What is the pathophysiology of plaque in patients with acute coronary syndrome (ACS)?

Pathophysiology of Plaque in Acute Coronary Syndrome

Acute coronary syndromes result from atherosclerotic plaque disruption (rupture or erosion) with superimposed thrombosis, vasoconstriction, and distal microembolization that reduces myocardial oxygen supply. 1

The Vulnerable Plaque: Structural Characteristics

The plaques most prone to causing ACS have distinct structural features that make them unstable 1:

• Large lipid-rich core with high concentrations of cholesteryl esters containing polyunsaturated fatty acids 1
• Thin fibrous cap (typically <65 micrometers) with disorganized collagen matrix 1
• Low smooth muscle cell density within the cap structure 1
• High macrophage density concentrated at the cap, particularly at the shoulder regions 1

A critical clinical pitfall: Three-quarters of infarct-related thrombi develop over plaques causing only mild to moderate stenosis on angiography, not necessarily severe stenoses. 1 This explains why patients with "non-critical" lesions can still experience acute MI.

Mechanisms of Plaque Disruption

Plaque disruption occurs through two primary mechanisms 1:

Active Rupture

• Macrophages secrete metalloproteinases that actively dissolve collagen, weakening the fibrous cap 1
• The lipid core forms through active collagen dissolution by these enzymes, not just passive lipid accumulation 1
• Inflammation plays the central role in this process, with elevated inflammatory markers (C-reactive protein, interleukin-6) correlating with clinical outcomes 1

Passive Disruption

• Physical forces concentrate at the weakest point of the fibrous cap, typically at the junction between the plaque and adjacent "normal" wall 1
• Circumferential wall stress, combined with the location, size, and composition of the lipid core, determines vulnerability 1

The Thrombotic Cascade

Once plaque disruption occurs, a dynamic thrombotic process unfolds 1:

1. Exposure of thrombogenic material: Plaque contents (tissue factor, von Willebrand factor, collagen) contact circulating blood 1
2. Coagulation cascade activation: This triggers rapid thrombus formation 1
3. Platelet adhesion and aggregation: Platelets initiate mural thrombus formation 1
4. Fibrin stabilization: Fibrin stabilizes the early, fragile platelet thrombus 1

The thrombotic response is dynamic: Thrombosis and spontaneous clot lysis occur simultaneously, often with associated vasospasm, causing intermittent flow obstruction. 1 This explains why 25-30% of patients undergoing primary PCI have a patent infarct-related artery on initial angiography. 1

Distal Microembolization

Platelet aggregates and plaque debris fragment and migrate downstream, occluding arterioles and capillaries even without epicardial artery occlusion. 1 This microembolization causes:

• Small areas of myocardial necrosis 1
• Troponin elevation without complete epicardial vessel occlusion 1
• Minimal myocardial damage that may not be visible on standard imaging 1

Clinical Spectrum Based on Pathophysiology

The degree of thrombosis and vessel occlusion determines the clinical presentation 1:

• Unstable angina: Transient ischemia from non-occlusive thrombus without myonecrosis (no troponin elevation) 1
• NSTEMI: Partially occlusive thrombus causing subendocardial ischemia with troponin elevation 1
• STEMI: Complete occlusive thrombus causing transmural ischemia progressing from subendocardium to subepicardium over 15-30 minutes (the "wave-front phenomenon") 1

Temporal Dynamics and Triggers

There is frequently a delay of up to 2 weeks between plaque rupture and clinical consequences. 1 This reflects the dynamic nature of thrombosis and lysis occurring at the plaque site.

Specific triggers for plaque disruption include 1:

• Circadian variation: Higher incidence in early morning hours due to β-adrenergic stimulation, increased vascular tone and blood pressure, hypercoagulability, and platelet hyper-reactivity 1
• Physical or emotional stress: Activities causing increased sympathetic stimulation and vasoconstriction 1

Alternative Mechanisms (Less Common)

While plaque rupture/erosion with thrombosis accounts for most cases, other mechanisms include 1:

• Coronary artery spasm (may occur on top of atherosclerotic plaque) 1
• Coronary embolism from cardiac or arterial sources 1
• Spontaneous coronary artery dissection 1
• Dynamic obstruction from vasoconstriction of epicardial or microvascular vessels 1

Key clinical implication: Approximately 5-10% of ACS cases occur without obstructive coronary disease on angiography, particularly in women, due to these alternative mechanisms including vasospasm, dissection, embolism, and microvascular dysfunction. 2