysplasia; MACE, major adverse cardiovascular events; MINOCA, myocardial infarction with non-obstructive coronary arteries; SCAD, spontaneous coronary artery dissection; SID, systemic inflammatory disease

Figure 5

Intracoronary imaging for the detection of plaque rupture, erosion, and calcified nodules. Panel I—plaque erosion: coronary angiography (left) shows severe stenosis in the mid-left anterior descending coronary artery (arrows B, C), where plaque erosion most frequently occurs. Optical coherence tomography (right) reveals an irregularly shaped luminal surface with attached mural thrombus (dotted outline) overlying the fibrous plaque (B, C) in the absence of plaque rupture. Fibroatheromas are visible proximal (A) and distal (D) to the subocclusive thrombus near a diagonal branch (asterisk). Panel II—plaque rupture: the culprit lesion is in the left anterior descending coronary artery (arrows F, G), with optical coherence tomography identifying a disrupted fibrous cap (red arrowheads) and a notable plaque cavity (F, G). Thin-cap fibroatheromas are detected in the proximal (E) and distal (H) segments of the lesion. Panel III—calcified nodules: coronary angiography shows a lesion in the proximal part of the left anterior descending coronary artery (arrows J, K). Optical coherence tomography reveals calcific infiltration of the vessel wall, with a superficial calcific sheet (I, 11–2 o’clock) and disruption of the luminal contour with overlying red thrombus (J, red arrowheads). An irregular calcified nodule (K, white arrowhead) causes significant image attenuation, potentially mimicking a thrombus, with endothelial integrity being preserved distally (L). Reprinted from Johnson et al.