Atherogenesis & Atherosclerosis

Question 1

Atherogenesis

Answer 1

formation of atheromatous (focal thickenings) in the arterial intima

Question 2

Response to injury hypothesis

Answer 2

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).

Question 3

Atherosclerosis

Answer 3

Multifaceted, progressive, inflammatory disease - affects large and medium-sized arteries
accumulation of lipids + fibrous stuff

Question 4

NO - function in atherogenesis

Answer 4

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

Question 5

Non-modifiable risk factors for atherogenesis

Answer 5

Age
Gender: pre-menopausal women protectec
Race: much less prevalent in CA, SA, Africa and Asia
F Hx

Question 6

Modifiable risk factors for atherogenesis

Answer 6

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)

Question 7

Hypercholesteremia pathophysiology (atherogenesis)

Answer 7

increase local production of reactive O species
accelerate the decay of NO, increases local shear stress
LDL can accumulate in subendothelial space more readily

Question 8

HTN pathophysiology (atherogenesis)

Answer 8

Endothelial dysfunction

Question 9

Smoking pathophysiology (atherogenesis)

Answer 9

endothelial dysfunction
vasoconstriction
harm reduced immediately after smoking

Question 10

Age pathophysiology (atherogenesis)

Answer 10

accumulation of damage

Question 11

Gender pathophysiology (atherogenesis)

Answer 11

protective effects of estrogen
effect lost if diabetic
men: 
- lack of estrogen
- lower HDL-C
- increased visceral fat
- higher rates of smoking

Question 12

Family Hx pathophysiology (atherogenesis)

Answer 12

onset of vascular disease symptoms or events in 1st degree relatives before age 60

• LDL/HDL
• HTN/DM
• elevated LpA

Question 13

Diet pathophysiology (atherogenesis)

Answer 13

trans/sat fats and high cholesterol –> endothelial damage and plaque development
caloric excess
higher levels of fruits and vegetables –> reduced CAD

Question 14

Exercise pathophysiology (atherogenesis)

Answer 14

BP, LDL, lipids, T1DM, improved heart function

Question 15

Dyslipidemia

Answer 15

elevated LDL and reduced HDL-C

Question 16

elevated LDL pathophysiology (atherogenesis)

Answer 16

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

Question 17

HDL-C

Answer 17

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

Question 18

Genetic factors in dyslipidemia

Answer 18

total > 4.5 mmol/L, triglycerides > 3, HDL < 0.7 are likely due to genetic factors

Question 19

Diabetes pathophysiology (atherogenesis)

Answer 19

2-4x higher risk of MI

thought to be due to dyslipidemia

Question 20

Visceral fat pathophysiology (atherogenesis)

Answer 20

releases more inflammatory factors than sc fat

Question 21

Physical signs of inherited dyslipidemia

Answer 21

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

Question 22

Framingham Risk Score

Answer 22

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