Atherosclerosis Flashcards
What is the definition of atherosclerosis?
chronic inflammatory disease of the tunica intima of medium and large arteries causing narrowing due to buildup of lipid followed by fibrosis
What is an atheroma?
earlier stage of atherosclerosis with buildup of lipid and lipid-laden macrophages in the tunica intima
What is vulnerable plaque?
atherosclerotic plaque with a large, loose atheromatous core and a thin fibrous cap–prone to rupture and occlusive superimposed thrombosis
What is the most common cause of death in the US?
atherosclerotic cardiovascular disease
Where does atherosclerosis occur?
medium (muscular arteries)–coronary and cerebral
large elastic arteries (aorta)
*favors branchpoints!
What are the 5 steps in the pathogenesis of atherosclerosis?
1) Malfunction of injured endothelial cells
2) Accumulation of lipid in tunica intima
3) Leukocyte recruitment into tunica intima
4) Foam cell formation
5) ECM deposition
What are the two most important causes of endothelial dysfunction?
1) Hemodynamic disturbances (places with turbulent flow)
2) Hypercholesterolemia (increase local oxygen free radical production–> decrease NO and dampens vasodilation)
What are the major effects of endothelial injury?
Decreased vasodilation (ex. NO and prostaglandins), increased release of inflammatory cytokines (ex. IL-1 and TNF-alpha) and decreased release of antithrombotic substances
When gets deposited into the tunica intima after endothelial injury?
LDL gets trapped by binding to ECM, is oxidized, glycated, and processed by macrophages and endothelial cells
What 2 things does oxidized LDL promote?
1) leukocyte recruitment
2) foam cell formation
What enzyme is produced by inflammatory cells, travels with circulating low-density lipoprotein (LDL), and hydrolyzes oxidized phospholipids in LDL?
Lipoprotein-associated phospholipase A2 (Lp-PLA2)
Lp-PLA2 increases the expression of what on the surface of endothelial cells?
MCP-1 (monocyte chemoattractant protein-1), ICAM-1 and VCAM-1
What other 2 effects does Lp-PLA2 have on endothelial cells? On macrophages?
Endothelial cells: vasodilate less in response to nitric oxide and undergo apoptosis.
Macrophages: upregulate MCP-1, secrete IL-1beta and apoptose.
What does the expression of VCAM-1 promote?
leukocyte adhesion
Recruitment of leukocytes to the tunica intima is dependent on what chemicals?
MCP-1, Interferon-inducible protein 10, and IL-8
What other than leukocytes is recruited to the tunica intima?
smooth muscle cells
What mediates the recruitment of SM cells to the tunica media?
PDGF, TNF-alpha, TGF-beta, and IL-1
What is a foam cell?
macrophages overstuffed with oxidized LDL
How do foam cells form?
monocytes are transformed to macrophages and phagocytose oxidized LDL through “scavenger receptors” that lack feedback mechanisms (so cell gets overstuffed!)
What chemicals are responsible for stimulating SM production of the ECM?
IL-1, TNF-alpha, TGF-beta, and FGF
What are the 5 Major Modifiable Risk factors for Athlersclerosis?
SHODDY
Smoking, Hypertension, Obesity, Diabetes, Dyslipidemia
What is the earliest (and reversible) form of lipid deposits int he tunica intima?
fatty streaks
What is a .3-1.5 cm raised yellow-white fibrofatty lesion composed of a soft lipid core (atheroma) covered by a fibrous cap?
atheromatous plaque
What is the structure composed of collagen, proliferating SM cells, macrophages, and lymphocytes?
fibrous cap
When do you see neovascularization in atherosclerosis?
it is a later feature
Describe neovascularization.
in-growth of capillaries from the vasa vasorum in the outer layer (adventitia) through the media and into the intima due to increased demand for oxygen and nutrients as the atherosclerosis presents the intima from getting proper nutrients from the lumen
What commonly can occur to the blood vessels made during neovascularizaiton?
they can rupture, causing intraplaque hemorrhage and rapidly increase the degree of arterial stenosis
What 3 factors predispose to thrombosis?
endothelial injury
hypercoagulability
abnormal blood flow (stasis and turbulence)
When is stasis a problem?
in veins and in arteries with aneurysms
Thrombosis due to plaque rupture (superimposed thrombosis) is likely to have what result?
100% occlusion of an artery and a transmural myocardial infarction
What are the 3 types of arteriosclerosis?
Arteriolosclerosis
Monckeberg medial sclerosis
Atherosclerosis
What are the 2 types of arteriolosclerosis?
hyaline or hyperplastic
What are causes of hyperplastic arteriolosclerosis?
Severe (malignant) hypertension
Autoimmune diseases, especially scleroderma and lupus
What are causes of hyaline arteriolosclerosis?
(“benign”) Hypertension
Diabetes mellitus
What are causes of Fibrinoid necrosis?
Severe (malignant) hypertension Autoimmune vasculitis (especially polyarteritis nodosa)
What is typically the first things to occur in metabolic syndrome?
obesity (followed by the diabetes, hyperlipidemia, and HTN)
What drug is being created as a mAb of IL-1 that may hinder the first step in atherosclerosis?
canakinumab
What are the 3 main components of an atherosclerotic plaque?
background eosinophilic (proteinaceous) debris
cholesterol clefts
foam cells
Cholesterol crystals contribute to the development of atherosclerosis by activating the inflammasome in macrophages that specifically results in the production of what?
caspace-1, which cleaves precursor forms of the inflammatory cytokine IL-1-beta into its biologically active form
Cholesterol crystals contribute to development of atherosclerosis in the same way that what other disease process works?
urate crystals of gout cause inflammation and injury in the same manner
How does the connection between cholesterol crystals and urate crystals influence treatment possiblilities for coronary artery disease?
low-dose colchicine has been shown to improve CRP, independent of aspirin and atorvastatin in stable coronary disease
What drug is being tested as a selective small molecule inhibitor of Lp-PLA2? What effects has it been shown to have?
Darapladib
lowers IL-6 and CRP levels
List the major causes of superficial erosion of coronary atheromata?
1) Apoptosis leads to desquamation (increased by oxidative stress and Hypochlorous acid produced from leukocytes)
2) Release of TF (which is procoagulant)
3) Modified LDL–> MMP-14–>MMP-2 that degrades type IV collagen
People taking statins have what characteristics to their plaques?
1) more fibrous character (that should confer resistance to rupture)
2) reduced lipid content
3) decreased macrophage activity (inflammation) in plaque
In patients with coronary artery disease, cerebrovascular disease or peripheral vascular disease, taking what drug every day produces a 25% reduction in the risk of cardiovascular death, myocardial infarction or stroke? Why?
Aspirin! Irriversible anti-platelet (to prevent thrombosis) and anti-inflammatory (because atherosclerosis is an inflammatory condition)
List the 4 determinants of plaque vulnerability.
(A) thinness of the fibrous cap
(B) size of the lipid (“necrotic”) core
(C) amount of inflammation
(D) amount of calcification
Up to 75% of events due to atherosclerosis are due to what?
plaque rupture
Up to 25% of events due to atherosclerosis are due to what?
plaque erosion (more frequently in women)
What is the result of T cells secreting interferon gamma in plaques?
strongly inhibits the ability of smooth-muscle cells to make the new collagen required to repair and maintain the integrity of the fibrous cap (see reduced levels of collagen mRNA if in high levels)
What is responsible for breaking down the collagen in atherosclerotic plaques? How?
macrophages overproduce all three human MMP interstitial collagenases - MMP-1, MMP-8, and MMP-13 that have the ability to break down collagen
Do T cells have any involvement in the breakdown of collagen in plaques?
YES! the T-cell–derived cytokine CD40 ligand (CD154) boosts the production of interstitial collagenase by human macrophages
What is LM?
left, main coronary artery
What is LAD?
left ascending coronary artery
What is LCX?
left circumflex
Branches of the LAD are called what?
diagonals and they are numbered: D1, D2, D3, etc.
Branches of the LCX are called what?
obtuse marginals and they are numbered: OM1, OM2, etc.
What is RCA?
right coronary artery
How many acute coronary disease events are in the LAD?
around 1/2
How many acute coronary disease events are in the LCX?
around 1/6
How many acute coronary disease events are in the RCA?
around 1/3
Why might methotrexate be helpful in preventing
atherosclerotic cardiovascular events?
Cell proliferation of fibroblasts, smooth muscle
cells, endothelial cells and lymphocytes plays
a role in atherosclerosis. Methotrexate is anti-inflammatory and prevents cell prolieration.
What is most likely to cause a STEMI in a young person with no history of atherosclerosis?
Coronary vasospasm due to stimulant abuse (cocaine, amphetamines)
When is thrombosis due to increased coagulant state more likely arterial than venous?
with lupus anticoagulant!
When is the risk when you undergo coronary angioplasty and stenting?
Atheroembolization. (Rare in coronary arteries, but not so rare in leg, renal or intestinal arteries with atheroemboli from the aorta).
Atheroembolism is commonly associated with what feature?
eosinophilia!!
