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Year 2 - BRS > 5.10 - Atherosclerosis and peripheral vascular disease > Flashcards

5.10 - Atherosclerosis and peripheral vascular disease Flashcards

1
Q

Why is coronary heart disease a rising burden?

A
  • 1990s - minor in world disease rankings
  • 2020 - 32% of global deaths
  • developing world –> diet and lifestyle
  • increasing levels of obesity and diabetes globally
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2
Q

What are the modifiable risk factors for coronary heart disease? (6)

A
  • smoking
  • lipids intake
  • blood pressure
  • diabetes
  • obesity
  • sedentary lifestyle
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3
Q

What are the non-modifiable risk factors for coronary heart disease? (3)

A
  • age
  • sex
  • genetic background
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4
Q

Describe the changes in epidemiology over the last decade that has altered the incidence of the risk factors of coronary heart disease? (5)

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
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5
Q

In the carotid, what do we get where we get carotid plaques?

A

Clear vortex formation exactly where we get carotid plaques

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6
Q

What are the main cell types involved in inflammation (atherosclerosis)? (5)

A
  • vascular endothelial cells
  • platelets
  • monocytes/macrophages
  • vascular smooth muscle cells
  • T lymphocytes
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7
Q

What is the function of vascular endothelial cells (atherosclerosis)? (2)

A
  • barrier function (e.g. to lipoproteins)
  • leukocyte recruitment
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8
Q

What is the function of platelets (atherosclerosis)? (2)

A
  • thrombus generation
  • cytokine and growth factor release
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9
Q

What is the function of monocytes/macrophages (atherosclerosis)? (4)

A
  • foam cell formation
  • cytokine and growth factor release
  • major source of free radicals
  • metalloproteinases (collagen-degrading enzymes)
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10
Q

What is the function of vascular smooth muscle cells? (3)

A
  • migration and proliferation (migrate from thick muscle layer into plaque and proliferate)
  • collagen synthesis (strengthens plaque)
  • remodelling and fibrous cap formation
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11
Q

What is the function of T lymphocytes (atherosclerosis)? (4)

A
  • macrophage activation - CD4 Th1
  • macrophage de-activation - CD4 Treg
  • VSMC (vascular smooth muscle cell) death - CD8 CTL
  • B-cell/antibody help - CD4 Th2
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12
Q

What was the previously thought mechanism of atherosclerosis (‘fatberg’ model)?

A

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

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13
Q

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

A
  • atherosclerosis has an inflammatory basis and is an active process (rather than just passive fat buildup)
  • CANTOS trial showed this - patients at high risk of atherosclerosis complications were injected with antibodies to IL-1
  • fewer major adverse cardiovascular events (MACE) such as stroke and MI in treated patients
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14
Q

Why did anti-IL1 cause fewer major adverse cardiovascular events in patients?

A

Multiple mechanisms including the fact that cholesterol crystals form which activate macrophages to secrete IL-1 (connect lipids and inflammation in atherosclerosis)

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15
Q

When can white blood cells injure host tissue?

A

If activated excessively or inappropriately

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16
Q

What are the main inflammatory cells in atherosclerosis?

A

Macrophages (derived from blood monocytes)

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17
Q

What are macrophage subtypes regulated by?

A

Combinations of transcription factors binding to regulatory sequences on DNA (but we do not yet understand the regulation)

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18
Q

What are the two main types of macrophages?

A
  • inflammatory macrophages
  • non-inflammatory macrophages
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19
Q

What do inflammatory macrophages do?

A

Adapted to kill microorganisms (germs)

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20
Q

What do non-inflammatory macrophages do?

A
  • normally homeostatic functions - may be parenchymal
  • alveolar resident macrophages - surfactant lipid homeostasis
  • spleen - iron homeostasis
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21
Q

What type of macrophages are involved in plaque formation?

A

Both inflammatory and non-inflammatory

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22
Q

What is low density lipoprotein (LDL)?

A
  • ‘bad’ cholesterol - synthesised in liver
  • carries cholesterol from liver to rest of the body including arteries
  • atherosclerotic risk factor
  • J-curve - need LDL to survive, very low levels can lead to mortality
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23
Q

What is oxidised LDL?

A
  • chemical and physical modifications of LDL by free radicals (ROS), enzymes, aggregation
  • oxidised LDLs are not a single substance but families of highly inflammatory and toxic forms of LDL found in vessel walls
  • (modification of LDL that is very bad for us)
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24
Q

What does LDL look like?

A
  • central core of fat
  • lipid monolayer
  • docking molecule ‘molecular address for fat delivery’ - apoprotein (some also interact with clotting and clot lysis)
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25
Q

What is high density lipoprotein (HDL)?

A
  • ‘good’ cholesterol
  • carries cholesterol from peripheral tissues including arteries back to liver (reverse cholesterol transport)
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26
Q

What happens to LDL in atherosclerosis?

A
  • LDLs leak through the endothelial barrier - likely due to endothelial activation in areas of vortex
  • LDL is trapped by binding to sticky matrix carbohydrates (proteoglycans) in the subendothelial layer and becomes susceptible to modification
  • LDL becomes oxidatively modified (oxidised LDL) by free radicals from activated macrophages
  • oxidised LDL is phagocytosed by macrophages (= now known as foam cells) and stimulates chronic inflammation
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27
Q

What is familial hypercholesterolaemia (FH)?

A
  • autosomal genetic disease (main form dominant with gene dosage)
  • massively elevated cholesterol (>20mmol/L, normal 1-5mmol/L)
  • failure to clear LDL from blood
  • xanthomas and early atherosclerosis - if untreated can cause fatal MI before 20yo
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28
Q

What receptors are involved with LDL?

A
  • LDL receptor (LDLR)
  • scavenger receptor
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29
Q

What is the LDL receptor?

A
  • expressed on liver and takes cholesterol into liver from LDL (receptor expression negatively regulated by intracellular cholesterol)
  • cholesterol synthesis 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
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30
Q

What are scavenger receptors?

A
  • not under feedback control
  • found in atherosclerotic lesions on macrophages
  • hoover up chemically modified LDL (macrophage –> foam cell)
  • now known that scavenger receptors are a family of pathogen receptors that ‘accidentally’ bind OxLDL
31
Q

How do PCSK9 inhibitors work?

A
  • additional regulatory control involves PCSK9 - degrades LDLR
  • LDLR removes cholesterol from blood and allows it to suppress cholesterol biosynthesis
  • PCSK9 deficient individuals are protected from cardiovascular disease
  • PCSK9 inhibitors are now in use for severe or statin-resistant hyperlipidaemia
32
Q

What are the roles of ABCA1 and ABCG1?

A
  • cholesterol export pumps (on macrophage) - initiate reverse cholesterol transport
  • 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 liver
33
Q

What does macrophage scavenger receptor A bind and what CD is it?

A
  • known as CD204
  • binds to oxidised LDL
  • binds to gram positive bacteria like Staphylococci and Streptococci
  • binds to dead cells
34
Q

What does macrophage scavenger receptor B bind and what CD is it?

A
  • known as CD36
  • binds to oxidised LDL
  • binds to malaria parasites
  • binds to dead cells
35
Q

When macrophages take up oxidised LDL what two pathways are activated?

A
  • activation of ‘bug clearance’ pathway leading to inflammation as macrophage mistakes LDL deposits as bugs and makes things worse
  • safe clearance of cholesterol and sent to HDL for reverse cholesterol transport - homeostatic response
36
Q

What can macrophages within plaques do that is problematic? (5)

A
  • generate free radicals that further oxidise lipoproteins - macrophages have oxidative enzymes that can modify native LDL
  • phagocytose modified lipoproteins and become foam cells through accumulation of modified LDLs
  • express cytokine mediators that recruit monocytes
  • express chemo-attractants and growth factors for VSMC
  • express proteinases that degrade tissue
37
Q

What oxidative enzymes can macrophages release? (3) - (generate free radicals that further oxidise lipoproteins)

A
  • NADPH oxidase e.g. superoxide O2
  • myeloperoxidase e.g. HOCl hypochlorous acid (bleach) from ROS + Cl-, HONOO peroxynitrite
  • generation of H2O2 - further oxidises LDL and also damages the inside of the artery and causes the plaque to fall apart
38
Q

How can macrophages become foam cells? (Phagocytose modified lipoproteins and become foam cells)

A

Phagocytose modified lipoproteins = macrophages accumulate modified LDLs (via scavenger receptors) to become enlarged foam cells

Staining: stained with brown-dyed antibody to CD68 (macrophage-specific lysosome protein)

39
Q

What are the two types of mediators released by macrophages that recruit monocytes? (express cytokine mediators that recruit monocytes)

A
  • cytokines
  • chemokines
40
Q

What are cytokines? (express cytokine mediators that recruit monocytes)

A

Protein immune hormones that activate endothelial cell adhesion molecules

41
Q

What cytokines are released from macrophages? (express cytokine mediators that recruit monocytes)

A
  • interleukin 1 - triggers intracellular cholesterol crystals and NFkB, coordinates multiple processes including cell death and proliferation, and elevated CRP
  • also upregulates VCAM-1 which mediates tight monocyte binding
  • atherosclerosis is reduced in mice without IL-1 and humans with anti-IL1 antibodies
42
Q

What are chemokines? (express cytokine mediators that recruit monocytes)

A

Small protein chemoattractants to monocytes

43
Q

What chemokines are released by macrophages? (express cytokine mediators that recruit monocytes)

A
  • 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
44
Q

What is a bad feature about the process of macrophages releasing cytokines and chemokines that recruit monocytes? (express cytokine mediators that recruit monocytes)

A

Positive feedback loop/vicious cycle leading to self-perpetuating inflammation

45
Q

Describe the ‘wound healing’ role of macrophages in atherosclerosis (express chemo-attractants and growth factors for VSMC)

A

Macrophages release growth factors (PDGF, TGF-B) that recruit VSMC and stimulate them to migrate, survive, proliferate and deposit extracellular matrix –> structurally strong collagen

46
Q

What three things do platelet derived growth factors (PDGF) promote? (express chemo-attractants and growth factors for VSMC)

A
  • vascular smooth muscle cell chemotaxis
  • vascular smooth muscle cell survival
  • vascular smooth muscle cell division (mitosis)
47
Q

What two things do transforming growth factor beta (TGF-B) do? (express chemo-attractants and growth factors for VSMC)

A
  • increased collagen synthesis
  • matrix deposition
48
Q

What overall change do PDGF and TGF-B do to VSMC? (express chemo-attractants and growth factors for VSMC)

A
  • VSMCs migrate from media to subendothelium, divide and stay alive in toxic environment
  • VSMCs then increase collagen synthesis to make the fibrous cap thicker - cells become less contractile (which they used to maintain BP normally in media)
  • VSMC reduced contractile filaments, increased matrix deposition genes
49
Q

What proteinases are released by macrophages? (express proteinases that degrade tissue)

A
  • metalloproteinases (MMPs) - family of 28 homologous enzymes that activate each other by proteolysis
  • degrade collagen using a catalytic mechanism based on zinc
50
Q

What does a stained image showing macrophages and collagen show? (express proteinases that degrade tissue)

A

The area that the macrophages occupy is devoid of collagen because the macrophage MMPs have degraded it there

51
Q

How do plaques erode/rupture? (express proteinases that degrade tissue)

A
  • collagen separates abnormal material made of dead macrophages from blood flowing through arteries
  • degradation by MMPs until it ruptures and blood flowing through artery touches abnormal material and coagulates
  • leads to occlusive thrombus and cessation of blood flow
52
Q

Why does macrophage apoptosis happen in atherosclerosis?

A
  • oxLDL derived metabolites are toxic e.g. 7-keto-cholesterol
  • macrophage foam cells have protective system that maintain survival in face of toxic lipid loading
  • once overwhelmed, macrophages die via apoptosis
53
Q

What does macrophage apoptosis in atherosclerosis cause release of?

A
  • 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
54
Q

What are macrophage functions in atherosclerosis pathophysiology? (6)

A
  • secrete inflammatory cytokines and chemokines
  • phagocytose, process and export cholesterol to reverse cholesterol transport (HDL)
  • secrete oxidants that damage cells and LDL
  • accumulate cholesterol and become sick and activated by cholesterol overload
  • secrete matrix metalloproteinases which degrade fibrous cap collagen
  • initiate death of VSMCs

Five macrophage functions from earlier + VSMC death + export to HDL

55
Q

What are the characteristics of vulnerable plaques? (5)

A
  • large soft eccentric lipid-rich necrotic core
  • increased VSMC apoptosis
  • reduced VSMC and collagen content
  • thin fibrous cap
  • infiltrate of activated macrophages expressing MMP
56
Q

What does dead heart muscle look like?

A
  • white compared to healthy brown muscle
  • normal heart muscle brown due to myoglobin present
  • when it dies it loses the brown colour, so MI heart is white/pale - coagulative necrosis
57
Q

What is Virchow’s Triad (three reasons for thrombosis)?

A
  • abnormal vessel wall
  • abnormal blood
  • abnormal flow
58
Q

How can abnormal vessel wall cause thrombosis in atherosclerosis?

A
  • ruptured plaque - grossly abnormal
  • macrophages express tissue factor
  • huge amounts of highly abnormal lipid
  • loss of endothelial surface
  • artery interior ripped apart and exposed
  • collagen exposed
  • toxic oxylipids exposed
  • dead cells exposed
59
Q

How can abnormal blood cause thrombosis in atherosclerosis?

A

May also play a role - increased clotting factors in at-risk patients

60
Q

How can abnormal flow cause thrombosis in atherosclerosis?

A

May also play a role - very tight stenoses

61
Q

How can the balance of bleeding/thrombosis be tipped?

A
  • protection against bleeding
  • protection against over-clotting
  • balance can be tipped towards thrombosis
62
Q

What can prevent formation of clots? (5)

A
  • antiplatelet drugs
  • aspirin
  • clopidogrel
  • thrombolytics (thrombolytic therapy to lyse clots)
  • percutaneous coronary intervention
63
Q

What produces thromboxane A2?

A

The prostaglandin thromboxane A2 is produced by platelets from arachidonic acid

64
Q

How does aspirin work?

A
  • aspirin irreversibly blocks COX
  • platelets cannot make more COX = prevents platelet aggregation
  • however endothelial cells can make more COX (PTGS1) and therefore inhibits platelet aggregation
65
Q

How does clopidogrel work?

A

Irreversibly blocks the ADP receptor on platelets

66
Q

What are clotting factors?

A
  • clotting factors are almost all serine proteases
  • they cut other proteins
  • plasmin cuts up fibrin
  • tissue plasminogen activator (and streptokinase) cut an inhibitor off plasmin, activating it
67
Q

What are the signs and symptoms of thrombosis?

A
  • death of the downstream tissues (heart and brain)
  • loss of function on one side of the body (major ischaemic stroke)
  • severe central crushing chest pain with fear, dizziness and nausea (MI)
  • angina
  • thrombogenic toxic material accumulates, walled off, until plaque rupture causes it to meet blood
68
Q

What is nuclear factor kappa B (NFkB)?

A
  • a transcription factor
  • a master regulator of inflammation (predominant non-redundant highly connected network hub)
69
Q

What does nuclear factor kappa B (NFkB) do in inflammation? (3)

A
  • directs multiple genes in concert
  • multiple different inflammatory stimuli including IL-1 and cholesterol crystals
  • coregulation (bind to and switch on) of multiple different inflammatory genes (also include IL-1)
70
Q

What is nuclear factor kappa B (NFkB) activated by? (3)

A
  • activated by numerous inflammatory stimuli:
    • scavenger receptors
    • toll-like receptors
    • cytokine receptors e.g. IL-1
71
Q

What does nuclear factor kappa B (NFkB) switch on? (3)

A
  • switches on numerous inflammatory genes:
    • matrix metalloproteinases
    • inducible nitric oxide synthase
    • IL-1
72
Q

What is a summary of atherosclerosis?

A
  1. risk factors (smoking, hypertension, diabetes, hyperlipidaemia, location - disturbed flow) disrupt endothelial cells and activate them, making them sticky + VCAM-1 expression
  2. monocytes (macrophages) bind to VCAM-1, entering the tissue
  3. endothelial cells also open up and let material out e.g. LDL which sticks and becomes susceptible to oxidation (ROS from macrophages)
  4. oxLDL binds to scavenger receptors in macrophage
  5. macrophages take up oxLDL –> larger and fatter (foam cells)
  6. macrophages secrete ROS, cytokines, chemokines, MMPs, apoptotic and growth factors
  7. activated macrophages release PDGF –> VSMC recruitment to secrete collagen and form fibrotic cap
  8. death - release and accumulation of tissue factor and toxic oxidised lipids
73
Q

What is the main mechanism by which LDL promotes atherosclerosis?

A

Deposited in artery walls, easily oxidises, and is taken up by plaque macrophages, causing their activation

Year 2 - BRS (84 decks)

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