Atherosclerosis

Question 1

Atherosclerosis is a subset of _____

Answer 1

. Atherosclerosis is a subset of arteriosclerosis

Question 2

Atherosclerosis

Answer 2

Atherosclerosis is hardening of arterial walls due to deposition of lipid and necrosis in the vessel wall

Question 3

arteriolosclerosis

Answer 3

hardening of small arteries and arterioles

Usually the result of hypertension and/or diabetes

Question 4

Muscular artery layers

Answer 4

Question 5

Cartoon of an advanced atherosclerotic lesion

Answer 5

Question 6

Getting from a normal muscular artery to an advanced atherosclerotic plaque takes ___.

Answer 6

Getting from a normal muscular artery to an advanced atherosclerotic plaque takes decades

Question 7

Advanced atherlsclerotic lesion H and E

Answer 7

Question 8

Atherosclerosis is a ___ in the arterial wall.

Answer 8

Atherosclerosis is a chronic inflammatory response in the arterial wall.

Question 9

Plaque rupture

Answer 9

Question 10

Plaque rupture is followed almost immediately by ____.

Answer 10

Plaque rupture is followed almost immediately by thrombosis.

The tissue exposed by the rupture is highly thrombogenic. This thrombus typically sits within the narrowed lumen of a turbulent vessel, and is then very prone to subsequent embolism or infarction.

Question 11

aneurysms

Answer 11

Extensively dilated vessel that may press up against other tissues or be prone to rupture.

Often the result of thrombosis, embolism, or extensive arteriosclerosis.

Question 12

____ disease is the leading global cause of death

Answer 12

Cardiovascular disease is the leading global cause of death

Question 13

Risk factors for atherosclerosis

Answer 13

• Age
• Genetics
• Family history
• Hypercholesterolemia (particularly LDL)
• Hypertension
• Smoking
• Diabetes
• Circulating C reactive protein
• Obesity

Question 14

Atherosclerosis occurs as a response to ___.

Answer 14

Atherosclerosis occurs as a response to endothelial injury.

Question 15

Fatty streak H and E

Answer 15

Question 16

____ is the earliest visible manifestation of atherosclerosis. It is found in many children and young adults.

Answer 16

Fatty streak is the earliest visible manifestation of atherosclerosis. It is found in many children and young adults.

Question 17

Fatty streaks are made up mostly of _____.

Answer 17

Fatty streaks are made up mostly of foam cells underneath the endothelium.

Question 18

xanthoma

Answer 18

Subcutaneous collection of foam cells visibile on gross surface anatomy

Question 19

PCSK9 Diagram

Answer 19

Question 20

PCSK9

Answer 20

Circulating protein that binds LDL receptor and targets the receptor (along with any bound LDL) for degradation in the lysosome.

Question 21

PCSK9 Gain of Function

Answer 21

Results in autosomal dominant hypercholesterolemia

Associated with low levels of LDL receptor and high levels of circulating LDL

Question 22

PCSK9 inhibitors

Answer 22

Emerging therapeutic which may be taken on top of statins and ezetimibe (which decreases dietary cholesterol absorption). Currently the only available treatments are mAbs, but small molecules and RNAi are down the road.

Question 23

While LDL circulates systemically, lesion development is ___.

Answer 23

While LDL circulates systemically, lesion development is not uniform, even within a single artery

Question 24

Regions of _____ are more prone to development of atherosclerotic lesions

Answer 24

Regions of non-laminar (turbulent) flow are more prone to development of atherosclerotic lesions

A consequence of this is that vascular branch points are particularly targets for atherosclerosis.

Question 25

oil red O stain

Answer 25

Turns lipids red. Used to highlight atherosclerosis in gross anatomy.

Question 26

Turbulent flow correlates with changes in endothelial gene expression that favor \_\_\_\_. This demonstrates the role of the endothelium as a \_\_\_\_.

Answer 26

Turbulent flow correlates with changes in endothelial gene expression that favor **inflammation**. This demonstrates the role of the endothelium as a **mechanosensor**. Some of these pro-inflammatory genes include **eNOS, VCAM-1 and cytokines (TNF, IL-1)**.

Question 27

Answer 27

Question 28

Early events in atherosclerotic plaque formation

Answer 28

Question 29

oxLDL is sensed by macrophages as \_\_\_.

Answer 29

oxLDL is sensed by macrophages as **a DAMP**.

Question 30

As smooth muscle cells are activated to move into the tunica media and surround a plaque, they change their gene expression to become \_\_\_\_.

Answer 30

As smooth muscle cells are activated to move into the tunica media and surround a plaque, they change their gene expression to become **more fibroblast-like, and start to create a fibrous capsule**.

Question 31

Where do cholesterol crystals in plaques come from?

Answer 31

Eventually, the cholesteryl ester droplets will kill foam cells by apoptosis. This results in expunging of the cholesteryl esters where they crystallize due their presence in concentrations approaching the K_sp of cholesterol.

Question 32

mature atherosclerotic plaque

Answer 32

Much stiffer/firmer than younger plaques due to **fibrosis,** **dystrophic calcification, and cholesterol crystals**.

Question 33

9 Steps of Atherosclerosis

Answer 33

1. Endothelial injury 2. Accumulation and retention of LDL in the intima 3. Oxidation of LDL to oxLDL 4. Activation of endothelium and tissue resident macrophages by oxLDL 5. Chronic inflammatory cells infiltrate area (thrombosis may also occur here) 6. Macrophages take up oxLDL via scavenger receptors, forming foam cells 7. Foam cells and macrophages produce inflammatory mediators, initiating smooth myocyte migration, proliferation, and differentiation. End result is fibrosis. 8. Foam cells undergo apoptosis, producing necrotic core, dystrophic calcification, and cholesterol crystals 9. Ongoing process of chronic inflammation and repetition of steps 5 to 8.

Question 34

stable atherosclerotic plaque

Answer 34

Atherosclerotic plaque with a **thick fibrous cap** that provides structure and stability. **Little necrosis and inflammation**. **Low risk of rupture**.

Question 35

Unstable atherosclerotic plaque

Answer 35

As lesion grows, hypoxia sets in, resulting in **wearing away of fibrous coat**. Core becomes more complex, more discrete pockets of necrosis, significant inflammation. **High risk of rupture**.

Question 36

Complex atherosclerotic plaque

Answer 36

Unstable plaque which contains calcification, hemorrhage, fissues, ulcerations, or frank rupture

Question 37

Atherosclerosis as an inflammatory disease

Answer 37

Question 38

How active chronic inflammation promotes plaque rupture

Answer 38

Question 39

Treatment options for atherosclerosis

Answer 39

LDL lowering treatments (mAbs, statins, ezetimibe, diet) Anti-inflammatories (COX-2 inhibitors, statins in context of disease)

Question 40

Answer 40

Cholesterol crystals on H and E

Question 41

Answer 41

Adipose tissue-resident macrophages

Question 42

"A sea of inflammatory cells and ghosts of adipocytes"

Answer 42

Liquefactive necrosis

Question 43

Liquefactive necrosis is ultimately caused by. . .

Answer 43

. . . excessive and persistent release of neutrophil digestive enzymes.

Question 44

Claudication

Answer 44

Foot pain while walking/exerting, often progressive. Caused by early lactic acid buildup due to hypoxia, and often due to atherosclerosis of the lower extremity.

Question 45

Carotid bruits

Answer 45

Swishing sound observed in the internal carotid artery, just superior to the branch point with the external carotid and common carotid. Indicative of turbulent flow due to atherosclerosis of the internal carotid junction.

Question 46

"Complicated" plaques

Answer 46

May be stable or unstable, term just refers to having discrete zones

Question 47

KLF-2

Answer 47

TF upregulated by endothelial cells in response to sensing laminar flow. Suppresses VCAM-1 expression in the presence of IL-1 and TNF. May be protective for atheroslcerosis.