Atherosclerosis

Question 1

Atherosclerosis risk factors

Answer 1

Smoking
HTN
diabetes
Hyperlipidaemia

Question 2

Where does atherosclerosis occur more frequently?

Answer 2

Birfucation/bends in blood vessels
Turbulent flow -> damage

Question 3

What mechanism underpins atherosclerosis

Answer 3

Inflammation of macrophages
(can be due to lipid accumulation)

Question 4

What is oxidised LDL?

Answer 4

Physically modified LDL which are highly inflammatory

Question 5

What does oxidised LDL bind to

Answer 5

Scavenger receptors on macrophages
Allow removal of cholesterol by HDL

Question 6

What is secreted by overactive macrophages (due to lipid accumulation)

Answer 6

ROS- O2 free radicals
Cytokines
Chemokines
MMP - enzymes that breakdown tissue
Apoptotic factors - kill host cells (can form an abscess)
Growth factors - trigger formation of scar tissue

Question 7

What are the two inflammatory factors that macrophages release, and what do they do?

Answer 7

Cytokines (promotes endothelial adhesion of inflammatory cells)
Chemokines (attract monocytes)

Question 8

What is the purpose of growth factors release?

Answer 8

Wound healing

Question 9

What are the functions of metalloproteinases?

Answer 9

Breakdown collagen and fibrous gap by activating proteolysis, can lead to plaque rupture

Question 10

What is released upon the death of overactive macrophages

Answer 10

Tissue factor (clotting factor)
OxyLipids - toxic and can trigger clotting in bloodstream

Question 11

What is the fatberg model of atherosclerosis

Answer 11

Fat buildup in the artery walls -> atherosclerosis

Question 12

What is the inflammatory model of atherosclerosis
(Virchow’s)

Answer 12

Chronic inflammation due increase in blood lipids -> atherosclerosis

Question 13

What are the oxidative enzymes that macrophage release?

Answer 13

NADPH Oxidase - forms superoxide O2-, also H2O2 which kills off melanocytes
Inducible nitric oxide synthase (iNOS) - prod ^ conc of NO which can bind and destroy proteins
Myeloperoxidase - forms HOCl (beach), HONOO (Peroxynitrite which releases NO)

Question 14

How do transcription factors affect contribute to atherosclerosis

Answer 14

Turned on by LDL/OxLDL -> macrophage activation

Question 15

What is an endothelial erosion lesion

Answer 15

Selective death of endothelial cells -> Thrombosis (typically non-occlusive)
Related to diabetes as opposed to lipids
Can cause N-STEMI

Lower raters of hyperlipidaemia/hypertension
Greater rates of obesity w

Question 16

What is the main transcription factor that regulates inflammation?

Answer 16

Nuclear Factor Kappa B (all receptors report here, which in turns activates upregulation of MMPs/IL-1 etc.)

Question 17

What are modifiable risk factors for coronary heart disease?

Answer 17

Smoking, Lipids, Blood Pressure, Diabetes, Obesity, Sedentary Lifestyle

Question 18

What are non-modifiable risk factors for coronary heart disease?

Answer 18

Age, Sex, Genetic Predisposition

Question 19

What are the two types of macrophages?

Answer 19

Inflammatory and Non-inflammatory

Question 20

Macrophage functions?

Answer 20

Inflammatory - kill microorganisms
Non-Inflammatory - homeostasis like alveolar surfactant

Question 21

What is LDL and what does it do?

Answer 21

Low Density Lipoprotein - carries cholesterol from liver to rest of the body

Question 21

Explain the J curve

Answer 21

LDL cholesterol isn’t inherently bad, a small amount is necessary for normal function

High cholesterol levels = highest risk of CVD
Very low cholesterol levels > risk than moderate levels

Question 22

What is HDL and what does it do?

Answer 22

High Density Lipoprotein - carries cholesterol from peripheral tissues back to liver
Reverse cholesterol transport

Question 23

What are the functions of apoproteins?

Answer 23

Proteins on surface of LDL - dock molecule to the sites of delivery

bind lipids

Question 24

How can subendothelial LDL lead to inflammation?

Answer 24

LDLs leak through endothelial barrier Become oxidised Phagocytosed by macrophages -> foam cells (fatty macrophage) Chronic inflamm

Question 25

What is a genetic disease that causes high cholesterol?

Answer 25

Familial Hyperlipidaemia - failure to clear LDL from blood

Question 26

What are the signs of familial hyperlipidaemia?

Answer 26

Xanthomas (fat bumps in skin), Early Atherosclerosis

Question 27

What is an enzyme involved in cholesterol production?

Answer 27

HMG-CoA-Reductase (targeted by statins)

Question 28

Mechanism of Cholesterol export pumps

Answer 28

ABCA1, ABCG1 Identify apolipoprotein A on HDL Export cholesterol to ApoAHDL for removal from tissues

Question 29

What are the two macrophage scavenger receptors?

Answer 29

MSR A (CD204) // MCR B (CD36)

Question 30

What does MSR A bind to?

Answer 30

gram positive bacteria, oxidised LDL, dead cells

Question 31

What does MSR B bind to?

Answer 31

malaria parasites, oxidised LDL, dead cells

Question 32

What are the homeostatic roles of macrophage scavenger receptors

Answer 32

Safe clearance of OxLDL Reverse cholesterol transport

Question 33

What is the main cytokine underpinning atherosclerosis

Answer 33

IL-1 triggers NFKb, cell death, prolif

Question 34

What is the main chemokine underpinning atherosclerosis

Answer 34

Monocyte chemotactic protein-1 (MCP-1) which binds CCR2

Question 35

What growth factors do macrophages release?

Answer 35

Platelet Derived Growth Factors Transforming Growth Factor Beta

Question 36

Role of Platelet Derived Growth Factors PDGF

Answer 36

vascular smooth muscle cell chemotaxis/survival/mitosis

Question 37

Role of Transforming Growth Factor Beta TGFb

Answer 37

^ collagen synthesis matrix deposition

Question 38

Components of Virchow's triad

Answer 38

Underpins thrombosis 1. Abnormal blood flow - stenosis 2. Abnormal blood - ^clotting factor 3. Abnormal vessel wall - exposed collagen due to plaque, and damage

Question 39

Aspirin mechanism of action - antiplatelet

Answer 39

Irreversibly blocks COX .: platelets cannot make thromboxane A2 and aggregation is inhibited

Question 40

Clopidogrel mechanism of action

Answer 40

Irreversibly blocks ADP receptor on platelets

Question 41

Endothelial cells use of COX

Answer 41

Can make the prostacyclin PG12 which inhibits platelet aggregation

Question 42

How do thrombolytic agents work

Answer 42

E.g. Tissue Plasminogen activator/Strepokinase Breakdown of plasminogen -> plasmin activated plasmin can breakdown fibrin mesh

Question 43

Thrombosis signs and symptoms

Answer 43

Tissue necrosis LOF on one side (Maj. ischaemic stroke) Heart attack - severe chest pain w/ nausea

Question 44

What is contained within ruptured plaques

Answer 44

lots of activated macrophages with xs lipid