cardioresp > 1B atherosclerosis > Flashcards

1B atherosclerosis Flashcards

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1
Q

What is coronary heart disease also known as?

A
  • Ischaemic heart disease- affects coronary arteries
  • Cerebrovascular disease- affects carotid arteries
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2
Q

What body systems does atherosclerosis affect?

A
  • Neurology → cerebrovascular disease
  • Cardiology → coronary disease
  • Cardiac surgery → revascularisation
  • Vascular surgery → revascularisation
  • Endocrinology → diabetes
  • Metabolic medicine → lipids
  • Acute medicine → heart attack/stroke
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3
Q

What are the modifiable risk factors for coronary heart disease?

A
  • Smoking
  • Blood pressure
  • Lipids intake
  • Diabetes
  • Obesity
  • Sedentary lifestyle
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4
Q

How do we lower smoking?

A

Smoking cessation

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5
Q

How can we lower blood pressure?

A

ABCD:
- ACE inhibitors first
- Beta blockers
- Calcium channel blockers
- Diuretics

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6
Q

How can we lower lipids intake?

A
  • Antihyperlipidaemic agents
  • Statins
  • Injecting with an antibody against PCSK9 molecule- reduces LDL a lot
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7
Q

How can we lower diabetes?

A
  • First line- dietary advice and weight loss to tackle the obesity if that’s the cause
  • Second line- Gastric surgery for weight loss
  • Third line- Metformin
  • Fourth line- Sulfonylureas
  • Fifth line- Insulin
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8
Q

What non-modifiable factors on coronary heart disease are there?

A
  • Age
  • Sex
  • Genetic background
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9
Q

Explain the risk factor multiplication of coronary heart disease

A
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10
Q

Describe the epidemiological changes over the last decade for some of the risk factors of atherosclerosis

A
  • Use of statin treatment has reduced hyperlipidaemia
  • Use of antihypertensive treatment has reduced hypertension
  • However, increased obesity has led to increased diabetes
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11
Q

New improvements in diabetes treatment have doubtful effect on macrovascular disease- what does this mean?

A
  • sulfonylureas have no effect
  • insulin has no effect
  • metformin may have some effect
  • New class of antidiabetic SGLT2 inhibitors do have an effect

This has changed the pathology of coronary thrombosis from plaque rupture → plaque erosion

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12
Q

Describe the progression of atherosclerosis from coronary artery at lesion-prone location to a type VI complicated lesion

A
  • Start off with smooth muscle cells
  • Macrophages come in and eat lipid and die of fat overload
  • This forms small pools of lipid
  • These coalesce to form extracellular core of lipid which sets off inflammatory reaction
  • Triggers smooth muscle cells to act like myofibroblasts in a healing wound so you get wall of vascular muscle cells and collagen surrounding fat in the middle
  • Inflammatory cells causes this to breakdown collagen and break smooth muscle cells
  • This cracks the plaque and forms a thrombus- the fat in the middle is also so concentrated that the cholesterol crystallises
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13
Q

When is the window of opportunity for primary prevention of atherosclerosis and clinical intervention?

A
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14
Q

What are the main cell types involved in inflammation in atherosclerosis?

A
  • Vascular endothelial cells
  • Platelets
  • Monocytes/macrophages
  • Vascular smooth muscle cells
  • T lymphocytes
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15
Q

What is the function of vascular endothelial cells?

A
  • Barrier function e.g. to lipoprotein
  • Leukocyte recruitment
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16
Q

What is the function of platelets?

A
  • Thrombus generation (in coronary/cerebral artery thrombosis or carotid embolism)
  • Cytokine and growth factor release when activated
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17
Q

What is the function of monocytes/macrophages in atherosclerosis?

A
  • Foam cell formation
  • Cytokine and growth factor release
  • Major source of free radicals
  • Metalloproteinases- collagen-degrading enzymes
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18
Q

What is the function of vascular smooth muscle cells?

A
  • Migration from media (thick muscle layer) into plaque then proliferate
  • Then make collagen which strengthens plaque (narrows lumen so makes unstable angina more likely but protects from full heart attack or MI)
  • Remodelling and fibrous cap formation
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19
Q

What is the function of T lymphocytes?

A

Macrophage activation

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20
Q

What was the previously thought mechanism of atherosclerosis?

A

That a build up of fat in the artery clogs it physically to limit blood flow

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21
Q

What is now known about the mechanism of atherosclerosis and what showed us this?

A
  • It has an inflammatory basis
  • CANTOS trial shows this where patients at high risk of atherosclerosis complications were injected with antibodies to IL-1
  • There were fewer major adverse cardiovascular events (MACE) such as stroke and heart attacks in treated patients
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22
Q

Why does inflammation happen in atherosclerosis?

A

Multiple mechanisms including the fact that cholesterol crystals form which activate macrophages to secrete IL-1

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23
Q

What does this image show?

A

Image to show macrophages in atherosclerosis making foam cells and becoming full of fat and dying.

Brown: macrophage specific protein (CD68).

The foam cell debris is very toxic and thrombogenic.

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24
Q

What are the 2 main classes of macrophages and what do they do?

A
  • Inflammatory macrophages
    • Adapted to kill microorganisms (germs) and nearby infected cells
  • Resident macrophages
    • Normally homeostatic: suppress inflammatory activity
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25
Give examples of resident macrophages and their roles
- alveolar resident macrophages- surfactant lipid homeostasis - osteoclasts- calcium and phosphate homeostasis - spleen- iron homeostasis
26
What is LDL?
- ‘bad cholesterol’- synthesised in liver - Carries cholesterol from liver to rest of body including arteries - is an atherosclerotic risk factor - Do need some- very low levels of LDL increase risk of mortality
27
When is LDL very bad for us?
- When oxidised due to the action of free radicals released from inflammatory cells - Oxidised LDLs aren’t a single substance but families of highly inflammatory and toxic forms of LDL found in vessel walls
28
What does LDL look like?
- A central core of fat - Lipid monolayer - Docking molecule ‘molecular address for fat delivery’
29
What is HDL?
- ‘good cholesterol’ - Carries cholesterol from peripheral tissues including arteries back to liver (reverse cholesterol transport)
30
What happens to LDLs in atherosclerosis?
- LDLs leak through endothelial barrier by uncertain mechanisms - LDL is trapped by binding to sticky matrix carbs (proteoglycans) in subendothelial layer and becomes susceptible to modification - Gets **oxidatively modified** by free radicals (partial burning) mediated by inflammatory cells - Oxidised LDL is phagocytosed by macrophages and stimulates chronic inflammation - There’s a **positive feedback loop** as this triggers macrophages to modify lipids further- so positive feedback between fat in arteries and inflammation - Macrophages keep taking up fat (become foam cells) until they die
31
What is familial hyperlipidaemia (FH)?
- It is the failure to clear LDL from blood - Massively elevated cholesterol (>20mmol/L where normal is 1-5) - Autosomal genetic disease - Xanthomas and early atherosclerosis- if untreated it can cause fatal MI before 20
32
What receptors are involved with LDL?
- LDL receptor - Scavenger receptor
33
What does LDL receptor do?
- Expressed on liver and takes cholesterol into liver from LDL (receptor’s expression is negatively regulated by intracellular cholesterol) - Cholesterol synthesis is also negatively regulated by cellular cholesterol- led to discovery of HMG-CoA reductase inhibitors (statins) for lowering plasma cholesterol - In LDLR-negative patients, macrophages accumulate cholesterol to form plaques
34
What is the scavenger receptor?
- not under feedback control - found in atherosclerotic regions on macrophages - they hoover up chemically modified LDL - Now known that scavenger receptors are a family of pathogen receptors that accidentally bind OxLDL
35
What does macrophage scavenger receptor A bind and what CD is it?
- known as CD204 - binds to oxidised LDL - binds to dead cells - binds to gram positive bacteria like staphylococci and streptococci
36
What does macrophage scavenger receptor B bind and what CD is it?
- known as CD36 - Binds to oxidised LDL - Binds to dead cells - Binds to malaria parasites
37
When macrophages take up oxidated LDL what 2 pathways are activated?
- Activation of ‘bug-clearance’ pathway leading to inflammation as macrophage mistakes the LDL deposits as bugs and makes things worse - Safe clearance of cholesterol and sent to HDL to engage reverse cholesterol transport- homeostatic response
38
When macrophage scavenger receptors are activated, how do they cause problems?
1) **Generate free radicals** that further oxidise lipoproteins 2) **Phagocytose modified lipoproteins** and become foam cells 3a) **Express cytokine mediators** that recruit monocytes 3b) **Express chemo-attractants and growth factors** for VSMC 3c) **Express proteinases** that degrade tissue
39
What enzymes are activated in generating free radicals that further oxidise lipoproteins?
- **NADPH Oxidase** e.g. superoxide O2- → this is a single unpaired electron on an oxygen which makes it very reactive (usually kills bacteria) - **Myeloperoxidase**- this takes the reactive oxygen and uses it to form hypochlorous acid (bleach) HOCl from ROS + Cl-, HONOO Peroxynitrite - Bleach further oxidises LDL and also damages inside of artery and causes plaque to fall apart. - **Generation of H2O2**
40
What are the two types of mediators released to recruit monocytes?
- Cytokines - Chemokines
41
What are cytokines?
Protein immune hormones that activate endothelial cell adhesion molecules.
42
What is the main cytokine involved in atherosclerosis?
IL-1 - Triggers e.g. intracellular cholesterol crystals and NFkB. - Coordinates multiple processes including cell death and proliferation; and elevated CRP. - Atherosclerosis is reduced in mice without IL-1 and humans with anti-IL-1 antibodies.
43
What are chemokines?
Small protein chemoattractant to monocytes.
44
Which chemokine is involved in atherosclerosis?
Monocyte chemotactic protein-1 (MCP-1). - MCP-1 binds to monocyte G-protein coupled receptor CCR2. - Atherosclerosis is reduced in MCP-1 or CCR2 deficient mice.
45
What is a bad feature about recruiting of monocytes?
It's a positive feedback loop leading to self-perpetuating inflammation.
46
Describe the 'wound healing' role of macrophages in atherosclerosis
Macrophages release growth factors that recruit vascular smooth muscle cells and stimulate them to migrate, survive, proliferate and deposit ECM (structurally strong collagen)
47
What three things do platelet derived growth factors (PDGF) promote?
- VSMC chemotaxis - VSMC survival - VSMC division (mitosis)
48
What two things does transforming growth factor beta (TGF-b) do?
- Increased collagen synthesis - Matrix deposition
49
What overall change do PDGF/TGF-b do to VSMC?
- The VSMCs come from media to subendothelium, divide and stays alive in the toxic environment - The VSMCs then increase collagen synthesis to make the fibrous cap thicker- the cells become less contractile (which they used to maintain bp when normally in media)
50
Which proteinases are expressed to degrade tissue?
- Metalloproteinases (MMPs)- family of 28 homologous enzymes that activate each other by proteolysis - They degrade collagen using a catalytic mechanism based on Zn
51
What is happening in this photo?
The same artery has been stained for macrophages (left) and for collagen (right) in red for both The area that the macrophages occupy is devoid of collagen because the macrophage MMPs have degraded it there
52
What is the end result of the collagen in the fibrous cap being eaten away?
- The collagen separates abnormal material made of dead macrophages from blood flowing through arteries - As it gets eaten by the MMPs, it gets weaker until it ruptures and the blood flowing through the artery touches the abnormal material and coagulates leading to an occlusive thrombus and cessation of blood flow
53
Describe the characteristics of vulnerable plaques
- Large soft eccentric lipid-rich necrotic core - Increased VSMC apoptosis - Reduced VSMC and collagen content - Thin fibrous cap - Infiltrate of activated macrophages expressing MMPs
54
What is the white part of the right image and why does it happen?
- Dead heart muscle - Heart muscle is usually brown because of the myoglobin in it - When it dies it loses the brown colour so MI is white
55
Why does macrophage apoptosis happen in atherosclerosis?
- The OxLDL derived metabolites are toxic e.g. 7-keto-cholesterol. - Macrophage foam cells have protective systems that maintain survival in the face of toxic lipid loading. - Once overwhelmed, macrophages die of apoptosis.
56
What does macrophage apoptosis in atherosclerosis cause release of?
- They release macrophage tissue factors and toxic lipids into the ‘central death zone’ called the **lipid necrotic core** - Thrombogenic and toxic materials accumulate and are walled off by the collagen until the plaque ruptures causing it to meet blood and triggers a clot
57
What is Nuclear factor kappa B (NFkB)?
- A transcription factor - A master regulator of inflammation
58
What does NFkB do in inflammation?
- It directs multiple genes in concert - There are multiple different inflammatory stimuli including IL-1, cholesterol crystals - NFkB then binds to and switches on or off loads of other specific inflammatory genes (also include IL-1)
59
What is NFkB activated by?
Numerous inflammatory stimuli - Scavenger receptors - Toll-like receptors - Cytokine receptors e.g. IL-1
60
What does NFkB switch on?
Numerous inflammatory genes - MMP - Inducible nitric oxide synthase - IL-1
61
What are LDLR and PCSK9?
PCSK9 degrades LDLRs which are receptors that allow LDL to enter hepatocytes. LDLR removes cholesterol from blood and allows it to suppress cholesterol biosynthesis. PCSK9-deficient humans are protected from cardiovascular disease.
62
When are PCSK9 inhibitors now in use for?
For **severe or statin-resistant hyperlipidaemia**: - Antibodies - Antisense -Si-RNA
63
Describe the mechanism of removing cholesterol from arteries and returning them to liver
- **ABCA1 ABCG1 cholesterol export pumps** - Export selective to **Apolipoprotein A** as interactor (found on HDL) - Export to HDL is reverse cholesterol transport - Removes cholesterol from arteries and initiates return to the liver
64
What are the signs and symptoms of atherosclerosis?
- Death of the downstream tissues (heart and brain) - Loss of function of one side of the body (major ischaemic 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
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