Download Pathogenesis of Aneurysms

Pathogenesis of Aneurysms
Aneurysm:
Permanent, localized dilation encompassing all three layers of blood vessel wall
50% increase in normal diameter of vessel
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Clinical Risk Factors for AAA
a. Age, Male gender, Smoking, HTN, CAD, Hyperlipidemia, COPD
b. Strongest modifiable risk factor: SMOKING!
c. AAA and Atherosclerosis
i. Strong associations between AAA and atherosclerosis, with atherosclerotic plaque often
present in aneurysm wall.
ii. Animal studies suggests AAA are caused by atherosclerosis.
iii. Associations with DM and AAA
iv. Histological differences
1. AAA – transmural process
2. Atherosclerosis – intimal process
Clinical and Basic Science Research in AAA Pathogenesis
a. AAA as a Distinct Pathologic Entity, 4 areas of research interest:
1. molecular genetics
2. inflammation and immune responses
3. proteolytic degradation of the aortic wall connective tissue
4. biomechanical wall stress
b. Problems in Aneurysm Research
i. Tissue samples from advanced disease
ii. No single, widely accepted animal model
Molecular Genetics
a. Locate and characterize genes involved in pathogenesis of disease
b. Develop means for genetic testing that may identify patients at high risk for developing disease
c. Data varies
i. AAA may be a multifactorial disease process or may be linked to loci of chromosome 4
and 19
d. Areas of study include genes that regulate matrix protein metabolism, inflammation, immune
function, and polymorphisms in protease, cytokine, and immunoregulatory genes.
Inflammation and Immune Responses
a. AAA
i. Inflammatory infiltrate of T-cells, B-cells, dendritics cells, plasma cells, and
macrophages located throughout all layers of the vessel wall (intima, media and
adventitia)
b. Atherosclerotic aorta
i. T-cells and macrophages in intima and media
c. Recruitment of the Inflammatory Cell Infiltrate
i. Elastin degradation product hypothesis – elastin in aorta breaks down, releases epitopes
that generate inflammatory reaction
ii. Autoimmune hypothesis – IgG and plasma cells recruited, hypothesize autoimmune
process
iii. Infectious etiology – Chlamydia pneumoniae
d. Cytokines and AAA
i. Proinflammatory cytokines – TNF , IL-6, IL-1, IFN-
e. Smooth Muscle Cell Depletion
i. Decreased medial smooth muscle density
f. Role of Prostaglandins
i. Increased Cox-2  increased PGE2 levels
ii. PGE2 – alters matrix metalloproteinase (MMP), cytokine expression, and smooth muscle
viability.
g. Oxidative Stress
i. Reactive oxygen species – NO synthase and heme oxygenase
Protease Production
i. Destroys extracellular matrix
Proteolytic Degradation of Aortic Wall Connective Tissue
a. Collagen
i. Tensile strength, present in media and adventitia, type I and III
ii. Increased collagen metabolism
b. Elastin
i. Viscous and elastic properties
ii. Made and secreted as tropoelastin, then crosslinked into insoluble fibers on a scaffold of
microfibrillar proteins forming the medial lamellae.
iii. Resistant to proteolytic degradation
iv. Fragmentation of medial lamellae and decreased concentrations of elastin
v. Increased stiffness in aneurysmal aortic wall
c. Proteolytic enzymes
i. Matrix metalloproteinases (MMP)
1. produced by aortic endothelial cells, smooth muscles cells and adventitial
fibroblasts and by inflammatory cells such as macrophages
2. secreted as proenzyme form, then activated
3. Dysregulation of MMP activity of malignancy and rheumatoid arthritis
ii. Matrix Metalloproteinase-9/Gelatinase B
1. Degrades elastin and partially hydrolyzed collagen
2. Increased amounts of MMP-9 to areas surrounding infiltrating macrophages in
aortic wall.
iii. Matrix Metalloproteinase-2/Gelatinase A
1. degrades elastin and also intact fibrillar collagen
2. requires other MMPs to be activated
3. Increased amounts, however some amounts are present in normal aortic walls
iv. Matrix Metalloproteinase 12/Macrophage elastase
1. In knockout mice, it has not been shown to be absolutely required for AAA
formation
v. Cystatin C – inhibitor of cysteine proteases
1. reduced in AAA tissue
Biomechanical Wall Stress
a. Unique Conditions in the Infrarenal Aorta
i. Predisposition to aneurysm formation
1. disturbed flow patterns
2. elastin-collagen ratio decreases distally  aorta more stiff
3. absence of vasa vasorum in diseased aorta and thrombus impair O 2 delivery
b. Aortic Wall Stress
i. Law of Laplace – Wall tension  Radius x Pressure
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