# Pathophysiology of Atherosclerosis and Acute Coronary Syndromes

## Overview

Coronary artery disease is the leading indication for cardiac surgery. Understanding the full continuum — from endothelial dysfunction to plaque formation, rupture, and the clinical syndromes that follow — is essential for surgical decision-making, including determining which patients benefit most from CABG versus percutaneous intervention.

## Atherosclerosis: Pathogenesis

### Endothelial Dysfunction — The Initiating Event

Under normal conditions, the vascular endothelium produces nitric oxide, prostacyclin, and tissue plasminogen activator, all of which serve antithrombotic, vasodilatory, and anti-inflammatory functions. Endothelial dysfunction is triggered by hypertension, hyperlipidemia, diabetes, smoking, and turbulent flow at arterial branch points. Once dysfunctional, the endothelium becomes permeable to lipoproteins, expresses adhesion molecules (VCAM-1, ICAM-1), and loses its vasodilatory capacity. The disease process preferentially begins at coronary artery bifurcations and the outer walls of branches, where disturbed flow and low shear stress prevail.

### Fatty Streak Formation

Oxidized LDL (oxLDL) crosses the dysfunctional endothelium into the subendothelial space. Monocytes adhere to adhesion molecules on the activated endothelium and migrate into the intima, where they differentiate into macrophages. These macrophages engulf oxLDL via scavenger receptors (SR-A, CD36), becoming foam cells. The accumulation of foam cells forms the fatty streak — the earliest visible lesion of atherosclerosis. At this stage, the process is still reversible with risk factor modification.

### Fibrous Plaque Development

Smooth muscle cells migrate from the media to the intima in response to growth factors (PDGF, TGF-beta) and begin synthesizing collagen, elastin, and proteoglycans. This forms a fibrous cap over the underlying lipid core. The mature plaque thus has two components: a collagen-rich fibrous cap providing structural integrity, and a necrotic lipid core composed of dead macrophages, cholesterol crystals, and cellular debris. Progressive plaque growth causes luminal narrowing, with angina typically developing when stenosis exceeds 70% (or 50% for the left main).

### Plaque Remodeling

An important concept is the Glagov phenomenon, or positive (outward) remodeling: the artery dilates to accommodate early plaque growth, maintaining lumen diameter. This means angiography can significantly underestimate total disease burden. Later, negative (inward) remodeling occurs, and the lumen narrows. Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) reveal the true plaque burden that angiography alone misses.

## Vulnerable Plaque Biology

### Features of the Vulnerable (Unstable) Plaque

Certain plaque characteristics predict a high risk of acute events. Vulnerable plaques have a thin fibrous cap (less than 65 micrometers), a large lipid-rich necrotic core (greater than 40% of plaque area), and active inflammation with macrophage infiltration and T-lymphocytes. Matrix metalloproteinases (MMPs) secreted by macrophages degrade the collagen in the fibrous cap. There is reduced smooth muscle cell content (fewer cells maintaining the cap), neovascularization from vasa vasorum (creating risk of intraplaque hemorrhage), and microcalcifications (spotty calcification on CT, which is distinct from the dense calcification seen in stable plaques).

### Stable vs. Vulnerable Plaque Features

| Feature | Stable Plaque | Vulnerable Plaque |
|---------|--------------|-------------------|
| Fibrous cap | Thick, collagen-rich | Thin (< 65 μm) |
| Lipid core | Small | Large (> 40% of plaque area) |
| Inflammation | Minimal | Active macrophage and T-cell infiltration |
| Smooth muscle cells | Abundant | Reduced |
| Calcification | Dense, sheet-like | Spotty microcalcifications |
| Neovascularization | Absent/minimal | Present (vasa vasorum) |
| MMP activity | Low | High (degrades fibrous cap) |
| Clinical behavior | Chronic stable angina | Acute coronary syndromes |

### Plaque Rupture vs. Plaque Erosion

Most acute coronary syndromes arise from one of two mechanisms. Plaque rupture accounts for 60–70% of cases and involves fracture of the fibrous cap, exposing the thrombogenic necrotic core to flowing blood and triggering thrombus formation. Plaque erosion accounts for 25–30% and involves endothelial denudation without actual cap rupture, with thrombus forming on the exposed intima. Erosion is more common in younger patients, women, and smokers. A third, rare mechanism (less than 5%) is the calcified nodule, where a protruding calcified mass disrupts the endothelium.

## Acute Coronary Syndromes

### Spectrum of ACS

The clinical presentation depends on the degree and duration of coronary occlusion. Unstable angina involves plaque disruption with a non-occlusive thrombus and no myocardial necrosis (negative troponins). NSTEMI involves a non-occlusive or transiently occlusive thrombus with myocardial necrosis (elevated troponins, no persistent ST elevation). STEMI involves a fully occlusive thrombus causing transmural ischemia (ST elevation on ECG, requiring emergent reperfusion).

### Comparison of ACS Subtypes

| Feature | Unstable Angina | NSTEMI | STEMI |
|---------|----------------|--------|-------|
| Thrombus | Non-occlusive | Non-occlusive or transiently occlusive | Fully occlusive |
| Troponin | Negative | Elevated | Elevated |
| ECG | ST depression, T-wave changes, or normal | ST depression, T-wave changes | Persistent ST elevation |
| Myocardial necrosis | No | Yes (subendocardial) | Yes (transmural) |
| Reperfusion urgency | Medical management | Early invasive strategy | Emergent (< 90 min PCI or < 12 hr lysis) |

### Thrombosis Cascade After Plaque Disruption

The sequence begins with platelet adhesion to exposed collagen and von Willebrand factor. Platelets then activate, releasing ADP and thromboxane A2 while undergoing conformational change in GP IIb/IIIa receptors. Fibrinogen cross-links activated platelets via GP IIb/IIIa, forming platelet aggregates. Tissue factor exposure activates the coagulation cascade. Thrombin generation converts fibrinogen to fibrin, stabilizing the thrombus. The clinical presentation ultimately depends on the balance between thrombus formation and endogenous fibrinolysis.

### Consequences of Coronary Occlusion

Subendocardial ischemia begins within seconds of occlusion. The wavefront of necrosis progresses from the subendocardium outward to the epicardium over 3 to 6 hours. This is why time is myocardium: early reperfusion (within 90 minutes for primary PCI, within 12 hours for fibrinolysis) salvages viable tissue. Reperfusion itself, however, can cause paradoxical tissue damage through calcium overload, oxidative stress, inflammation, and microvascular obstruction — a phenomenon known as reperfusion injury.

## Chronic Stable Angina

### Pathophysiology

A fixed stenosis exceeding 70% limits coronary flow reserve, which is the ratio of maximal flow to resting flow and is normally 4 to 5 times baseline. With significant stenosis, this ratio drops below 2 times, and demand ischemia occurs when myocardial oxygen demand exceeds supply during exertion. Very severe stenoses (above 90%) can produce supply ischemia, with reduced baseline flow even at rest.

### Clinical Assessment for Surgical Decision-Making

Stress testing with imaging identifies ischemic burden. Coronary angiography defines anatomy, stenosis severity, and suitability for revascularization. Fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) provide physiologic assessment of stenosis significance — FFR below 0.80 or iFR below 0.89 indicates hemodynamic significance. The FAME trials demonstrated that FFR-guided PCI improves outcomes compared to angiographic guidance alone. CT angiography offers noninvasive assessment of coronary anatomy, plaque burden, and calcification.

## Surgical vs. Percutaneous Revascularization — Patient Selection

### CABG vs. PCI: Key Comparative Factors

| Factor | Favors CABG | Favors PCI |
|--------|-------------|------------|
| Anatomy | Left main, 3-vessel disease, complex lesions | 1-2 vessel disease, simple lesions |
| SYNTAX score | > 33 (high complexity) | < 22 (low complexity) |
| Diabetes | Multivessel disease (FREEDOM trial) | Not a primary driver |
| LV function | Reduced LVEF | Preserved LVEF |
| Surgical risk | Low-moderate | High (elevated STS score, frailty) |
| Clinical setting | Elective with complex disease | Acute STEMI (primary PCI first-line) |
| Age consideration | Younger (long-term arterial graft benefit) | Older with high comorbidity burden |

### Factors Favoring CABG

CABG is generally favored for left main disease (especially with a SYNTAX score above 33), three-vessel disease (particularly with reduced LVEF), diabetes with multivessel disease (per the FREEDOM trial), complex anatomy (bifurcation disease, chronic total occlusions, heavy calcification), the need for concomitant cardiac surgery, high SYNTAX scores (above 33), and younger patients who benefit from the long-term survival advantage of arterial grafts.

### Factors Favoring PCI

PCI is generally preferred for single- or two-vessel disease without left main involvement, low SYNTAX scores (below 22), high surgical risk (based on STS score or frailty), and acute STEMI (where primary PCI is first-line for reperfusion). Patient preference with informed shared decision-making also plays an important role.

<image>Cross-sectional progression of an atherosclerotic plaque in four stages: (1) normal artery with intact endothelium; (2) fatty streak with foam cells and lipid deposits in the intima; (3) stable fibrous plaque with a thick fibrous cap, small lipid core, and smooth muscle cells; (4) vulnerable plaque with a thin fibrous cap, large necrotic lipid core, inflammatory cell infiltration, and neovascularization. Each stage is clearly labeled with key cellular and molecular features.</image>

<image>Illustration showing the two mechanisms of acute coronary syndrome: plaque rupture versus plaque erosion. The left panel shows plaque rupture with a fractured fibrous cap and thrombus forming on the exposed lipid core. The right panel shows plaque erosion with an intact fibrous cap but denuded endothelium with thrombus formation on the exposed intimal surface. Platelet aggregation and fibrin mesh are shown in both panels.</image>

<image>Flowchart diagram showing the spectrum of acute coronary syndromes from plaque disruption to clinical presentation: plaque disruption leads to thrombus formation, which can be non-occlusive (unstable angina/NSTEMI pathway with no ST elevation and either negative or positive troponins) or occlusive (STEMI pathway with ST elevation and positive troponins). The corresponding ECG patterns and coronary angiography findings are shown for each pathway.</image>

## Clinical Pearls

Atherosclerosis is an inflammatory disease, not simply a lipid storage disease — understanding this drives modern medical therapy including statins and anti-inflammatory agents. The Glagov phenomenon means angiography underestimates plaque burden, and intravascular imaging reveals the true extent of disease. Most acute coronary syndromes arise from non-flow-limiting plaques (less than 70% stenosis) that rupture, which is why treating only tight stenoses does not prevent future events. Plaque erosion is increasingly recognized, especially in younger patients and women, and may respond differently to therapy than plaque rupture. In diabetic patients with multivessel disease, CABG is superior to PCI (FREEDOM trial) due to more complete revascularization and bypass graft protection against future proximal disease progression. The SYNTAX score integrates anatomic complexity and guides the heart team discussion about optimal revascularization strategy. Coronary artery disease is diffuse, and CABG grafts bypass entire segments of disease while protecting against future proximal occlusion — this is the fundamental advantage of surgical revascularization over focal PCI.

## References

- **Libby P.** The changing landscape of atherosclerosis. *Nature.* 2021;592(7855):524-533.
- **Virmani R, Kolodgie FD, Burke AP, et al.** Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. *Arterioscler Thromb Vasc Biol.* 2000;20(5):1262-1275.
- **Serruys PW, Morice MC, Kappetein AP, et al.** SYNTAX trial: PCI vs. CABG in three-vessel and left main disease. *N Engl J Med.* 2009;360(10):961-972.
- **Farkouh ME, Domanski M, Sleeper LA, et al.** FREEDOM trial: CABG vs. PCI in diabetic patients with multivessel disease. *N Engl J Med.* 2012;367(25):2375-2384.
- **Glagov S, Weisenberg E, Zarins CK, et al.** Compensatory enlargement of human atherosclerotic coronary arteries. *N Engl J Med.* 1987;316(22):1371-1375.