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CVS > Coronary heart disease and atherosclerosis > Flashcards

Coronary heart disease and atherosclerosis Flashcards

1
Q

Modifiable risk factors

A 
Smoking
Lipids Intake
Blood Pressure
Diabetes
Obesity
Sedentary Lifestyle
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2
Q

Non-modifiable factors

A

Age
Sex
Genetic background

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3
Q

Risk factor multiplication

A

16x higher risk if hypertension, high cholesterol, smoking

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4
Q

Changes in epidemiology over the last decade

A 
Reduced hyperlipidaemia (statin treatment)
Reduced hypertension (antihypertensive treatment
Increased obesity = Increased diabetes
New improvements in diabetes treatment have doubtful effect on macrovascular disease
Changing pathology of coronary thrombosis possibly related to altered risk factors (reduced emphasis on hyperlipidaemia and increased emphasis on obesity)
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5
Q

If risk factors are general, why is atherosclerosis focal?

A

Where vessels hit the bifocation, there is a more disordered blood flow (turbulent) which encourages the atherosclerosis formation

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6
Q

LDL deposition

Bind to?

A

Low density lipoproteins (LDL) deposit in the subintimal space and binds to matrix proteoglycans

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7
Q

Progression of atherosclerosis
(slide 12, lecture 21)
Core name?

A

Necrotic core

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8
Q

If fibrous thickening doesn’t happen enough then?

A

fibrous part can crack apart mechanically which triggers a thrombus that can block off a coronary artery which causes an MI. (You want a thick fibrous cap then)

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9
Q

Type VI (complicated lesion) appearance?

A

Stratified appearance (lines)

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10
Q

Immune cells

A

Vascular endothelial cells

Platelets

Monocyte-macrophages

Vascular smooth muscle cells

T lymphocytes

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11
Q

Immune cells

A 
Vascular endothelial cells
Platelets
Monocyte-macrophages
Vascular smooth muscle cells
T lymphocytes
Macrophages: Inflammatory macrophages+ Resident macrophages
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12
Q

T lymphocytes role?

A

Macrophage activation

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13
Q

Vascular smooth muscle cells role?

A

Migration into the plaque and proliferation
Collagen synthesis- make the fibrous cap thicker and more robust
Remodelling & fibrous cap formation

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14
Q

Monocyte-macrophages role?

A

Foam cell formation
Cytokine and growth factor release
Major source of free radicals
Metalloproteinases- macrophages produce enzymes that degrade the fibrous cap and make it less thick and more rupture-prone

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15
Q

Platelets role?

A

Thrombus generation

Cytokine and growth factor release which influences the growth of the arterial plaque

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16
Q

Platelets role?

A

Thrombus generation

Cytokine and growth factor release which influences the growth of the arterial plaque

17
Q

Inflammatory macrophages role?

A

Adapted to kill microorganisms (germs)

18
Q

Resident macrophages role?

Examples?

A

Normally homeostatic - suppress inflammatory activity, e.g…
Alveolar resident macrophages - surfactant lipid homeostasis
Osteoclasts - calcium and phosphate homeostasis
Spleen - iron homeostasis

19
Q

Lipoproteins types

A

LDL
Bad’ cholesterol - Synthesised in liver.
Carries cholesterol from liver to rest of the body including arteries.

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

Oxidised LDLs, modified LDLs
Due to action of free radicals on LDL. (see later)
Not one single substance, several steps occur to get to this stage.
Families of highly inflammatory and toxic forms of LDL found in vessel walls.

20
Q 
LDL structure
(slide 17, lecture 21)
A

-

21
Q

Modification of subendothelial trapped LDL

A

LDLs leak through the endothelial barrier by uncertain mechanisms.
LDL is trapped by binding to sticky matrix carbohydrates (proteoglycans) in the sub-endothelial layer and becomes susceptible to modification.
Best studied modification is oxidation - represents partial burning
LDL becomes oxidatively modified by free radicals. Oxidised LDL is phagocytosed by macrophages and stimulates chronic inflammation!
Macrophages now known as ‘foam cells’

22
Q

FH

A

Familial hyperlipidemia
Autosomal genetic disease.
Massively elevated cholesterol (20mmol/L).
Failure to clear LDL from blood.
Xanthomas and early atherosclerosis; if untreated fatal myocardial infarction before age 20.

23
Q

Q1: Which of the following is known to significantly increase cardiovascular risk by acting as an atherosclerotic risk factor?
A: High level of high density lipoprotein cholesterol
B: High level of low density lipoprotein cholesterol in familial hypercholesterolemia
C: Hepatitis B infection
D: Malaria
E: Blood pressure lowering medication
F: Clotting Factor VIII deficiency

A

B
A is wrong because it’s the other way round- it engages in cholesterol transport to the liver
C- Hepatitis B has nothing to do with it
D- same as C
E- protective instead
F- less likely to get thrombosis from this

24
Q

Macrophage scavenger receptors

A 
Macrophage scavenger receptor A
Known as CD204
Binds to oxidised LDL
Binds to Gram-positive bacteria like Staphylococci & Streptococci
Binds to dead cells
Macrophage scavenger receptor B
Known as CD36
Binds to oxidised LDL
Binds to malaria parasites
Binds to dead cells
25
Q

What can happen to Arterial Ox-LDL deposits?

A

Inflammation:
Activation of ‘bug-detector’ pathways (the immune system mistakes the Aterial Ox-LDL deposits for a pathogen and triggers an inflammatory response= bad)

Homeostasis:
Safe clearance+ reverse cholesterol transport
(removed from the plaque and engage in emigration where the macrophages take the fat out of the plaque in a lymph node or interact with HDL to ‘suck’ the cholesterol out of the plaque into the HDL to the liver through reverse cholesterol transport.)

26
Q

Macrophages within plaques step 1

A

I. Generate free radicals that further oxidise lipoproteins:
Macrophages have oxidative enzymes that can modify native LDL.
a) NADPH Oxidase, for example superoxide O2-.
b) Myeloperoxidase, for example, HOCl hypochlorous acid (bleach) from ROS + Cl-, HONOO Peroxynitrite.
LDL gets oxidised, triggers macrophages which think it’s a bug and oxidise it further etc (positive feedback loop)
O2-.: dot is a single unpaired electron, this is in NADPH Oxidase which oxidises anything in vicinity (usually LDL, which makes it more oxidised)
HONOO is the same as HOCl but derived from hydrogen peroxide instead: both are free radicals and oxidise readily

27
Q

Macrophages within plaques step 2

A

II. Phagocytose modified lipoproteins, & become foam cells
Macrophages accumulate modified LDLs to become enlarged foam cells.

28
Q

Macrophages within plaques step 3a

A

IIIa. Express cytokine mediators that recruit monocytes
Plaque macrophages express inflammatory factors that are involved in monocyte recruitment.
1) Cytokines – protein immune hormones that activate endothelial cell adhesion molecules
Interleukin-1 upregulates vascular cell adhesion molecule 1 VCAM-1
VCAM-1 mediates tight monocyte binding (VCAM 1- vascular cell adhesion molecule 1, makes endothelial cells sticky, mediates tight monocyte binding (makes endothelial cells sticky from monocytes))
Atherosclerosis is reduced in mice without IL-1 or VCAM-1

2) 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.

Both of these set up positive feedback loop / vicious cycle leading to self-perpetuating inflammation.

29
Q

Macrophages within plaques step 3b

change in vascular smooth muscle cells

A

Express chemo-attractants & growth factors for VSMC
“Wound healing” role of the macrophage in atherosclerosis - Macrophages release complementary protein growth factors that recruit VSMC and stimulate them to proliferate and deposit extracellular matrix
1) Platelet derived growth factor
Vascular smooth muscle cell chemotaxis
Vascular smooth muscle cell survival
Vascular smooth muscle cell division (mitosis)

2) Transforming growth factor beta
Increased collagen synthesis from smooth muscle cells
Matrix deposition

Normal medial vascular smooth muscle cells to Atherosclerotic:
Normal= High Contractile filaments+ low matrix deposition genes
Atherosclerotic= low contractile filaments+ high matrix deposition genes
Conversion happens with PDGF + TGF-b
Atheroscleoritc synthetic vascular smooth muscle cells are less good at contracting but better at making collagen than contractile cells

30
Q

Macrophages within plaques step 3c

Effect of plaque erosion/rupture ?

A 
IIIc. Express Proteinases that degrade tissue
Metalloproteinases (=MMPs): 
Family of ~28 homologous enzymes
Activate each other by proteolysis.
Degrade collagen.
Catalytic mechanism based on Zn.

Effect of plaque erosion/rupture - Blood coagulation at the site of rupture may lead to an occlusive thrombus and cessation of blood flow.
Where there are WBCs there isn’t collagen- macrophages eat a hole in the plaque and make it more rupture-prone
At the site of plaque rupture, blood clots form because it’s full of pro-coagulant factors, very severe and rapid thrombus formation= complete blockage of blood flow= MI

31
Q

Pathology of a ruptured plaque

A 
Large soft eccentric lipid-rich necrotic core
Increased VSMC apoptosis
Reduced VSMC & collagen content  
Thin fibrous cap
Infiltrate of activated 
macrophages expressing MMPs
32
Q

Macrophage apoptosis

A

OxLDL derived metabolites are toxic eg 7-keto-cholesterol is very toxic.
Macrophage foam cells have protective systems that maintain survival in face of toxic lipid loading.
Once overwhelmed, macrophages die via apoptosis.
Release macrophage tissue factors and toxic lipids into the ‘central death zone’ called lipid necrotic core.
Thrombogenic and toxic material accumulates, walled off, until plaque rupture causes it to meet blood.

33
Q

Nuclear Factor kappa B (NFkB)

Activated by?

A

Transcription Factor
Master regulator of inflammation

Activated by numerous inflammatory stimuli:
Scavenger receptors
Toll-like receptors
Cytokine receptors

Switches on numerous inflammatory genes
Matrix metalloproteinases
Inducible nitric oxide synthase

NF-kappa-B directs multiple genes in concert
Multiple different inflammatory stimuli→ NF-κ-B→ Coregulation of multiple different inflammatory genes

34
Q

Diagrammatic summary - macrophages in atherosclerosis

slide 25, lecture 21

A

Risk factors lead to activation of endothelial cells which become more leaky which lets LDL through and it binds to that specific place (see before), it gets readily oxidised and binds to the scavenger receptors that have mistaken it for a bug, which activates the macrophages and causes them to take up the oxidised LDL. This results in lipid accumulation in the macrophages as well as NFkB activation.
Inflammation activation mode causes ROS (Reactive Oxgen Species) to be secreted which further oxidises LDL which causes the vicious cycle, cytokines which further activate the endothelial cells which make them sticky from monocytes which causes another vicious cycle, chemokines attract more monocytes which causes another vicious cycle, MMPs (matrix metal…. Proteins?) degrade the collage and make the fibrous cap thinner which makes it more likely to rupture
Secretion of growth factors that regenerates more collagen that makes it thicker again (more stable and less rupture prone), can also redirect cholesterol through HDL back to the liver

35
Q

Q2: Which of the following statement is CORRECT for ruptured plaques?
A: Have an excess of structurally strong collagen synthesised by an excess of vascular smooth muscle cells
B: Have excess of activated macrophages containing excess lipid
C: Are safe since they do not cause thrombosis or myocardial infarction
D: Are mechanically stabilised due to insufficient expression of proteases by macrophages

A

B

36
Q

Q3: Which of the following statement is CORRECT for atherosclerotic risk factors?
A: Are expected to decrease globally leading to a decrease in cardiovascular disease worldwide
B: Include high blood pressure, diabetes, hyperlipidaemia, smoking, age, and anatomically localising branches and bends
C: Are not worth treating since atherosclerosis is fundamentally a degenerative disease
D: Do not modify vascular and leukocyte cell functions

A

B

37
Q

Q4: Which of the following statement is CORRECT for Low density lipoproteins?
A: Is decreased in familial hypercholesterolemia
B: May be modified in vessel wall to a form that activates macrophages like a pathogen would
C: Is formed in vessel walls and carries cholesterol back to the liver
D: Is characterised by the presence of a lipid bilayer
E: Is not measured clinically since there are no worthwhile ways to reduce its level

A

B

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