Atherosclerosis/CHD

Question 1

What are the modifiable risk factors for CHD?

Answer 1

Smoking, Lipid intake, BP, Diabetes, Obesity and sedentary lifestyle

Question 2

What are the non-modifiable risk factors for CHD?

Answer 2

Age, Sex, Genetic background

Question 3

How has intervention modified the epidemiology of CHD?

Answer 3

Reduced population levels of hyperlipidaemia due to statins, and reduced hypertension due to antihypertensives means that plaques now primarily driven by obesity

Question 4

What are LDLs?

Answer 4

Bad cholesterol - synthesised in liver, carried from liver to arteries (needed for normal function, so shows J-curve)

Question 5

What are HDLs?

Answer 5

Good cholesterol - carrying from peripheral tissues to the liver

Question 6

What is the structure of LDLs?

Answer 6

Has lipid monolayer and a docking molecule (apolipoproteins), with cargo fat (triglycerides and cholesterol esters) for fuel

Question 7

Where are atheroscleroses most often found?

Answer 7

At branching where there is disturbed flow and branching

Question 8

What is LDL deposition?

Answer 8

LDLs deposit in subintimal space - binding to matrix proteoglycans

Question 9

What is the modification of subendothelially trapped LDLs?

Answer 9

Bind to sticky matrix carbohydrates (proteoglycans), becoming susceptible to modification and are oxidised (partial burning) by free radicals; phagocytosed by macrophages to lead to chronic inflammation/foam cell formation

Question 10

What are the two types of Macrophage Scavenger Receptors?

Answer 10

MSR A

MSR B

Question 11

What does MSR A do?

Answer 11

CD204, bind oxLDL, dead cells and gram positive bacteria to cause inflammation and destruction

Question 12

What does MSR B do?

Answer 12

CD36, bind oxLDL, malaria parasites and dead cells for safe clearance and reverse cholesterol transport

Question 13

What are the five actions of macrophages?

Answer 13

Generate free radicals

Phagocytose modified lipoproteins

Express cytokine mediators to recruit monocytes

Express chemo-attractants and growth factors

Express metalloproteinases

Question 14

Describe the action of macrophage free radicals:

Answer 14

NADPH oxidase and myeloperoxidase (hypochlorous acid from ROS + Cl-) - bleach secreted to walls to oxidise LDLs

Question 15

What happens when macrophages engulf modified lipoproteins?

Answer 15

Accumulate modified LDLs and become enlarged foam cells

Question 16

What do the chemokines expressed by macrophages do?

Answer 16

Chemokines attract monocytes (MCP1 binding to GPCR CCR2 attracts monocyte, so if deficient then atherosclerosis reduced) and cytokines activate endothelial cell adhesion molecules (IL1 upregulates VSMC VCAM-1 that mediates tight monocyte binding - reduced IL1/VCAM-1 expression reduces atherosclerosis)

Question 17

What do the chemo-attractants and growth factors expressed by Macrophages do?

Answer 17

Platelet derived growth factor and transforming growth factor beta for “wound healing” role - release complementary protein growth factors to recruit VSMCs and stimulate to proliferate (in atherosclerosis then reduced contractile filaments and increased matrix deposition genes)

Question 18

What do the metalloproteinases expressed by macrophages do?

Answer 18

Family of 28 homologous enzymes that activate each other by proteolysis to degrade collagen (catalytic mechanism based on Zn); blood coagulation at site of rupture may lead to occlusive thrombus and cessation of flow - DEGRADE WALL OF PLAQUE SO RUPTURES AND CAUSES THROMBUS

Question 19

What are ruptured plaques?

Answer 19

Macrophages mean fibrous cap becomes so thin that will break and rupture, allowing necrotic core to contact blood and cause thrombus formation

Question 20

What are vulnerable plaque characteristics?

Answer 20

Large, soft, eccentric lipid-rich necrotic core with increased VSMC apoptosis, reduced VSMC/collagen content, thin fibrous cap and infiltrate of activate macrophages expressing metalloproteinases

Question 21

What is macrophage apoptosis?

Answer 21

OxLDL derived metabolites (e.g. 7-keto-cholesterol) toxic to macrophages, and while foam cells have protective systems to survive, when overwhelmed they will die via apoptosis; release macrophage tissue factors and toxic lipids to lipid necrotic core, so that thrombogenic and toxic material accumulates and is walled off until plaque ruptures, so meets blood

Question 22

What is Nuclear Factor Kappa B (NFkB)?

Answer 22

Master regulator of inflammation, activated by scavenger/toll-like/cytokine receptors, switching on inflammatory genes (e.g. Matrix metalloproteinases and inducible nitric oxide synthase) - can be activated by many stimuli and coregulate multiple genes