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Cardiovascular > Atherosclerosis: Part 1 (Nichols) > Flashcards

Atherosclerosis: Part 1 (Nichols) Flashcards

1
Q

What is atherosclerosis and what causes it?

A

Disease of arterial intimal thickening due to lipid accumulation, chronic inflammation, and repair response.

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2
Q

What vessel types (elastic, muscular, arterioles) are involved in atherosclerosis?

A

medium (muscular) and large (elastic) arteries

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3
Q

What are constitutional risk factors?

A

Factors like age and sex

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4
Q

What are modifiable risk factors?

A

Factors like high cholesterol, hypertension, and smoking

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5
Q

What is Nichols’s mnemonic for remembering the risk factors for atherosclerosis?

A 
SHODDY
Smoking
Hypertension
Obesity
Diabetes Mellitus
DYslipidemia
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6
Q

Atherosclerosis is a disease of response to ______ cell injury.

A

endothelial

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7
Q

List the steps of pathogenic progression of atherosclerosis.

A

Malfunction of injured endothelial cells (increased vascular permeability, platelet adhesion)
Accumulation of lipid in tunica intima (oxidized LDL)
Leukocyte (monocytes, but also smooth muscle (SM) myocytes) recruitment into tunica intima
Foam cell formation (macrophages & SM myocytes)
Factor release from activated platelets, macrophages, and vascular wall cells (chemotaxis of monocytes, T cells)
Extracellular matrix deposition and myocyte proliferation

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8
Q

What are the dominant lipids in atheromatous plaques?

A

cholesterol and cholesterol esters

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9
Q

How does familial hypercholesterolemia contribute to atherosclerosis and vascular disease?

A

genetic defect in LDL receptors and inadequate hepatic LDL uptake, can accelerate atherosclerosis. Can precipitate MIs before age 20.

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10
Q

How does hypercholesterolemia directly impair endothelial function?

A

By increasing local reactive oxygen species production.
Besides causing membrane and mitochondrial damage, oxygen free radicals accelerate nitric oxide decay, dampening its vasodilator activity.

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11
Q

What do free radicals do to the lipoproteins present in the intima of blood vessels?

A

They oxidize lipoproteins in the intima and cause the lipids to accumulate and be taken up by macrophages (via scavenger receptors)

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12
Q

How do SM myocytes take up lipoproteins once in the intima?

A

LDL-receptor related proteins

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13
Q

This proinflammatory cytokine is produced when cholesterol crystals and free fatty acids accumulate in the macrophages trapped in the intima:

A

IL-1

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14
Q

IL-1, when produced during inflammasome activation, serves to recruit:

A

leukocytes, including monocytes and lymphocytes.

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15
Q

What is the net result of macrophage and T cell activation by IL-1?

A

Local production of cytokines and chemokines that recruit and activate more inflammatory cells.

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16
Q

What do activated macrophages do to enhance LDL oxidation?

A

Produce reactive oxygen species.

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17
Q

What do activated macrophages do to enhance smooth muscle cell proliferation?

A

Release of elaborate growth factors

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18
Q

What impact do leukocytes have on vascular wall pathology?

A

Release of cytokines/chemokines that attract more leukocytes and SM myocytes. Cytokines such as IFN-gamma also activate macrophages as well as endothelial cells and SM cells (proliferation of SM cells and synthesis of ECM proteins [notably collagen]).

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19
Q

Several growth factors are implicated in SM cell proliferation, including:

A

Platelet-derived growth factor (PDGF, released by locally adherant platelets, as well as macrophages, endothelial cells and SM cells), Fibroblast growth factor (FGF), and transforming growth factor-alpha (TGF-alpha)

20
Q

What is responsible for stabilizing atherosclerotic plaques?

A

collagen secreted by SM cells

21
Q

Why is uptake by the scavenger receptor of macrophages bad compared to uptake via the LDL receptor?

A

No feedback inhibition from the scavenger receptor. Macrophages will take up massive quantities of LDL, become dysfunctional foam cells, and die.

22
Q

What happens to the foam cells when they die?

A

They release the lipids back into the intima, to be taken up by active macrophages and SM myocytes.

23
Q

How does HDL counter atherosclerosis?

A

likely helps clear cholesterol from accumulations in the intima. Efflux, bruh.

24
Q

Do SM myocytes proliferate once getting into the intima?

A

You betcha. Due to presence of cytokines.

25
Q

What releases monocyte chemoattractand protein-1?

A

Macrophages feeding on LDL

26
Q

What are the three principle components of an atherosclerotic plaque?

A

1) SM cells, macrophages, T-cells
2) ECM (collagen, elastic fibers, proteoglycans)
3) lipid (intracellular & extracellular)

27
Q

What makes up the superficial fibrous cap of atherosclerotic plaques?

A

SM cells and relatively dense collagen fibers

28
Q

Normally, the intima is how many cells thick?

A

2 cells thick

29
Q

Is the atheroma considered more or less severe when teh lipid accumulates greatly extracellularly as opposed to intracellularly?

A

More severe. Foam cells are dying en masse and releasing lipids into the extracellular space, only to me taken up by more macrophages/SM cells.

30
Q

An advanced atheroma has a characteristic “_______” core.

A

Necrotic/lipid (called necrotic due do dying foam cells releasing LDL)

31
Q

What contributes to the focality of atherosclerotic lesions, since there is uniform exposure of vessel walls to such factors as cigarette smoke toxins, elevated LDL, and hyperglycemia?

A

sudden changes in vascular hemodynamics (turbulence at branch points) that make certain portions of a vessel wall more susceptible to plaque formation.

32
Q

Describe why we see neovascularization in atherosclerosis and explain a complication of neovascularization.

A

Neovascularization is the ingrowth of capillaries through the tunica adventitia and media to cells in massively thickened tunica intima demanding vasa vasorum in an artery normally not needing them because O2 and nutrients can not reach these cells by diffusion due to the thickened intima.
Complication: These abnormal, irregular small blood vessels are prone to rupture.

33
Q

Using size as a descriptor, what is the difference between the onion-skin appearance of hyperplastic arteriolosclerosis compared to that found in scleroderma?

A

Onion-skin thickening is much thicker in scleroderma.

34
Q

What are the causes of hyperplastic arteriolosclerosis?

A

Severe (malignant) hypertension

Autoimmune disease, esp. scleroderma & SLE

35
Q

You see a histological cross section of an artery. Lots of pink stuff has replaced the normal tissue. The artery’s intima is full of acellular pink stuff. What is going on?

A

Fibrinoid necrosis. Most commonly due to autoimmune vasculitis (esp. polyarteritis nodosa) and malignant hypertension.

36
Q

What does hyaline arteriolosclerosis look like in cross-section?

A

It looks like acellular dense pink fluff, almost as if it is inside the lumen of the BV. No nuclei present between it and the lumen of the BV.

37
Q

What are the two common causes of hyaline arteriolosclerosis?

A

benign hypertension

Diabetes mellitus

38
Q

What does amyloidosis look like in histological cross-section?

A

Very similar to hyaline arteriolosclerosis but you can see nuclei of the tunica intima between the pink stuff and the lumen of the BV. Also there are alternating streaks of light and dark pink. Heterogenous pinkness.

39
Q

What are the main causes of amyloidosis in the US today?

A

Chronic systemic inflammation, esp. rheumatoid arthritis. Genetic causes such as transthyretin amyloidosis (prevalent in Africans Americans).
Not commonly: multiple myeloma

40
Q

Injured endothelial cells secrete more of these and less of these things:

A

More: IL-1 and TNF-alpha BAD
Less: Superoxide dismutase (antioxidant), nitric oxide (vasodilator), prostacyclin (antithrombotic) BAD

41
Q

What is an endogenous anti-inflammatory that counters the effects of IL-1?

A

anti-interleukin-1 beta

Exogenous Ab: canakinumab (in stage 3 clinical trials currently)

42
Q

How does calcification look in an atheroma in cross-section (H&E stain)?

A

blackness

43
Q

What is worse, a thin or thick fibrous capsule around a necrotic core of an atheroma?

A

Thin is worse because it may RUPTURE (vulnerable plaque) leading to thrombus formation which may occlude the entire lumen much faster than an atheroma would.

44
Q

What appears to be more important in the pathology of atherosclerosis, IL-1 or TNF?

A

IL-1, hence why it is a good target for targeted therapy.

45
Q

Cholesterol crystals of atherosclerosis cause injury by the same mechanism as urate crystals of gout. What treatment modality used in treating gout can also be applied to treatment of atherosclerosis to mitigate inflammation?

A

Colchicine reduced coronary artery disease endpoints by 60% in a clinical trial by improving CRP levels.

46
Q

Why do foam cells get so fat?

A

Scavenger receptors have no feedback inhibition to tell them to stop eating.

47
Q

What is the single MOST important factor predisposing to death from a heart attack?

A

Endothelial cell injury

Cardiovascular (10 decks)

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