Inflammation and CAD

Question 1

what contributes to the development of atherosclerosis?

Answer 1

inflammation

Question 2

what are the big 3 modifiable risk factors for atherosclerosis?

Answer 2

hyperlipidemia, hypertension, and diabetes (all synergistic)

Question 3

What is the first stage in the development of atherosclerosis?

Answer 3

chronic endothelial injury

Question 4

what is the second stage in the development of atherosclerosis?

Answer 4

endothelial dysfunction

Question 5

what is the third stage in the development of atherosclerosis?

Answer 5

macrophage activation and smooth muscle recruitment

Question 6

what is the fourth stage in the development of atherosclerosis?

Answer 6

macrophages and smooth muscle cells engulf lipid

Question 7

what is the 5th and final stage of development of atherosclerosis?

Answer 7

smooth muscle proliferation, collagen and other extracellular matrix deposition

Question 8

what are the most common causes of chronic injury and or dysfunction of endothelium?

Answer 8

hypertension and hyperlipidemia

Question 9

where do most lesions of atherosclerosis tend to occur at?

Answer 9

openings of exiting vessels, branch points, posterior abdominal aorta

Question 10

what does chronic endothelial injury lead to?

Answer 10

an acute inflammatory response

Question 11

what occurs during the endothelial dysfunction phase (stage 2)?

Answer 11

there is increased permeability, leukocyte adhesion, monocyte adhesion, and emigration into the intima

Question 12

what are some characteristics of endothelial cells in the basal state?

Answer 12

they are non-adhesive and they have a non-thrombogenic surface

Question 13

what are some characteristics of endothelial cells in the activated state?

Answer 13

they have increased expression of procoagulants, adhesion molecules, and pro-inflammatory factors

Question 14

what molecules increase expression of P&E selectins on endothelium and ligands on leukocytes?

Answer 14

IL-1 and TNF

Question 15

what is the long term effects of IL-1 and TNF increasing the expression of P&E selectins on endothelium and ligands on leukocytes?

Answer 15

there will be changes in the hemodynamics in the microenvironment

Question 16

what do the macrophages begin secreting when they begin phagocytosing debris?

Answer 16

TNF, IL-1, and IL-6

Question 17

what effect does edema have on the tissue?

Answer 17

it brings plasma proteins into the intimate contact with the damaged area

Question 18

what are the proteins that are in the inflammatory exudate?

Answer 18

clotting proteins, complement, kinin cascade, and fibrinolytic protein

Question 19

what does the kinin cascade cause?

Answer 19

vasodilation, increase in permeability of blood vessels

Question 20

what does fibrinolytic protein cause?

Answer 20

degrades the clot when the wound has healed

Question 21

what happens once the macrophages start moving into the area that has suffered endothelial dysfunction?

Answer 21

it starts to thicken and increase the amount of cells

Question 22

what are the lipids in atheromatous plaques?

Answer 22

cholesterol and cholesterol esters

Question 23

what happens to the cholesterol and cholesterol esters that are deposited in the intima and retained there?

Answer 23

they are phagocytosed by the macrophages and then partially oxidized (aka modification)

Question 24

what is uptake?

Answer 24

when the modified LDL starts to accumulate within the macrophages and smooth muscle cells

Question 25

what does the process of retention, modification, and uptake of LDL stimulate?

Answer 25

an inflammatory response

Question 26

what are the macrophages that being to accumulate the partially oxidized LDL now known as?

Answer 26

foam cells

Question 27

foam cells collect in lesions known as what?

Answer 27

fatty streaks

Question 28

what can sense oxidized lipids?

Answer 28

scavenger receptor CD36 on monocytes or TLR-4

Question 29

what happens when monocytes recognize oxidized lipids through their scavenger receptor CD36?

Answer 29

they differentiate to M1 (classical) tissue macrophages; then produce and release acute phase cytokines, transform to foam cells

Question 30

what is the inflammasome?

Answer 30

a signaling system for detection of pathogens and stressors

Question 31

what does the recruitment and assembly of inflammasome proteins result in?

Answer 31

the production of large quantities of both IL-1 and IL-18 which are potent inflammatory cytokines

Question 32

What effect do cholesterol crystals have on neutrophils?

Answer 32

they cause the neutrophils to deploy their NETs

Question 33

what is the role of the neutrophil's NETs?

Answer 33

they provide scaffolding for platelet and RBC activation-; netosis will stimulate the macrophages to have an inflammatory response

Question 34

several growth factors are implicated in smooth muscle proliferation. What are these growth factors?

Answer 34

PDGF, Fibroblast growth factor, TGF-alpha

Question 35

What is PDGF released by?

Answer 35

locally adherent platelet macrophages, endothelial cells, and smooth muscle cells

Question 36

what acts as a smooth muscle chemokine?

Answer 36

TGF-alpha

Question 37

when does the adaptive immune system start responding?

Answer 37

stage 4

Question 38

What can the modified LDL lead to?

Answer 38

events leading to APC activation and subsequent loss of tolerance to ApoB of LDL- autoreactive Ts and Bs- they lose their tolerance

Question 39

What are the mediators of the adaptive immunity?

Answer 39

IFN-gamma, TNF-alpha, and IL-17

Question 40

what cells are responsible for the adaptive immunity?

Answer 40

Th1, Th17, and b cells

Question 41

over time a soft fatty streak becomes covered with what?

Answer 41

a fibrous cap

Question 42

what does the center of the plaque contain?

Answer 42

it is necrotic and it contains lipids, debris, foam cells and thrombus

Question 43

some plaques are more prone to rupture than others. What plaque type is more likely to rupture?

Answer 43

thin fibrous caps- the red thrombus

Question 44

which type of plaque is more stable and more likely to erode?

Answer 44

the white thrombus- thick fibrous cap

Question 45

which plaque more frequently causes STEMI?

Answer 45

the red thrombus

Question 46

what is the prominent cell type in a red thrombus?

Answer 46

macrophages

Question 47

what is the prominent cell type in a white thrombus?

Answer 47

smooth muscle cells

Question 48

what is a major inflammatory marker?

Answer 48

high sensitivity C-reactive protein

Question 49

what effect do steroids have on CAD?

Answer 49

they increase cardio vascular adverse events and mortality

Question 50

what effect do NSAIDs have on CAD?

Answer 50

they increase cardio vascular events due to destabilizing the plaque

Question 51

what effect does the COX2 inhibitor have on CAD?

Answer 51

it increases CVD mortality

Question 52

what is instrumental in driving atherosclerosis and comes off the inflammasome?

Answer 52

IL-1 beta

Question 53

what is ACZ885 (canakinumab)?

Answer 53

it was a human mAb, that selectively blocked the IL-1beta inflammatory pathway