Atherogenesis & Atherosclerosis Flashcards
Atherogenesis
formation of atheromatous (focal thickenings) in the arterial intima
Response to injury hypothesis
o Repetitive endothelial injury Increased permeability, leukocyte adhesion and thrombosis Accumulation of LDL and oxidized products in vessel wall Migration of monocytes into Transformation of monocytes into macrophages and then foam cells
Platelet adhesion Activated platelets, macrophages, vascular wall cells release factors to recruit smooth muscle cells (SMC) SMC proliferation and extracellular matrix production Lipid accumulation both extracellularly and within cells (macrophages and SMCs).
Atherosclerosis
Multifaceted, progressive, inflammatory disease - affects large and medium-sized arteries
accumulation of lipids + fibrous stuff
NO - function in atherogenesis
endothelial NO synthase eNO: generate NO with atheroprotective characteristics
-enhances vascular relaxation, inhibition of platelet aggregation, inhibition of endothelial-dependent monocyte adhesion
Inducible NO synthase iNOS: enzyme in macrophages, produces NO with antimicrobial functions based on potent oxidative properties
- bind H2O2 or O2 radicals to produce highly reactive species
Non-modifiable risk factors for atherogenesis
Age
Gender: pre-menopausal women protectec
Race: much less prevalent in CA, SA, Africa and Asia
F Hx
Modifiable risk factors for atherogenesis
Diet
Smoking
Exercise
Alcohol
Physiological: obesity, HTN, hyperlipidemia, hyperhomocysteinemia, diabetes
Traditional: hypercholesteremia
Non-traditional: lipoprotein A, hyperhomocysteinemia, herpes, chlamydia, oxidative stress, depression (associated with platelet aggregation)
Hypercholesteremia pathophysiology (atherogenesis)
increase local production of reactive O species
accelerate the decay of NO, increases local shear stress
LDL can accumulate in subendothelial space more readily
HTN pathophysiology (atherogenesis)
Endothelial dysfunction
Smoking pathophysiology (atherogenesis)
endothelial dysfunction
vasoconstriction
harm reduced immediately after smoking
Age pathophysiology (atherogenesis)
accumulation of damage
Gender pathophysiology (atherogenesis)
protective effects of estrogen effect lost if diabetic men: - lack of estrogen - lower HDL-C - increased visceral fat - higher rates of smoking
Family Hx pathophysiology (atherogenesis)
onset of vascular disease symptoms or events in 1st degree relatives before age 60
- LDL/HDL
- HTN/DM
- elevated LpA
Diet pathophysiology (atherogenesis)
trans/sat fats and high cholesterol –> endothelial damage and plaque development
caloric excess
higher levels of fruits and vegetables –> reduced CAD
Exercise pathophysiology (atherogenesis)
BP, LDL, lipids, T1DM, improved heart function
Dyslipidemia
elevated LDL and reduced HDL-C
elevated LDL pathophysiology (atherogenesis)
Elevated LDL (+apolipoprotein B) accumulate in the artery wall and taken up as aggregated LDL/oxidized LDL by macrophages or smooth muscle cells --> foam cell formation even lower LDL levels can harm in the presence of endothelial damage
Triglycerides do not correlate as strongly, but make LDL more likely to be digested into smaller and denser particles
HDL-C
reverse cholesterol transport: ability to remove excess cholesterol delivered to arterial cells by LDL
induce relaxation of artery wall
ratio of apoB/apoA-a (HDL) - strongest modifiable predictor risk for MI
no effective therapy
Genetic factors in dyslipidemia
total > 4.5 mmol/L, triglycerides > 3, HDL < 0.7 are likely due to genetic factors
Diabetes pathophysiology (atherogenesis)
2-4x higher risk of MI
thought to be due to dyslipidemia
Visceral fat pathophysiology (atherogenesis)
releases more inflammatory factors than sc fat
Physical signs of inherited dyslipidemia
Corneal arcus: white ring overlying outer edges of iris
Xanthelasma: flat or raised yellow patches on the eyelid or just below the eyes
Planar xanthomas of the palms: orange-brown palm creases
Tendon xanthomas: thickening/nodules in Achilles tendons/extensor tendons of hands/ patellar tendons)
Eruptive xanthomas: single or bunches of reddish-yellow bumps over the back, buttocks, hands, elbows, feet
Framingham Risk Score
10 yr risk of non-fatal MI or coronary death factors: age total cholesterol smoking HDL systolic BP
risk 2x in the presence of 1st degree relative with vascular disease
