ATHEROSCLEROSIS - Pathology Notes (Robbins) - 10 Marks

DEFINITION

EPIDEMIOLOGY

• Sites most affected (in decreasing order): Abdominal aorta > coronary arteries > popliteal arteries > descending thoracic aorta > internal carotid arteries > Circle of Willis vessels
• Causes: Ischemic heart disease (MI), stroke, aortic aneurysm, peripheral vascular disease
• Death rate in Eastern Europe is 3-5x higher than the USA; Africa, India, Southeast Asia rates now exceed the USA

RISK FACTORS

FLOW CHART: Risk Factors

RISK FACTORS FOR ATHEROSCLEROSIS
│
├── NON-MODIFIABLE (Constitutional)
│   ├── Genetics / Family history (most important independent RF)
│   ├── Age (incidence of MI increases 5x between ages 40-60)
│   ├── Male sex (premenopausal females relatively protected by estrogen)
│   └── Clonal hematopoiesis (CHIP - pro-inflammatory monocytes)
│
└── MODIFIABLE
    ├── MAJOR
    │   ├── Hyperlipidemia (↑LDL, ↓HDL, ↑Lp[a]) ← most important
    │   ├── Hypertension
    │   ├── Cigarette smoking
    │   └── Diabetes mellitus
    │
    └── ADDITIONAL / EMERGING
        ├── Inflammation (↑CRP, IL-6)
        ├── Hyperhomocysteinemia
        ├── ↑Plasminogen activator inhibitor-1
        ├── Lipoprotein(a) [Lp(a)]
        ├── Obesity
        └── Physical inactivity

• ↑LDL cholesterol = most important modifiable RF
• ↓HDL = independent risk factor (HDL promotes cholesterol efflux/reverse transport)
• LDL-lowering with statins reduces risk of MI by ~30%
• Oxidized LDL is far more atherogenic than native LDL

PATHOGENESIS

FLOW CHART: Pathogenesis of Atherosclerosis

ENDOTHELIAL INJURY / DYSFUNCTION
(Hyperlipidemia, HTN, Smoking, Hemodynamic turbulence, Toxins)
        │
        ▼
ENDOTHELIAL DYSFUNCTION
• ↑Permeability to lipoproteins
• ↑Leukocyte adhesion molecule expression (VCAM-1, ICAM-1)
• Pro-thrombotic state
• ↓Nitric oxide (vasodilatory, anti-inflammatory)
        │
        ├──────────────────────────────────────────┐
        ▼                                          ▼
LDL ACCUMULATION IN INTIMA             MONOCYTE ADHESION & MIGRATION
• LDL oxidized by free radicals        into intima
• Oxidized LDL is cytotoxic to ECs     ↓
• Triggers further inflammation        MACROPHAGES (via M-CSF)
        │                              + FOAM CELLS
        └────────────────┬─────────────┘
                         ▼
              FATTY STREAK FORMATION
        (earliest lesion - yellow intimal discoloration)
        Foam cells = macrophages + SMCs engorged with lipid
                         │
                         ▼
              PLATELET ADHESION
        (exposed subendothelial collagen)
                         │
                         ▼
        RELEASE OF GROWTH FACTORS & CYTOKINES
        (PDGF from platelets, macrophages, ECs)
        (FGF, TGF-α, TNF, IL-1, MCP-1)
                         │
                         ▼
        SMC RECRUITMENT (from media → intima)
        SMC PROLIFERATION + ECM SYNTHESIS
        (collagen, proteoglycans → FIBROUS CAP)
                         │
                         ▼
        ADVANCED ATHEROSCLEROTIC PLAQUE
        • Fibrous cap (collagen, SMCs, macrophages)
        • Necrotic/lipid core (foam cell debris,
          cholesterol crystals, calcium)
        • Shoulder region (most inflammatory)

MORPHOLOGY

Gross Appearance

• Flat or slightly raised yellow intimal streak or spot
• Composed of foam cells (lipid-laden macrophages + SMCs)
• Reversible - can appear in aorta of infants/children (harmless at this stage)
• Precursor to atherosclerotic plaques

• Yellow-white raised intimal lesion, 0.3-1.5 cm diameter
• May coalesce → larger plaques
• Eccentric distribution (not circumferential)
• Patchy, irregular distribution throughout the vessel

Components of a Mature Plaque (Microscopic)

LUMEN
    │
    ▼
┌─────────────────────────────────┐
│        FIBROUS CAP              │
│  • SMCs, macrophages, foam      │
│    cells, T lymphocytes         │
│  • Collagen, elastin,           │
│    proteoglycans                │
│  • Neovascularization           │
│  SHOULDER (most vulnerable      │
│   to rupture - most inflamed)   │
├─────────────────────────────────┤
│       NECROTIC/LIPID CORE       │
│  • Cell debris                  │
│  • Cholesterol crystals         │
│  • Foam cells                   │
│  • Calcium deposits             │
│  • Intraplaque hemorrhage       │
│    (rupture of vasa vasorum)    │
└─────────────────────────────────┘
    │
MEDIA (compressed, may atrophy)
    │
ADVENTITIA

Fig. 8.5B - Robbins & Kumar Basic Pathology: Fibrous cap (containing SMCs, macrophages, foam cells, lymphocytes, collagen, elastin, proteoglycans, neovascularization) overlying a Necrotic center (cell debris, cholesterol crystals, foam cells, calcium). Shoulder areas are the sites most prone to rupture.

PATHOGENESIS DIAGRAM (Robbins Classic)

Robbins Fig. 8.8 - Step-by-step progression: (1) Chronic endothelial injury from hyperlipidemia, HTN, smoking, hemodynamic factors → (2) Endothelial dysfunction with monocyte adhesion and platelet adhesion → (3) Macrophage activation, SMC recruitment, lipid accumulation (Fatty streak) → (4) Macrophages and SMCs engulf lipid (Fibrofatty atheroma) → (5) SMC proliferation, collagen/ECM deposition, extracellular lipid accumulation → Advanced plaque with foam cells, lipid debris, collagen

STABLE VS. VULNERABLE PLAQUE

Robbins Fig. 8.14 - Stable plaques: thick fibrous cap, small lipid core, minimal inflammation. Vulnerable plaques: thin fibrous cap, large lipid core, marked inflammation - prone to rupture.

CONSEQUENCES / COMPLICATIONS

FLOW CHART: Complications of Atherosclerosis

ATHEROSCLEROTIC PLAQUE
        │
        ├──── GRADUAL STENOSIS (>70% occlusion)
        │     → Chronic ischemia
        │     → Stable angina
        │     → Intermittent claudication
        │     → Mesenteric ischemia
        │
        ├──── ACUTE PLAQUE CHANGE (rupture/erosion)
        │         │
        │    THREE TYPES:
        │    1. Rupture/Fissuring → exposed thrombogenic core
        │                         → THROMBOSIS (occlusive)
        │                         → MYOCARDIAL INFARCTION
        │                         → ISCHEMIC STROKE
        │                         → SUDDEN CARDIAC DEATH
        │    2. Erosion/Ulceration → exposed subendothelial
        │                           basement membrane
        │                           → partial thrombosis
        │    3. Intraplaque Hemorrhage → rupture of vasa vasorum
        │                               → rapid plaque expansion
        │
        ├──── ATHEROEMBOLISM
        │     • Plaque debris → microemboli downstream
        │     • Can cause renal failure, bowel ischemia
        │
        └──── ANEURYSM FORMATION
              • Plaque ischemia of media
              • SMC loss + ECM degradation in media
              • Weakens wall → dilatation
              → Abdominal Aortic Aneurysm (AAA) most common
              → Risk of rupture → hemorrhage → death

LESION SEQUENCE (AHA Classification)

TYPE I - Initial lesion
(isolated macrophage foam cells)
        ↓
TYPE II - Fatty streak
(multiple foam cell layers; visible yellow streaks)
[REVERSIBLE STAGE]
        ↓
TYPE III - Intermediate lesion
(foam cells + small extracellular lipid pools)
        ↓
TYPE IV - Atheroma
(large lipid core = "gruel"; endothelium intact)
        ↓
TYPE V - Fibroatheroma
(lipid core + fibrous cap = classic plaque)
[MOST CLINICALLY SIGNIFICANT]
        ↓
TYPE VI - Complicated lesion
(surface defect, hematoma, hemorrhage, thrombosis)
[CAUSES ACUTE EVENTS - MI, STROKE]

KEY MOLECULES SUMMARY TABLE

IMPORTANT EXAM POINTS (10-Mark Answer Tips)

1. Definition: Chronic inflammatory disease of large/medium arteries - always mention "response to injury hypothesis"
2. Fatty streak = earliest lesion - foam cells - reversible
3. Plaque components: Fibrous cap (collagen, SMCs) + Necrotic core (lipid, calcium, debris)
4. Vulnerable plaque = thin cap + large lipid core + marked inflammation = rupture → ACS
5. Sites: Abdominal aorta > coronary > popliteal arteries
6. Complications: Stenosis, thrombosis (MI, stroke), aneurysm, atheroembolism
7. Role of oxidized LDL as central pathogenic molecule
8. Foam cells = macrophages + SMCs engorged with oxidized LDL via scavenger receptors

REFERENCES

• Robbins & Kumar Basic Pathology, 11th ed. - Chapter 8 (Vascular Diseases), pp. 316-324
• Robbins, Cotran & Kumar Pathologic Basis of Disease, 10th ed. - Chapter 11 (Blood Vessels), pp. 466-478