Atherosclerosis II Flashcards
pathogenesis: endothelial cell dysfunction
-does not require denudation, localized to intima
-enhanced by agents toxic to endothelial cells (smoking,
homocysteine, diabetes)
-increased in areas of high turbulence and pressures (bifurcations, ostia)
components of atherosclerosis
- endothelial cell dysfunction
- increased vascular permeability
- increased binding of platelets, monocytes
- accumulation of lipids
pathogenesis: increased binding of platelets, monocytes
- activation of endothelial cells
- platelets, monocytes roll and adhere as they do in inflammation
- expression of adhesion molecules by activated endothelial cells, platelets, and monocytes results in adhesion and migration (monocytes which become macrophages)
pathogenesis: accumulation of lipids
-both intracellular (early) and extracellular (late)
deposition
accumulation of lipids
- “insudation” or direct deposition due to increased
vascular permeability - finish later
pathogenesis: oxidized lipids
-The most important receptor is not the LDL receptor, but
the scavenger receptor that binds oxidized lipids.
-oxidized lipids are also chemotactic for monocytes;
they decrease macrophage motility and increase
production of inflammatory cytokines
-oxidized lipids are also thought to be toxic to
endothelial cells and smooth muscle cells
key points of serum lipids
-7% of body’s cholesterol circulates as LDL
-IDL is the immediate precursor to LDL
-(VLDL is immediate precursor to IDL)
-HDL is NOT related to VLDL/IDL/LDL – has
different apoproteins
-LDL: Apo-protein B and E
-HDL: Apo-protein AI and AII
-HDL can scavenge excess cholesterol and is
protective
increased cholesterol levels
-suppress cholesterol synthesis;
induce esterification and storage of cholesterol;
and suppresses the synthesis of LDL receptors.
how is most LDL cleared
cleared by and metabolized in the liver via cell surface receptors
pathogenesis: activation of monocytes; secretion of cytokines
migration of monocytes into intima
-begin to accumulated lipid, resulting in foam cells
-insudation of lipid (particularly oxidized lipid) may by
chemotactic for monocytes
-secrete cytokines (IL-1/TNF) and other factors which
cause migration and proliferation of smooth muscle cells
(FGF, TGF-b; PGDF from platelets)
-toxic oxygen species from macrophages may result in
further oxidation of lipid species
pathogenesis: migration and proliferation of smooth muscle cells
-respond to production of cytokines by endothelial cells,
platelets, and macrophages in intima
-migrate from media into intima
-accumulate lipid and for foam cells
-secrete extracellular matrix, including collagen
-formation of fibrous cap over necrotic lipid center
pathogenesis: aging
Fibrotic plaque becomes unstable
-“fracture” of fibrous plaque results in exposure of collagen and adhesion of platelets
-thrombosis can cause acute occlusion of medium
sized arteries (coronary arteries, cerebral vessels)
-fracture can also lead to “rupture” with embolization of cholesterol
key components of pathology of atherosclerosis
- Fibrous cap
- Necrotic lipid center
- “Shoulders” with activated cells
- Foam cells
- Migrating and proliferating smooth muscle cells
pathology: organization
- all events in intima
- endothelium is usually intact
- fibrous cap is made up of modified smooth muscle cells and dense connective tissue (collagen)
- smooth muscle cells act as modified fibroblast like cells which proliferate and secrete ECM
- combination of fibrosis and calicification results in raised, white to yellow lesions
lipid accumulating in organization
both intracellularly and extracellularly
-yellow centers with lipid and necrotic debris are
described as “gumatous” (like gruel)
-BOTH macrophages and smooth muscle cells take up
oxidized LDL to form foam cells
-Necrotic center consists of foam cells, lipid, and debris
-Cholesterol deposition may result in formation of
cholesterol crystals
what do “shoulders” represent in atherosclerosis
collections of activated macrophages, lymphocytes, and proliferating smooth muscle cells
-smooth muscle cells migrate from media into intima and
proliferate
-activated smooth muscle cells secrete cytokines which
result in smooth muscle migration/proliferation
-endothelial cell proliferation results in ANGIOGENESIS
(similar to granulation tissue)
fatty streak evolution
-earliest lesions thought to begin as fatty streaks
-fatty streaks are not raised lesions, but do contain
foam cells; they do not contain migrating and
proliferating smooth muscle cells
-fatty streaks contain variable amount of
proteoglycans, extracellular lipid, and T cells
-once thought to appear in adolescence, can now
be seen in toddlers
with age, lesions progress with
-increasing amounts of lipid deposition
-increasing macrophage activation
-increased smooth muscle cell migration/proliferation
-resulting in a raised lesion with an intact endothelium and
fibrous cap
what does further progression result in
degenerative changes:
-progressive calcification
-fissuring of the endothelium, resulting in platelet
deposition and thrombus formation
-rupture of the plaque with embolization of the
lipid contents
what does progression lead to?
eccentric narrowing of the lumen
decreased blood flow leads to
end organ ischemia
decreased blood flow in diabetes
associated with development of gangrene of the extremities
-intermittent ischemia of the lower extremities is called claudication and is characterized by cramping of the muscle which are not getting enough oxygen (particularly with exertion)
decreased blood flow in renal circulation
-salt and water retention via the renin-angiotension
how can progression lead to angina
compromised of coronary circulation results in exertion ischemia and angina (not MI)
