Inflammation and CAD

Question 1

What are risk factors for atherosclerosis?

Answer 1

• Genetics
• FHx
• Increasing age
• XY chromosomes
• Hyperlipidemia
• Htn
• Smoking
• Diabetes
• Vitamin deficiencies
• Obesity/ Sedentary lifestyle
• Chronic inflammation

Question 2

What is the most common chronic injury to endothelium?

Answer 2

• Htn & Hyperlipiemia

Question 3

Where does atherosclerosis occur?

Answer 3

• Most lesions occur at openings of vessels. branch points, or posterior abdominal aorta

Question 4

What does the endothelial dystunction stage lead to?

Answer 4

• Increased permeability leukocyte adhesion, monocyte ahesion and emigration
• Acute Inflammatory Response

Question 5

What are the characteristics of an activated endothelium ?

Answer 5

• Increased expression of procoagulants, adhesion molecules and proinflammatory factors
• Altered expression of chemokines cytokines and growth factors

Question 6

What are the characteristics of an endothelium in a basal state?

Answer 6

• Non adhesive
• Non thrombogenic surface

Question 7

With endothelial dysfunction what does the altered phenotype lead to?

Answer 7

• Proinflammatory andp rothormbogenic
• Initates thrombus formation, atherosclerosis and vascular lesions

Question 8

Why is edema important?

Answer 8

• Brings plasma proteins into intimate contact with damaged area

Question 9

What proteins are found in the inflammatory exudate (seen with edema)?

Answer 9

• Clotting proteins
• Complement
• Kinin casscade:
  
  • vasocilation, increase permeability, stimulate pain receptors
• Fibrinolytic protein:
  
  • degrades clot

Question 10

Describe the circulating lipids in response to endothelial injury.

Answer 10

• Lipids in atheromatous plaques are cholesterol and cholesterol esters
• LDL gets deposited into the intima and retained and gets phagocytsed by macrophages and then oxidized
• Modified LDL accumultates within the macrophages and smooth muscle cells called uptake
• Uptake stimulates an inflammatory response to the toxic form of LDL (Foam Cells)
• Foam cells collect in lesions called fatty streak

Question 11

What is the receptor for oxLDL?

Answer 11

Scavenger receptor on monocytes CD36

Question 12

What promotes infalmmasome activation within a foam cell?

Answer 12

Cholesterol crystals

Question 13

What is an inflammasome?

Answer 13

• Signaling system for detection of pathogens and stressors
• Recruitment and assembly of inflammasome proteins results in production of Il-1 and IL-18 (potent inflammatory cytokines)

Question 14

What is NeTosis?

Answer 14

• Scaffolding for platelet RBC activation aggregation nd thrombosis
• Stimulates macrophage to have inflammatory response
• Comes from Neutrophil

Question 15

What stimulates Sm mm growth?

Answer 15

• PDGF released by adherent platelets macrophages and endothelial cells and sm mm cells
• Fibroblast growth factor
• TGF-alpha
  
  • sm mm chemokine
• Proliferating sm mm cells synthesize ECM including collagen

Question 16

Mediators of adaptive immunity with CAD and Atherosclerosis? What do they result in?

Answer 16

• IFN-y
• TNF-a
• IL-17

Increased:

• adhesion moleculs
• cytokine release
• HLA II expression and Ag persentation
• OxLDL uptake
• Macrophage activation

Results in fatty streaks

Question 17

Describe the atherosclerotic plaque.

Answer 17

• Fatty streak gets covered with a fibrous cap of dense collagen fibers
• Center of plaque is necrotic with lipid, debris, foam cells and thrombus
• Surrounded by zone of inflammatory cells and sm mm cells

Question 18

Compare thrombosis due to erosion vs rupture.

Answer 18

Thrombosis: (White thrombus)

• Fibrous cap is thick and intact
• Sm mm cells prominent
• Neutrophil extracellulr traps (NETs) involved
• More frequent in Non-STEMI

Rupture: Red thrombus

• Thin fibrous cap with fissure
• Macrophages prominent
• Usually expansively remodeled
• More frequent in STEMI

Question 19

What are the inflammatory marker emerging risk factors?

Answer 19

• High sensitivity C-reactive protein (HSCRP)
• Serum amyloid A

Question 20

What are the pro coagulant marker risk factors?

Answer 20

• Plasma homocysteine
• Tissue Plasminogen activator
• Plasminogen activator inhibitor

Question 21

How do you treat atherosclerosis?

Answer 21

Non specific agents:

• Steroid: increase in CV adverse events and mortality
• NSAIDs: increase because they destabilize plaques

Selective inhibitor:

• COX2 inhibitor: increases CVD mortality

Question 22

How can you block IL-1Beta inflammatory path?

Answer 22

• ACZ885 canakinumab selectively blocks it
• IL-1B is crucial in driving atherosclerosis

Question 23

What is the CANTOS study?

Answer 23

• high and medium dose decreased percent of HSCRP and IL-6
• no change in LDL
• Decreased HSCRP decreased all cause mortality rate and cadriovascular mortality over the 5 years

Question 24

CANTOS/CIRT study?

Answer 24

• Cardiovasuclar inflammation reduction trial
• Low dose methotrexate , all patients were post MI with T2DM
• No reduction in IL-1b IL-6 or HSCRP or CV events