2.1 Pathophysiology & Classification of Acute Coronary Syndromes

Atherothrombotic Pathophysiology of ACS

Acute Coronary Syndrome (ACS) represents a continuous clinical spectrum ranging from unstable angina (UA) to non-ST-segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI). The unifying hallmark of ACS is sudden impairment of coronary blood flow, leading to an imbalance between myocardial oxygen supply and demand. In more than 90% of clinical cases, ACS is precipitated by acute disruption of a pre-existing atherosclerotic plaque within an epicardial coronary artery.

Atherosclerosis develops over decades as low-density lipoprotein (LDL) particles accumulate within the arterial intima, undergo oxidation, and trigger a chronic inflammatory cascade. Macrophages engulf oxidized LDL to form foam cells, establishing fatty streaks. Over time, vascular smooth muscle cells migrate into the intima, synthesizing extracellular matrix and collagen to form a protective fibrous cap over a necrotic core composed of lipids, cell debris, and cholesterol crystals. The vulnerability of a plaque to acute rupture depends less on the degree of luminal stenosis and more on plaque composition—specifically, a thin fibrous cap (<65 µm), a large necrotic core (>40% of total plaque volume), and high local concentrations of inflammatory macrophages secreting matrix metalloproteinases (MMPs) that degrade collagen.

Plaque Disruption Mechanisms: Rupture, Erosion, and Calcified Nodules

Three distinct pathological mechanisms initiate acute coronary arterial thrombosis:

1. Plaque Rupture (60-70% of ACS Cases): Mechanical degradation or physical stress breaks the thin fibrous cap of a vulnerable thin-cap fibroatheroma (TCFA). The exposure of highly thrombogenic subendothelial matrix components—specifically type I and III collagen, tissue factor, and von Willebrand factor (vWF)—to circulating arterial blood instantly triggers the coagulation cascade and platelet activation. Plaque rupture is the predominant etiology in STEMI, older adults, hyperlipidemic patients, and men.
2. Plaque Erosion (25-35% of ACS Cases): Characterized by denudation or desquamation of endothelial cells over an intact, proteoglycan- and hyaluronan-rich matrix without full fibrous cap rupture. Erosion typically lacks a large necrotic core or heavy macrophage infiltration. Thrombosis in plaque erosion is driven primarily by neutrophil extracellular traps (NETs) and hyaluronan breakdown. It occurs more frequently in younger individuals, females, smokers, and patients presenting with NSTEMI or Unstable Angina.
3. Calcified Nodules (2-5% of ACS Cases): Eruption of dense, nodular calcification breaking through the fibrous cap into the vessel lumen. This pattern is primarily observed in older patients with heavily calcified, tortuous coronary arteries and chronic kidney disease.

The Thrombotic Cascade and Platelet Dynamics

Following plaque disruption, local thrombosis proceeds through rapid, sequential phases:

• Platelet Adhesion: Circulating platelets adhere to exposed subendothelial collagen via glycoprotein (GP) Ia/IIa receptors and to von Willebrand factor via GP Ib/IX/V receptor complexes under high arterial shear stress.
• Platelet Activation & Secretion: Adherent platelets undergo dramatic shape changes, extending pseudopods and releasing intracellular storage granules containing adenosine diphosphate (ADP), serotonin, calcium, and tissue factor, while simultaneously synthesizing thromboxane A2 (TXA₂) de novo from arachidonic acid via COX-1 (TXA₂ is not stored in granules, which is why aspirin's COX-1 blockade abolishes it). Released ADP binds to platelet P2Y₁ and P2Y₁₂ purinergic receptors, establishing an autocrine and paracrine amplification loop.
• Platelet Aggregation: Conformational activation of platelet GP IIb/IIIa receptors (integrin αIIbbeta₃) allows cross-linking of adjacent platelets via circulating fibrinogen and von Willebrand factor, forming a platelet plug (the "white thrombus").
• Coagulation Cascade Activation: Exposed tissue factor activates Factor VIIa, driving the extrinsic coagulation cascade to generate thrombin (Factor IIa). Thrombin converts fibrinogen into insoluble fibrin strands, entrapping red blood cells to stabilize the clot (the "red thrombus").

Plaque Disruption (Rupture / Erosion)
  └──> Collagen & Tissue Factor Exposure
        └──> Platelet Adhesion (GP Ib/IX + vWF)
              └──> Platelet Activation (ADP & TXA2 Release)
                    └──> GP IIb/IIIa Activation & Fibrinogen Cross-linking
                          └──> Thrombin Generation & Fibrin Meshwork Formation
                                └──> Intracoronary Thrombus Occlusion

Ischemic Depth: Transmural vs. Subendocardial Ischemia

The extent of myocardial ischemia and cell death is governed by the anatomy of the ventricular wall and the duration, severity, and location of coronary vessel occlusion.

Transmural Ischemia

Transmural ischemia involves full-thickness cellular hypoxia extending from the endocardium across the myocardium to the epicardium. It is caused by acute, complete, and sustained occlusion of a major epicardial coronary artery without sufficient collateral blood flow. On the 12-lead ECG, transmural ischemia and injury express as persistent ST-segment elevation in the leads overlying the ischemic zone, reflecting an injury current directed from the endocardium toward the epicardium. Unrelieved transmural ischemia results in wave-front necrosis that spreads from the vulnerable subendocardium outward toward the epicardium, culminating in full-thickness myocardial infarction within 6 hours.

Subendocardial Ischemia

Subendocardial ischemia is confined to the inner third to half of the ventricular wall. The subendocardium is uniquely vulnerable to ischemia because it experiences the highest intramyocardial systolic wall tension, highest compressive forces during ventricular contraction, highest metabolic oxygen demand, and receives coronary perfusion exclusively during diastole. Subendocardial ischemia occurs when coronary blood flow is partially obstructed by a subocclusive thrombus, severe fixed atherosclerotic stenosis, or when systemic demand exceeds supply (e.g., severe tachycardia, profound anemia, or shock). Electrophysiologically, subendocardial injury creates a vector directed away from the epicardial recording leads, producing ST-segment depression and/or T-wave inversion.

Clinical Spectrum and Classification of ACS

ACS is classified clinically based on symptom presentation, 12-lead ECG changes, and serial cardiac biomarker assays (specifically cardiac troponin I or T).

1. Unstable Angina (UA)

Unstable angina represents an acute ischemic state without detectable myocardial necrosis. UA presents in one of three clinical patterns: (1) Rest angina (prolonged, usually >20 minutes, occurring at rest); (2) New-onset angina (marked limitation of physical activity, Canadian Cardiovascular Society Class III or IV); or (3) Crescendo angina (previously diagnosed stable angina that has become distinctly more frequent, longer in duration, or lower in threshold). ECG may demonstrate dynamic ST-segment depression or T-wave inversion during pain episodes. By definition, serum cardiac troponins remain below the 99th percentile upper reference limit (URL).

2. Non-ST-Segment Elevation Myocardial Infarction (NSTEMI)

NSTEMI shares identical clinical presentations and pathophysiological roots with Unstable Angina, but is distinguished by measurable subendocardial myocardial necrosis. A subocclusive or transiently occlusive thrombus causes localized cellular ischemia and death, releasing cardiac troponin into systemic circulation above the 99th percentile URL. ECG findings include horizontal or downsloping ST-segment depression (≥0.5 mm in contiguous leads), T-wave inversion (≥1.0 mm), or may even be non-specific/normal.

3. ST-Segment Elevation Myocardial Infarction (STEMI)

STEMI is an acute emergency resulting from sudden, complete epicardial coronary artery occlusion. It requires immediate, emergent reperfusion therapy to limit transmural myocardial necrosis. ECG criteria require new J-point ST-segment elevation in at least two anatomically contiguous leads (≥1.0 mm in all leads except V2-V3, where the threshold is sex- and age-adjusted: ≥1.5 mm in women, ≥2.0 mm in men aged 40 and older, and ≥2.5 mm in men under 40). Under the 2025 ACC/AHA/ACEP/NAEMSP/SCAI ACS guideline a new or presumed-new left bundle branch block (LBBB) is no longer a stand-alone STEMI equivalent — clinical correlation is required, and the Smith-modified Sgarbossa criteria are applied to diagnose occlusion in LBBB or ventricular-paced rhythms. Cardiac troponins are elevated, confirming transmural tissue necrosis.

4. Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA)

MINOCA is defined by criteria meeting universal myocardial infarction standards (positive cardiac troponin with ischemic symptoms or ECG changes) where diagnostic coronary angiography demonstrates no epicardial artery stenosis ≥ 50%. MINOCA accounts for 5-10% of all MI presentations and is more common in females and younger patients. Pathophysiological etiologies fall into epicardial or microvascular categories:

• Coronary Vasospasm (Prinzmetal Angina): Intense hyper-reactivity of vascular smooth muscle causing transient total vessel occlusion.
• Spontaneous Coronary Artery Dissection (SCAD): Non-iatrogenic intramural hematoma forming within the tunic media, compressing the false and true lumen. Strongly associated with peripartum status, fibromuscular dysplasia, and connective tissue disorders.
• Microvascular Dysfunction: Impaired coronary microvascular resistance restricting subendocardial flow despite normal epicardial arteries.
• Plaque Disruption without Obstructive Lesion: Plaque rupture or erosion with non-obstructive residual stenosis (<50%).

In MINOCA presentations, secondary diagnostic testing—specifically Cardiac Magnetic Resonance (CMR) imaging—is the gold standard to rule out non-ischemic mimics such as acute myocarditis, Takotsubo (stress-induced) cardiomyopathy, and occult pericarditis.

ACS Diagnostic Comparison Matrix