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Blood Vessels and Lymphatics - Atherosclerosis & Aneurysms

2nd MBBS Pathology | Exam-Oriented Notes (Robbins / Harsh Mohan Level)

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PART 1: ATHEROSCLEROSIS

Definition

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Risk Factors (TABLE - Frequently Asked in Exams)

Exam Tip: "Increasing age, male sex, family history, hyperlipidemia, hypertension, cigarette smoking, and diabetes mellitus are the major risk factors." Risk factors have greater than additive (multiplicative) effects on each other.

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PATHOGENESIS - Response to Injury Hypothesis (Ross, 1993)

• Caused by: hypercholesterolemia, hypertension, cigarette smoke toxins, hemodynamic disturbances (turbulent flow at bifurcations), homocysteine, infections
• Results in: increased permeability, enhanced leukocyte adhesion, altered gene expression
• Laminar (non-turbulent) flow is atheroprotective (upregulates KLF-2 transcription factor)
• Turbulent, non-laminar flow at vessel bifurcations and ostia is atheroprone (explains why plaques form at these sites)

• LDL enters the vessel wall through dysfunctional endothelium
• LDL is oxidized by reactive oxygen species (ox-LDL)
• Ox-LDL is chemotactic for monocytes and stimulates monocyte adhesion molecules (VCAM-1)

• Monocytes adhere to endothelium (via VCAM-1, ICAM-1) and migrate into intima
• Differentiate into macrophages under influence of M-CSF
• Macrophages phagocytose ox-LDL via scavenger receptors (SR-A, CD36) - NOT the normal LDL receptor
• Lipid-laden macrophages = FOAM CELLS (earliest recognizable lesion = fatty streak)

• Cholesterol crystals activate NLRP3 inflammasome in macrophages
• Inflammasome cleaves pro-IL-1β → active IL-1 (key proinflammatory cytokine)
• T lymphocytes recruited → produce IFN-γ → further activates macrophages and SMCs
• Macrophages produce reactive oxygen species (enhance LDL oxidation), growth factors, cytokines

• Growth factors (PDGF from platelets/macrophages, FGF, TGF-α) recruit SMCs from media into intima
• SMCs proliferate and synthesize collagen, elastin, proteoglycans (ECM)
• SMCs also take up lipid → additional foam cells
• This converts a fatty streak → fibrous/fibrofatty plaque (mature atheroma)

• Continued ECM deposition forms the fibrous cap
• Central necrotic core develops from dead foam cells + extracellular lipid
• Late: calcification occurs
• Neovascularization within the plaque (from adventitia) - a source of intraplaque hemorrhage

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MORPHOLOGY (Gross + Microscopy - Very Frequently Asked)

Gross (Macroscopic) Appearances:

• Flat, yellow intimal streaks
• Composed of lipid-laden macrophages (foam cells) and SMCs
• Present even in aortas of infants and children
• Not all fatty streaks progress to plaques

• Location: Intima of large elastic arteries (aorta, carotid, iliac) and medium muscular arteries (coronary, popliteal)
• Predilection sites: aortic bifurcation, coronary ostia, carotid bifurcation, circle of Willis
• Gross appearance: White-yellow raised lesion, protruding into vessel lumen
• Usually eccentric (involving only part of the vessel circumference)
• On cut section: soft yellow-grey lipid core with overlying white-grey fibrous cap
• Advanced plaques show: calcification (gritty, chalky texture), surface ulceration, superimposed thrombus, intraplaque hemorrhage

Microscopy (Histology):

Exam Tip (Cholesterol Clefts): On H&E, cholesterol crystals appear as needle-shaped empty clefts (spaces) because the lipid is dissolved during tissue processing.

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Stable vs. Vulnerable (Unstable) Plaques

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Pathology / Complications of Atherosclerosis (MOST IMPORTANT FOR EXAM)

COMPLICATIONS MNEMONIC: "RACE TO DEAD"
R - Rupture/Ulceration → thrombosis
A - Aneurysm formation
C - Calcification (dystrophic)
E - Embolism (cholesterol/thrombus)
T - Thrombosis (superimposed)
O - Obstruction (luminal stenosis)
D - Dilation (vessel wall weakening)
E - Erosion (endothelial)
A - Acute ischemia (critical stenosis)
D - Downstream ischemia

• Disruption of fibrous cap → exposes thrombogenic lipid core and subendothelial collagen
• Triggers platelet aggregation + thrombus formation
• Causes: Acute Myocardial Infarction, Unstable Angina, Sudden Cardiac Death
• Vulnerable plaques (thin cap + large lipid core) are paradoxically more dangerous than stable, heavily calcified plaques

• Gradual lumen narrowing → stable chronic ischemia
• Critical stenosis: >70-75% cross-sectional area reduction
• Glagov phenomenon: Outward remodeling compensates early, maintaining lumen size; eventually fails

• Superimposed on ruptured/ulcerated plaque
• Can totally occlude the vessel (MI) or embolize distally

• Cholesterol crystal emboli from ulcerated plaque
• "Atheroembolism" or "blue toe syndrome"

• Ischemia of medial SMCs (increased diffusion distance from lumen through thickened intima)
• Loss of elastic fibers → wall weakening
• Abdominal aortic aneurysm (AAA) is the classic example

• Coronary arteries → Myocardial infarction, ischemic cardiomyopathy
• Cerebral arteries → Stroke, TIA, vascular dementia
• Renal arteries → Renovascular hypertension, renal failure
• Mesenteric arteries → Mesenteric ischemia
• Peripheral arteries → Intermittent claudication, gangrene

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PART 2: ATHEROSCLEROTIC PLAQUE - Risk Factors & Morphology

(Covered in full above; summary for quick revision below)

ATHEROMATOUS PLAQUE (Cross-section)

         LUMEN
    _______________
   |   FIBROUS CAP  |  ← SMCs + Collagen + Foam cells + Lymphocytes
   |_______________|
   | NECROTIC CORE |  ← Lipid + Cholesterol clefts + Foam cells + Calcium
   |  (soft gruel) |
   |_______________|
        MEDIA       ← Thinned, atrophic smooth muscle

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PART 3: ANEURYSMS

Definition

Classification

A. By Wall Structure:

B. By Macroscopic Shape:

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Causes of Aneurysms

• Increased MMP (especially from macrophages) degrades elastin and collagen
• Decreased TIMP expression
• Th2 cytokines (IL-4, IL-13) drive elastolytic MMP production in AAA
• Result: loss of elastic fibers → loss of wall recoil → progressive dilation

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PART 4: ABDOMINAL AORTIC ANEURYSM (AAA)

Key Facts (High Yield)

• Most common aortic aneurysm
• Atherosclerosis is the major etiologic factor
• Most common in males > 50 years who smoke
• Rarely develops before age 50
• Incidence <5% in males >60 years despite near-universal abdominal aortic atherosclerosis (other factors clearly contribute)

Gross Features (Morphology) - Frequently Asked

• Location: Below the renal arteries (infrarenal aorta) and above the aortic bifurcation - between renal arteries and the bifurcation
• Can extend to involve iliac arteries
• Shape: Saccular or fusiform
• Size: Usually >3 cm; often >5.5 cm (surgical threshold); up to 25 cm in length
• Severe complicated atherosclerosis at the base
• Destruction and thinning of the underlying aortic media
• Contains a laminated mural thrombus (bland, poorly organized) - layered appearance
• Can occlude renal or mesenteric artery ostia by thrombus extension

Three AAA Variants:

1. Inflammatory AAA (~5% of cases): Dense perianeurysmal and retroperitoneal fibrosis; sheets of lymphocytes and plasma cells; may be related to IgG4-related disease
2. Mycotic (Infective) AAA: Infected from bacteremia/adjacent sepsis
3. Aortoiliac Occlusive Disease (Leriche Syndrome): Atherosclerotic occlusion at aortic bifurcation; triad of claudication + impotence + absent femoral pulses

Complications of AAA:

• Rupture - most feared complication; retroperitoneal hemorrhage, can be fatal
  • Risk of rupture ↑ sharply when diameter >5.5 cm
• Obstruction of branch vessels (renal, mesenteric, vertebral arteries)
• Embolism from mural thrombus → lower limb ischemia
• Impingement on adjacent structures (vertebrae - erosion, duodenum, ureters)
• Aorto-duodenal/aorto-venous fistula

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PART 5: ATHEROSCLEROSIS OF AORTA - Gross, Microscopy, Pathogenesis

Sites of Predilection in Aorta:

• Posterior abdominal aorta (most severely affected) - due to non-laminar flow
• Abdominal aorta > thoracic aorta (in severity)
• Ostia of exiting branch vessels
• Aortic bifurcation

Gross Appearance (Sequence of Lesions):

1. Fatty streaks - flat, yellow, lipid streaks in intima (aorta most common site in young)
2. Fibrous plaques - raised, pearly white/grey nodular lesions protruding into lumen; firm consistency
3. Complicated plaques:
   • Surface ulceration (crater-like defects)
   • Calcification (dystrophic, "eggshell" or "pipestem" appearance)
   • Superimposed thrombus (grey-red, layered)
   • Intraplaque hemorrhage (dark red areas within plaque from rupture of neovessels)
   • Atheroembolism (yellow cholesterol crystals/fragments in downstream vessels)

Microscopy:

• Intima: Foam cells, cholesterol clefts (empty needle-shaped spaces), fibrosis, calcification, necrotic debris, inflammatory infiltrate (lymphocytes, macrophages)
• Fibrous cap: Dense collagen (stains blue on Masson trichrome), SMCs, scattered foam cells
• Media: Thinned, attenuated; SMC loss; elastic fibers disrupted (Weigert elastic stain shows fragmentation)
• Adventitia: Thickened, may show lymphoplasmacytic infiltrate, thickened vasa vasorum

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QUICK REVISION SUMMARY TABLE

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Sources: Robbins, Cotran & Kumar Pathologic Basis of Disease (10th ed.), Chapter 11 - Blood Vessels; Robbins & Kumar Basic Pathology (11th ed.) - aligned with Harsh Mohan Textbook of Pathology exam content for 2nd MBBS.