patoloji-ders-notlari

Title

Serdar Balcı

Pathology of Atherosclerosis

Serdar BALCI, MD

Arteriosclerosis

Hardening of the arteries
Arteriolosclerosis
- Affects small arteries and arterioles
- Ischemic injury
- Hyaline and hyperplastic arteriolosclerosis → hypertension
Mönckeberg medial sclerosis
- Presence of calcific deposits in muscular arteries
- Older than 50
- Do not affect lumen, usually are not clinically significant
Atherosclerosis

Atherosclerosis

Intimal atheromas (atherosclerotic, atheromatous plaques)

Lipid core, necrotic debris, fibrous cap

Obstruct lumen

Prone to rupture

Thrombosis

Emboli

Aneurysm

Robbins Basic Pathology

Familial Hypercholesterolemia

Postmenopausal woman

Robbins Basic Pathology

Immune complex

Irradiation

Robbins Basic Pathology

Vascular injury

Endothelial cell loss or dysfunction

Stimulates smooth muscle cell growth and associated matrix synthesis

Migration of smooth muscle cells or smooth muscle cell precursor cells into the intima.

These cells proliferate, and synthesize ECM similar to fibroblasts fill in a wound

Form a neointima, covered by an intact endothelial cell layer

Neointimal response occurs with any form of vascular damage or dysfunction
Infection
Inflammation
Immune injury
Physical trauma
- Balloon catheter, hypertension
Toxic exposure
- Oxidized lipids, cigarette smoke

Robbins Basic Pathology

Neointimal smooth muscle cells

Do not have capacity to contract like medial smooth muscle cells
Have capacity to divide
Have a considerably greater synthetic capacity
A subset is derived from circulating precursor cells
Migratory, proliferative, and synthetic activities of the intimal smooth muscle cells are regulated by
- growth factors and cytokines produced by platelets, endothelial cells, macrophages, activated coagulation and complement factors

After endothelial layer is restored

No more muscle proliferation

Thickened neointima stays

Recurrent injury, recurrent thickening

Robbins Basic Pathology

Accumulation of lipoproteins (mainly oxidized LDL and cholesterol crystals) in the vessel wall

Platelet adhesion

Monocyte adhesion to the endothelium, migration into the intima

Differentiation into macrophages and foam cells

Smooth muscle from media or circulating precursors

Robbins Basic Pathology

Lipid accumulation within macrophages

Release inflammatory cytokines

Smooth muscle cell recruitment from activated platelets, macrophages, and vascular wall cells

Smooth muscle cell proliferation and ECM production

Robbins Basic Pathology

Hemodynamic Disturbances

Plaques occur in turbulent blood flow areas
- At ostia of exiting vessels
- At branch points
- Along the posterior wall of the abdominal aorta
Nonturbulent laminar flow induce endothelial genes to protect against atherosclerosis

Lipids

Increased LDL cholesterol levels

Decreased HDL cholesterol levels

Increased levels of lipoprotein(a)

Hypercholesterolemia

The dominant lipids in plaques are cholesterol and cholesterol esters
Homozygous familial hypercholesterolemia
- Defective LDL receptors
- Inadequate hepatic LDL uptake
- Myocardial infarction by age 20
Diabetes mellitus, hypothyroidism
- Cause hypercholesterolemia
- Premature atherosclerosis
Correlation between the severity of atherosclerosis and the levels of total plasma cholesterol or LDL
Lowering serum cholesterol by diet or drugs
- Slows the rate of progression of atherosclerosis
- Regression of some plaques
- Reduces the risk of cardiovascular events.

Chronic hyperlipidemia hypercholesterolemia

Directly impair endothelial cell function
- Increasing local oxygen free radical production
- Oxygen free radicals accelerate NO decay, decrease vasodilator activity
Lipoproteins accumulate within the intima
- Oxidized LDL and cholesterol crystals
Oxidized LDL
- Stimulates the local release of growth factors, cytokines, and chemokines
- Increase monocyte recruitment
- Cytotoxic to endothelial cells and smooth muscle cells

Inflammation

Normal vessels do not bind inflammatory cells
In atherogenesis, dysfunctional endothelial cells express vascular cell adhesion molecule-1 (VCAM-1)
- Binds monocytes and T cells
- Migrate into the intima under the influence of locally produced chemokines
Monocytes differentiate into macrophages and engulf lipoproteins
Activated macrophages produce toxic oxygen species
- LDL oxidation, secrete growth factors, stimulate smooth muscle cell proliferation
T lymphocytes
- Inflammatory cytokines (IFN-γ)
- Stimulate macrophages, endothelial cells, and smooth muscle cells
Activated leukocytes and vascular wall cells release growth factors
- Promote smooth muscle cell proliferation and matrix synthesis

Fatty streaks

Appear in the aortas of infants <1 year
Present in virtually all children > 10 years
- Regardless of genetic, clinical, or dietary risk factors
The relationship of fatty streaks to atherosclerotic plaques is uncertain
Fatty streaks may evolve into plaques, not all progress

Robbins Basic Pathology

Atherosclerotic Plaque

Intimal thickening and lipid accumulation

White to yellow raised lesions

Range from 0.3-1.5 cm, coalesce to form larger masses

Thrombus may superimpose, red-brown color

Patchy, involve a portion of arterial wall, eccentric

Most extensively involved vessels
- Infrarenal abdominal aorta
- Coronary arteries
- Popliteal arteries
- Internal carotid arteries
- Circle of Willis
In the same patient more severe in the abdominal aorta than in the thoracic aorta
Vessels of the upper extremities, mesenteric and renal arteries usually are spared, except at their ostia
**Severity of atherosclerosis in one artery does not predict its severity in another. **
Cells
- Smooth muscle cells, macrophages, and T cells
Extracellular matrix
- Collagen, elastic fibers, and proteoglycans
Intracellular and extracellular lipid
Progressively enlarge
- Cell death and degeneration
- Synthesis and degradation of ECM (remodeling)
- Thrombus organization
- Often undergo calcification

Robbins Basic Pathology

Atherosclerotic plaque in the coronary artery. fibrous cap and a central necrotic (largely lipid) core

Lumen narrowed

Robbins Basic Pathology

internal and external elastic membranes are attenuated

media of the artery is thinned under the most advanced plaque

Robbins Basic Pathology

junction of the fibrous cap and core

inflammatory cells, calcification neovascularization

Robbins Basic Pathology

Occlusion of smaller vessels
- Affect tissue perfusion
Plaque rupture
- Expose atherosclerotic debris
- Acute vascular thrombosis
- Distal embolization
Destruction of the underlying vessel wall
- Aneurysm, secondary rupture, thrombosis

Clinical complications of atherosclerosis

Rupture, ulceration, erosion

Hemorrhage into plaque

Atheroembolism

Aneurysm formation

Robbins Basic Pathology

Atherosclerotic Stenosis

At early stages
- Remodeling of the media preserve the luminal diameter by increasing the vessel circumference
Later atheroma prevents blood flow
- Critical stenosis tissue ischemia
Coronary artery 70% fixed occlusion
- At rest perfusion is adequate
- Exertion demand, chest pain develops because of cardiac ischemia (stable angina)
Bowel ischemia
Sudden cardiac death
Chronic IHD
Ischemic encephalopathy
Intermittent claudication (ischemic leg pain)

Acute Plaque Change

**Plaque erosion or rupture **

Thrombosis

Partial or complete vascular obstruction

Tissue infarction

Plaque changes:

Rupture/fissuring, exposing highly thrombogenic plaque constituents

Erosion/ulceration, exposing the thrombogenic subendothelial basement membrane to blood

Hemorrhage into the atheroma, expanding its volume

Robbins Basic Pathology

Vulnerable plaques

Large numbers of foam cells

Abundant extracellular lipid

Few smooth muscle cells

Clusters of inflammatory cells

Robbins Basic Pathology

ANEURYSMS

Robbins Basic Pathology

True aneurysm, saccular type

Wall bulges outward and may be attenuated but is otherwise intact.

Robbins Basic Pathology

True aneurysm, fusiform type.

There is circumferential dilation of the vessel.

Robbins Basic Pathology

False aneurysm

Wall is ruptured, creating a collection of blood (hematoma) bounded externally by adherent extravascular tissues

Robbins Basic Pathology

Dissection. Blood has entered the wall of the vessel and separated (dissected) the layers.

Robbins Basic Pathology

Aneurysms

Defective elastin and collagen synthesis
- Mutations in TGF-β
- Regulates smooth muscle cell proliferation and matrix synthesis
Marfan syndrome
- Defective synthesis of scaffolding protein fibrillin
- Abnormal sequestration of TGF-β in the aortic wall
- Dilation due to dysregulated signaling
- Progressive loss of elastic tissue
Type IV Ehlers-Danlos syndrome
- Defective type III collagen synthesis with aneurysm formation
Excessive connective tissue degradation
- MMP and/or TIMP polymorphisms

Cystic medial degeneration

Loss of smooth muscle cells
Or change in the smooth muscle cell synthetic phenotype
- Atherosclerosis cause ischemia in the media
- Hypertension cause luminal narrowing of vasa vasorum
- Smooth muscle loss, elastic loss in media
- Cystic medial degeneration

Robbins Basic Pathology

Causes of Aneurysms

Hypertension and Marfan in ascending aortic aneurysms

Atherosclerosis in abdominal aortic aneurysms

Trauma

Vasculitis

Congenital defects

Infections

Mycotic aneurysms

Embolization of a septic embolus, usually as a complication of infective endocarditis
Extension of an adjacent suppurative process
Direct infection of an arterial wall by circulating organisms
Tertiary syphilis is a rare cause of aortic aneurysms
- Obliterative endarteritis __ in vasovasorum__
- Ischemic injury
- Aneurysmal dilation

Abdominal Aortic Aneurysm

Typically occur between the renal arteries and the aortic bifurcation

Saccular or fusiform

Up to 15 cm in diameter and 25 cm in length

Robbins Basic Pathology

Aortic Dissection

Blood divides apart the laminar planes of the media

Form a blood-filled channel within the aortic wall

Robbins Basic Pathology

B: Histologic preparation showing the dissection and intramural hematoma (asterisk). Aortic elastic layers are black and blood is red in this section, stained with the Movat stain

Robbins Basic Pathology

Cardiac tamponade

Rupture into pleural, peritoneal cavity

Compress coronary arteries

Re-enter aorta, covered with endothelium

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