Fundamentals of Atherogenesis

Question 1

what is atherosclerosis?

Answer 1

Is the principal cause of heart attack, stroke and gangrene of the extremities

Question 2

what is the main problem of atherosclerosis?

Answer 2

is plaque rupture leading to thrombus formation, partial/complete arterial blockage leading to a heart attack

Question 3

what are the risk factors For Atherosclerosis?

Answer 3

Age
Tobacco Smoking
High Serum Cholesterol
Obesity
Diabetes
Hypertension
Family History

Question 4

which is the best-known risk factor for coronary artery disease
1. Obesity
2. Diabetes
3. Gender
4. Age

Answer 4

AGE

Question 5

where are atherosclerosis plaques distributed?

Answer 5

Found within peripheral and coronary arteries
Focal distribution along the artery length

Question 6

describe how Distribution may be governed by haemodynamic factors

Answer 6

Changes in flow/turbulence (eg at bifurcations) cause the artery to alter endothelial cell function. Wall thickness is also changed leading to neointima. Altered gene expression in the key cell types is key.

Question 7

Q: Which of the following is not in artery walls?
1.Tunica intima
2.Tunica media
3.Epithelial cells
4.Neutrophils

Answer 7

EPITHELIAL CELLS

Question 8

what does an atherosclerotic plaque consist of:

Answer 8

• Lipid
  -Necrotic core
  -Connective tissue
  -Fibrous “cap”

Question 9

what will the plaque eventually do to the vessel?

Answer 9

will either occlude the vessel lumen resulting in a restriction of blood flow (angina), or it may “rupture” (thrombus formation – death).

Question 10

what initiates atherosclerosis?

Answer 10

1. Initiated by an injury to the endothelial cells which leads to endothelial dysfunction.
   2.Signals sent to circulating leukocytes which then accumulate and migrate into the vessel wall.
2. Inflammation ensues

Question 11

name 4 examples of good inflammation

Answer 11

Pathogens
Parasites
Tumors
Wound healing

Question 12

name 8 examples of bad inflammation

Answer 12

Myocardial reperfusion injury
Atherosclerosis
Ischaemic heart disease
Rheumatoid arthritis
Asthma
Inflammatory bowel disease
Shock
Excessive wound healing

Question 13

what ignites inflammation in the arterial wall?

Answer 13

LDL
Endothelial dysfunction- in response to injury hypothesis

Question 14

what ignites inflammation in the arterial wall-LDL?

Answer 14

can pass in and out of the arterial wall
in excess it accumulates in arterial wall, and undergoes oxidation and glycation

Question 15

once inflammation is initiated what occurs to the chemoattractants?

Answer 15

are released from endothelium and send signals to leukocytes.

AND/OR

are released from site of injury and a concentration-gradient is produced.

Question 16

what are the inflammatory cytokines found in plaques

Answer 16

IL-1 - canakinumab
IL-6 – tocilizumab**
IL-8
IFN-g
TGF-b
MCP-1
(C reactive protein)

Question 17

Leukocyte recruitment to vessel walls - summary

Answer 17

capture
rolling
slow rolling
firm adhesion
transmigration

Question 18

describe the fatty streak stage of Progression of Atherosclerosis

Answer 18

-Earliest lesion of atherosclerosis
-Appear at a very early age (<10 years)
-Consist of aggregations of lipid–laden macrophages and T lymphocytes within the intimal layer of the vessel wall

Question 19

describe the intermediate lesions (2) stage of Progression of Atherosclerosis

Answer 19

Composed of layers of :
-Lipid laden macrophages (foam cells)

-Vascular smooth muscle cells

-T lymphocytes

-Adhesion and aggregation of platelets to vessel wall

-Isolated pools of extracellular lipid

Question 20

describe the fibrous plaques stage (3) of Progression of Atherosclerosis

Answer 20

Impedes blood flow
Prone to rupture
Covered by dense fibrous cap made of ECM proteins including collagen (strength) and elastin (flexibility) laid down by SMC that overlies lipid core and necrotic debris
May be calcified
Contains: smooth muscle cells, macrophages and foam cells and T lymphocytes

Question 21

describe the plaque rupture (4 )stage of Progression of Atherosclerosis

Answer 21

Plaques constantly grow and recede.
Fibrous cap has to be resorbed and redeposited in order to be maintained.
If balance shifted eg in favour of inflammatory conditions (increased enzyme activity), the cap becomes weak and the plaque ruptures.
Basement membrane, collagen, and necrotic tissue exposure as well as haemorrhage of vessels within the plaque
Thrombus (clot) formation and vessel occlusion

Question 22

describe the plaque erosion (5)stage of Progression of Atherosclerosis

Answer 22

-Second most prevalent cause of coronary thrombosis
-Lesions tend to be small ‘early lesions’
- A thickened fibrous cap may lead to collagen triggering thrombosis rather than tissue factor (as in plaque rupture)
- A platelet-rich clot may overlie the luminal surface.
-There is usually a small lipid core

Question 23

what are the treatments used for coronary artery disease?

Answer 23

PCI - Percutaneous Coronary Intervention

More than 90% of patients require stent implantation

Restenosis was a major limitation, no longer though due to drug eluting stents

Question 24

Q: What are coronary stents used in patients today made of?
1. Metal
2. Plastic
3. Polymers

Answer 24

metal

Question 25

describe aspirin

Answer 25

irreversible inhibitor of platelet cyclo-oxygenase

Question 26

describe Clopidogrel/Ticagrelor

Answer 26

inhibitors of the P2Y12 ADP receptor on platelets and other drugs with antiplatelet actions

Question 27

describe statins

Answer 27

inhibit HMG CoA reductase, reducing cholesterol synthesis

Question 28

describe PCSK9 inhibitors

Answer 28

monoclonal antibodies that inhibit PCSK9 protein in the liver which leads to improved clearance of cholesterol from the blood.