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2 Mechanisms of Atherosclerosis

Chronic Endothelial Injury Elevated Lipids

 Endothelium (epithelial lining of blood vessels (damaged by  Elevation of plasma LDL levels results in penetration of LDL into the arterial
various mechanisms-----smoking, hypertension, microbial wall---lipid accumulation in smooth muscle cells and local macrophages (fatty
infection drugs etc streak)
 Increased adhesion of platelets and the chemotaxis of  Plaque becomes “fibrous”
monocytes and T lymphocytes to the site of injury---migration  Oxidized LDL---chemotactic---migration of monocytes---inflammatory lesion
of smooth muscle cells---plaque formation (“fatty”) plaque  Oxidized LDL---also cytotoxic to endothelial cells; loses its ability to remove
cells loaded with lipids) cholesterol from atherosclerotic plaques
Risk Factors for CAD
Lipids Levels Hypertension Smoking Diabetes Mellitus
 Elevated levels of LDL, Lp(a)  Associated with  Increases the risk of CAD and peripheral  Hyperinsulinemia---damages
and reduced levels of HDL endothelial damage artery disease vascular endothelium
 Provides initial lesions into  Nicotine and other tobacco-derived
which inflammatory cells chemicals are toxic to vascular endothelium
infiltrate  Smoking---increases LDL, decrerases HDL
 If LDL levels are elevated, levels, raises blood carbon monoxide
fatty streak begins to (produces endothelial hypoxia), promote
form vasoconstriction, increases platelet
Obesity Homocysteine thrombus formation, and increases plasma Oxidative Stress
 Hypertriglyceridemia  Promotes vascular fibrinogen concentration  Increased production of
commonly associated with endothelial injury that  Promotes formation of peroxides reactive oxygen spp or
obesity predisposes blood vessels deficiency of antioxidant
 A diet that is high in saturated to atherosclerosis defenses---amplify the risk of
fatty acids or calories will  Formation of reactive CAD
contribute to oxygen spp w/c are then
hypertriglyceridemia able to oxidize lipids,
Exercise multiplying their Inflammation
atherogenic potential  Detected by CRP (C-reactive
 Promote thrombosis protein)
Disorders of Lipid Metabolism
Hyperlipoproteinemias: (Hyperlipidemia):
Primary of Familial HLP Secondary HLP
 No apparent underlying disease present  Caused by underlying disorder
 Related to inherited disorder
Fredrickson-Levy Classification
Elevated Chylomicrons Increased LDL/ Primary Hypercholsterolemia
(Familial Chylomicronemia or Fredrickson Type I) (Fredrickson Type II)
 Formed at the intestinal wall following a meal, cleared from the  Familial hypercholesterolemia
by the lipoprotein lipase (LPL)  2 major forms:
 Apoprotein CHI---required as cofactor for LPL
 Accumulation of chylomicrons results in extremely elevated  Homozygous (type IIa)
triglycerides---may result in xanthoma formation o Early or premature atherosclerosis
 Mild to severe pancreatitis, hepatosplenomegaly o Increase occurrence of MI before age 30
 Sera of patients w/ chylomicronemia---creamy layer forming at o Drug therapy to reduce LDL
the surface of a fasting specimen
 Elevated: triglycerides, VLDL, cholesterol  Heterozygous (thype IIb)
 Decreased HDL o Treatable w/ dietary changes
o Elevated VLDL
Increased IDL Increased VLDL
(Familial Dysbetalipoproteinemia or Fredrickson Type III) (Familial Hypertriglyceridemia or Fredrickson Type IV)
 Inherited disorder characterized by the inability to degrade  Relatively common
chylomicron remnants and IDL  Primary---autosomal recessive
 Elevated total cholesterol and triglycerides, IDL, VLDL and  Secondary disorder---may be the result of drug therapy, estrogen therapy,
chylomicrons alcoholism, GSD, obesity, DM, or hypothyroidism
 Elevated triglycerides and cholesterol, VLDL
Increased VLDL with Increased Chylomicrons Absent LDL
(Fredrickson Type V) (Abetalipoproteinemia)
 Results in markedly elevated triglycerides levels either due to  Autosomal recessive trait results in no LDLs due to a lack of apolipoproteinemia B
an impaired ability to remove the triglyceride-rich lipoproteins o Homozygous
 Familial form  No detectable triglycerides, phospholipids and apoB; low total cholesterol,
 Associated with increased apoC-III which inhibits lipoprotein HDL
lipase o Heterozygotes
 Symptoms over age of 20: xanthomas, episodic bouts of  Appear normal, low LDL levels
abdominal pain w/ or w/o pancreatitis  Cannot absorb fats and accumulate large lipid-filled vacuoles in the intestinal
 Elevated: Chylomicrons, VLDL mucosal cells that block the absorption of the essential fat soluble vitamins
 LPE (lipoprotein electrphoresis)---heavy chylomicron and pre-  Result in failure to thrive in infancy, progressive degeneration of nervous system,
beta bands are the prominent features loss of night vision
 Lack of Vit. K---prolonged prothrombin time
 Unabsorbed fats---metabolized by microbial intestinal organisms---produce
steatorrhea, foul-smelling, soft stools
 Peripheral blood smears---50-70% of erythrocytes w/ spiny projections
Decreased HDL
Tangier Disease
 Low levels of HDL; very high triglycerides  Complete absence of HDL; low levels of Apo A1 and ApoAII
 Obesity, diet, excessive alcohol consumption, lack of  Cholesterol esters ten to accumulate in various tissues (liver, spleen, lymph
exercise---reduced HDL levels nodes, cornea, skin)
 Heterozygotes---reduced HDL; do not accumulate the cholesterol esters in
 Major problem---increased risk of atherosclerosis
 Low LDL and total cholesterol levels; normal to slight Hypertriglyceridemia
Lipid Lysosomal Abnormalities Gaucher’s Disease
 Manifest in early childhood  Most common LSD
 Abnormal accumulation of the intermediate substrates of the  Caused by deficiency of beta-glucocerebrosidase---accumulation of
lipid pathways (toxic to the cells) glucocerebroside
 Psychomotor deterioration and developmental retardation o Type 1 (chronic, nonneuropathic)
 Accumulates in REC (liver, spleen)---hepatosplenomegaly and  more common
lipid-laden cells in bone marrow, CNS  occurs primarily in adults
o LAMP-1 (lysosome-associated membrane protein)  normocytic or hypochromic anemia w/ thrombocytopenia, leucopenia,
 Increased in plasma in 70% of individual with lysosome bone pain, hepatosplenomegaly
storage disorder  Pigmentation of the skin, associated w/ better prognosis
o LAMP-2 o Type II (infantile neuropathic)
 Survive no more than 2 years
o Type III (juvenile neuropathic)
 May survive into adolescence
 Presence of Gaucher’s cells---lipid-laden macrophages, in the BM and elevated
serum acid phosphatase
Niemann-Pick Disease Krabb’s Disease
(Sphingomyeline Lipidosis) (Galactocerebroside Lipidosis or Globoid Cell Leukocystrophy)
 Deficiency of sphingomyelinase result in accumulation of  The result of galactocerbroside accumulation due to a deficiency of the enzyme
sphingomyelin galactocerebroside-beta-galactosidase
 Types A, B,C D  Affects the CNS and results in severe mental and motor deterioration
 Types A, C, and D  Blindness and deafness
--being more acute neuropathic disorder resulting in  Laboratory: elevated protein and the (+) of globoid cells (large multinucleated
fatal psychomotor and intellectual deterioration macrophages) in the CSF
 Splenomegaly and hepatomegaly  Fatal within 6 and 12 months of onset
 Niemann-Pick cells—macrophages loaded with sphingomyelin
o Type A
▪ Affect newborn infants
o Type C
▪ Later onset
o Type B
▪ Chronic with no neurologic involvement
Fabry’s Disease Tay-Sachs Disease
(Angiokeratoma Corporis Diffusum Universale) (Gm2 Gangliosidosis)
 Deficient α-galactosidase  Jewish ancestry
 Accumulation of ceramide trihexoside in CNS  Accumulation of Gm2 ganglioside in the neurons of CNS due to deficiency of
 Severe pain in the extremities and characteristic hexosaminidase A
angiokeratoma (reddish lesions) on buttocks and around the  Psychomotor deterioration and dementia
navel  Blindness associated with a cherry red spot in the retina
 Hypertension and heart problem---ceramide trihxoside
promotes narrowing of the arteries