🫀🫁Cardio & Resp🫀🫁 - Atherosclerosis & Peripheral Vascular Disease

Question 1

What are the modifiable risk factors for atherosclerosis and coronary heart disease?

Answer 1

Smoking
Lipid intake
Blood pressure
Diabetes
Obesity
Sedentary lifestyle

Question 2

What are the non-modifiable risk factors?

Answer 2

Age
Sex
Genetic background

Question 3

How do risk factors interact when it comes to cardiovascular diseases?

Answer 3

Risk factor multiplication

Question 4

How has the epidemiology of the risk factors for atherosclerosis and peripheral vascular disease changed over the last decade?

Answer 4

Question 5

How was it proved that atherosclerosis has an inflammatory basis?

Answer 5

CANTOS trial
Patients at high risk of atherosclerosis complications injected with antibodies to Interleukin -1 (IL-1)
Fewer major adverse cardiovascular events (MACE) mostly stroke and heart attacks in treated patients
Multiple mechanisms including cholesterol crystal formation connect lipids and inflammation in atherosclerosis

Question 6

What are the main cell types involved in atherosclerosis?

Answer 6

Vascular endothelial cells
Platelets
Monocyte-macrophages
Vascular smooth muscle cells
T lymphocytes

Question 7

What is the involvement of vascular endothelial cells in atherosclerosis?

Answer 7

Barrier function
Leukocyte recruitment

Question 8

What is the involvement of platelets in atherosclerosis?

Answer 8

Thrombus generation
Cytokine and growth factor release

Question 9

What is the involvement of Monocyte-macrophages in atherosclerosis?

Answer 9

Foam cell formation
Cytokine and growth factor release
Major source of free radicals
Metalloproteinases

Question 10

What is the involvement of vascular smooth muscle cells in atherosclerosis?

Answer 10

Migration and proliferation
Collagen synthesis
Remodelling and fibrous cap formation

Question 11

What is the involvement of T lymphocytes in atherosclerosis?

Answer 11

Macrophage activation – CD4 Th1
Macrophage de-activation – CD4 Treg
Vascular smooth muscle cell death – CD8 CTL
B-cell / Antibody help – CD4 Th2

Question 12

What are the main inflammatory cells in atherosclerosis?

Answer 12

Macrophages - derived from blood monocytes

Question 13

What is LDL?

Answer 13

“Bad cholesterol”
Synthesised in liver
Carries cholesterol from liver to rest of the body including arteries
High levels associated with health issues

Question 14

What is HDL?

Answer 14

“Good cholesterol”
Carries cholesterol from ‘peripheral tissues’ including arteries back to liver (=“reverse cholesterol transport”)

Question 15

What happens to LDL in the pathogenesis of atherosclerosis?

Answer 15

Modification of subendothelial trapped LDL
LDLs leak through the endothelial barrier –likely due to endothelial activation in areas of vortex blood flow
LDL is trapped by binding to sticky matrix carbohydrates (proteoglycans) in the sub-endothelial layer and becomes susceptible to modification

Question 16

What are oxidised and modified LDLs?

Answer 16

Chemical and physical modifications of LDL by free radicals, enzymes, aggregation
Families of highly inflammatory and toxic forms of LDL found in vessel walls

Question 17

How are LDLs modified?

Answer 17

Best studied modification is oxidation – free radical attack from activated macrophages
LDL becomes oxidatively modified by free radicals. Oxidised LDL is phagocytosed by macrophages and stimulates chronic inflammation

Question 18

What is familial hyperlipidemia?

Answer 18

Autosomal genetic disease (main form dominant with gene dosage)
Massively elevated cholesterol (>~20 mmol/L). (effective ‘normal’ ~1-5 mmol/L)
Failure to clear LDL from blood.
Xanthomas and early atherosclerosis; if untreated fatal myocardial infarction before age 20

Question 19

How is cholesterol synthesis regulated?

Answer 19

Negatively regulated by cellular cholesterol

Question 20

What family of drugs are HMG-CoA reductase inhibitors and what is their effect?

Answer 20

“statins”
Lower plasma cholesterol

Question 21

What is the role of PCSK9?

Answer 21

LDLs enter a cell through the LDL receptor (LDLR)
PCSK9 degrades LDLRs, therefore stopping cholesterol from entering cells (i.e. keeping cholesterol in the blood plasma)
PCSK9 inhibitors used to supplement statins, allowing cells to uptake as much cholesterol as possible
LDLR removes cholesterol from blood and allows it to suppress cholesterol biosynthesis
PCSK9-deficient humans are protected from cardiovascular disease

Question 22

What is reverse cholesterol transport?

Answer 22

Transport of cholesterol from cells to the liver for excretion - prevents cholesterol build up and atherosclerosis

Question 23

How does cholesterol leave cells in reverse cholesterol transport?

Answer 23

Leaves via cholesterol export pumps ABCA1 and ABCG1

Question 24

What happens to cholesterol after ABCA1 and ABCG1?

Answer 24

Apolipoprotein A (ApoA) found on HDL particles
ABCA1 and ABCG1 are selective for ApoA, which means they specifically interact with HDL particles
Cholesterol from the cell binds to HDL via ApoA, facilitated by ABCA1 and ABCG1 transporters

Question 25

What happens to cholesterol in the artery walls once it has bound to HDL?

Answer 25

It is returned to the liver - undergoes excretion

Question 26

Outline macrophage scavenger receptor A

Answer 26

Known as CD204 Binds to oxidised LDL Binds to Gram-positive bacteria like Staphylococci & Streptococci Binds to dead cells Activation of ‘bug-detector’ pathways - leads to **inflammation**

Question 27

What are the 2 possible fates of oxidised LDL?

Answer 27

Binds to either macrophage scavenger receptor A or B Stimulates either the A pathway or B pathway

Question 28

Outline macrophage scavenger receptor B

Answer 28

Known as CD36 Binds to oxidised LDL Binds to malaria parasites Binds to dead cells Safe clearance - reverse cholesterol transport Homeostasis

Question 29

What happens to phagocytes that phagocytose oxidised/modified lipoproteins?

Answer 29

They become foam cells

Question 30

What are foam cells?

Answer 30

Lipid-filled macrophages Release pro-inflammatory substances

Question 31

What do foam cells release?

Answer 31

Free radicals Reactive oxygen species Cytokines Chemokines

Question 32

What is the effect of free radicals?

Answer 32

Further oxidisation of lipoproteins

Question 33

Outline the cytokines produced in the pathogenesis of atherosclerosis

Answer 33

Cytokines – protein immune hormones that activate endothelial cell adhesion molecules IL-1 - triggers intracellular cholesterol crystals and NFkB. Coordinates multiple processes including cell death and cell proliferation; and elevated CRP (Atherosclerosis is reduced in mice without IL-1 and humans with anti-IL-1 antibodies)

Question 34

Outline the chemokines produced in the pathogenesis of atherosclerosis

Answer 34

Chemokines - small proteins chemoattractant to monocytes Monocyte chemotactic protein-1 (MCP-1) MCP-1 binds to a monocyte G-protein coupled receptor CCR2 (Atherosclerosis is reduced in MCP-1 or CCR2 deficient mice)

Question 35

What is the role of macrophages in atherosclerosis (specifically plaque formation)?

Answer 35

"Wound healing" Macrophages release growth factors to recruit VSMCs This stimulates VSMCs to migrate, survive, proliferate, and deposit extracellular matrix (e.g., collagen), mimicking a wound healing process within the vessel wall

Question 36

Which 2 growth factors do macrophages release that contribute to plaque formation?

Answer 36

Platelet derived growth factor Transforming growth factor beta

Question 37

What is the role of platelet derived growth factor?

Answer 37

VSMC chemotaxis VSMC survival VSMC division (mitosis) i.e. Encourages VSMCs to: Migrate to the lesion site Survive in the atherosclerotic environment Proliferate (divide) and contribute to plaque formation

Question 38

What is the role of transforming growth factor beta?

Answer 38

Increased collagen synthesis Matrix deposition Strengthens the plaque structure but also increases rigidity

Question 39

What is expressed by macrophages and endothelial cells (among others) that directly degrades tissue?

Answer 39

Metalloproteinases (MMPs)

Question 40

What are metalloproteinases (MMPs)

Answer 40

Family of ~28 homologous enzymes Activate each other by proteolysis Degrade collagen (Catalytic mechanism based on Zn)

Question 41

What is the effect of MMPs?

Answer 41

Degradation of collagen Tissue degradation Weakens plaque, increased risk of rupture and possible thrombosis

Question 42

What occurs upon foam cell death?

Answer 42

Release and subsequent accumulation of tissue factor and toxic oxidised-lipids

Question 43

Briefly outline the atherosclerotic cycle

Answer 43

Question 44

What are the characteristic of a vulnerable (to rupture) plaque?

Answer 44

Large, soft, eccentric lipid-rich necrotic core Increased VSMC apoptosis Reduced VSMC and collagen content Thin fibrous cap Infiltrate of activated macrophages expressing MMPs

Question 45

What are the signs/symptoms of atherosclerosis (specifically ruptured plaque leading to thrombosis)

Answer 45

Death of downstream tissues (heart and brain most significant) Loss of function of one side of the body (major ischemic stroke) Severe central crushing chest pain with fear, dizziness and nausea (myocardial infarction ‘heart attack) Angina Thrombogenic and toxic material accumulates, walled off, until plaque rupture causes it to meet blood - subsequent effects

Question 46

What is nuclear factor kappa B (NFkB) and what is its role in atherosclerosis?

Answer 46

A transcription factor that plays a critical role in the inflammatory response involved in atherosclerosis A “Master regulator” of inflammation; predominant non-redundant highly connected network hub Activated by numerous inflammatory stimuli -Scavenger receptors -Toll-like receptors -Cytokine receptors e.g. IL-1 Switches on numerous inflammatory genes -Matrix metalloproteinases -Inducible nitric oxide synthase -Interleukin-1