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Y2 - BRS - CVR > Atherosclerosis & Peripheral Vascular Disease Tutorial > Flashcards

Atherosclerosis & Peripheral Vascular Disease Tutorial Flashcards

1
Q

What is atherosclerosis?

What can atherosclerosis affect?

A

Plaque (fatty deposits) formed via a complex imflammatory process - composed of inflammatory cells (macrophages), smooth muscle cells and accumulation of lipids

Arteries and blood flow - can lead to heart attack (MI), stroke, etc.

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2
Q

What are the risk factors of atherosclertoic CVD?

A 
Modifiable =
Smoking
Lipids intake 
BP
Diabetes
Obesity
Sedentary lifestyle

Non-modifiable =
Age
Sex
Genetic background

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3
Q

How can risk factors be assessed numerically?

A

Multiply the risk factors e.g. if smoking increases atherosclerosis by 1.6x, hypertension by 3x and high cholesterol by 4x; the numerical risk factor would be 1.6 x 3 x 4 = x16

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4
Q

What are the changes in epidemiology over the last decade that consequently affects occurrence of atherosclerosis?

A

Reduced hyperlipidaema (statin treatment)

Reduced hypertension (antihypertensive treatment)

Increased obesity leading to increased diabetes

New improvements in diabetes treatment have doubtful effects on macrovascular disease

Changing pathology of coronary thrombosis possibly related to altered risk factors

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5
Q

Why is atherosclerosis focal, if the risk factors are general (e.g. hypertension, hyperlipidaemia)?

A

Depends on blood flow

Tends to happen at sites with turbulent flow as it sets up a lot of inflammatory changes in the vessel wall

Eventually leading to focal atherosclerosis depending on where the in the arteries the blood flow got messed up (i.e. turbulent instead of laminar)

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6
Q

Where does LDL deposit to set off inflammatory response in atherosclerosis?

A

Low density lipoproteins (LDL) deposit in the subintimal space of an artery (lies between the intima and adventitia) and binds to matrix proteoglycans

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7
Q

What are the stages of progression to developing atherosclerosis?

A

Artery at lesion prone location - adaptive thickening of SMC

Type II lesion - macrophage foam cells

Type III lesion (prearthroma) - small pools of extracellular lipid

Type IV lession (atheroma) - extracellular lipid continues to build forming the core of the plaque

Type V lesion (fibroatheroma) - fibrous thickening via proliferation of abscess wall surrounding the extracellular lipid at the core

Type VI lesion (complicated lesion) - fissure (small tear in blood vessel) and hematoma (bleeding outside blood vessel) in this lesion leads to ruptured plaque with overlying thrombus

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8
Q

When does a type VI (complicated) lesion lead to acute coronary syndrome (ACS)?

A

When stenosis (narrowing) of artery outweights collateralisation (formation of new blood vessels to bypass block and supply same area)

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9
Q

What is the natural progression of atherosclerosis?

What are the complications of atherosclerosis?

A

Normal artery –> intermediate lesion –> advanced lesion –> complications

Enlarged lipid core = stenosis of artery
Ruptured plaque = lipid thrombosis
Leads to ACS

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10
Q

When is the window of opportunity for primary prevention?

A

Normal –> intermediate –> advanced lesions:
Lifestyle modifications
Risk factor management

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11
Q

When is it important to gain clinical intervention?

A 
During complications:
Secondary prevention
Catheter based interventions
Revascularisation surgery
Treatment of heart failure
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12
Q

What are the main cell types involved in atherogenesis?

A 
Vascular endothelial cells
Monocyte macrophages
Vascular smooth muscle cells
Platelets
T lymphocytes
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13
Q

What are the main immune cells involved?

How do they contribute to atherogenesis / atherosclerosis progression?

A

Macrophages and monocytes - foam cell formation, cytokine and growth factor release, major source of free radicals, metalloproteinases (degrade collagen and allow for SMC migration)

T-lymphocytes - macrophage activation

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14
Q

What are the main vascular cells involved?

How do they contribute to atherogenesis / atherosclerosis progression?

A

Vascular endothelial cells - barrier function (e.g. to lipoproteins), leukocyte recruitment

Vascular smooth muscle cells - migration and proliferation, collagen synthesis, remodelling and fibrous cap formation

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15
Q

What cells in the blood are involved in atherosclerosis?

How do they contribute to atherogenesis / atherosclerosis progression?

A

Platelets - engage in cytokine and growth factor release, leads to thrombus generation esp. during rupture of plaque

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16
Q

How do we know atherosclerosis has an inflammatory response involved?

A

CANTOS trial

Patients at high risk of atherosclerosis complications were recruited

Blind trial where some were injected with IL-1 antibodies, control group got placebo

Fewer major adverse cardiovascular events (MACEs) in drug group VS strokes / heart attacks in placebo

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17
Q

What does the CANTOS trial suggest in treatment of preventing CVD?

A

IL-1 Abs successful treatment in preventing CVD events

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18
Q

How do macrophages primarily contribute to atherosclerosis?

A

Macrophages engulf lipids (e.g. oxi-LDL) until they become weighed down by the lipids and form foam cells

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19
Q

What is the death zone?

A

Lipid necrotic core
Dead / dying macrophages with ingested / accumulated cholesterol release the cholesterol
Cholesterol crystallises = crystalline form of cholesterol deposited

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20
Q

How can WBCs cause harm?

What are the 2 main classes of macrophages how is the production of macrophages from blood monocytes controlled??

A

White blood cells can injure host tissue if they are activated excessively or inappropriately

Inflammatory and Resident macrophages
Controlled / regulated by combination of transcription factors binding to regulatory sequences on DNA (not yet fully understood)

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21
Q

What is the function of inflammatory macrophages?

A

Adapted to kill microorganisms (germs)

22
Q

What are the functions of resident macrophages?

A

Normally homeostatic - suppress inflammatory activity

Alveolar resident macrophages - surfactant lipid homeostasis

Osteoclasts - calcium and phosphate homeostasis

Spleen - iron homeostasis

23
Q

What are the 3 types of lipoproteins and what are their functions?

A

Low Density Lipoproteins (LDL) = synthesised in liver and carries cholesterol from liver to rest of body, often called ‘bad’ cholesterol, but we all require it in small amount, LDL risk curve is a ‘U’ shape, not a ‘/’

High Density Lipoproteins (HDL) = carries cholesterol from ‘peripheral tissues’ including arteries back to liver (=“reverse cholesterol transport”), ‘good’ cholesterol

Oxidised LDLs (oxi-LDLs), modified LDLs = formed due to action of free radicals on LDLs, they are not one single substance i.e. families of highly inflammatory and toxic forms of LDL are found in vessel walls

24
Q

How does oxidised LDL (oxi-LDL) lead to atherosclerosis?

A

LDL oxidatively modified by free radicals

Leads to macrophage activation

25
Q

How are LDLs trapped in the subendothelium modified?

A

LDLs leak through endothelial barrier by uncertain mechanisms

Lals are trapped by binding to the sticky matrix carbohydrates (proteoglycans) in the subendothelial layer and become susceptible to modification e.g. oxidation

LDL becomes oxidatively modified by free radicals - oxi-LDL is phagocytosed by macrophages and this stimulates chronic inflammation

26
Q

What are foam cells?

A

The macrophages that engulf the oxi-LDLs are known as ‘foam cells’

27
Q

What is Familial hyperlipidemia (FH)?

A

Autosomal genetic disease - failure to clear LDL from blood leads to massively elevated cholesterol (20 mmol/L)

Those with FH would die in their teens / 20s from CVD complications due to build up of LDL and atherosclerosis

28
Q

Why was the discovery of the LDL receptor important in FH and cholesterol homeostasis in medicine?

A

Brown and Goldstein discovered LDL receptor

Cholesterol synthesis is negatively regulated by cellular cholesterol, so in LDL-receptor negative patients, it would lead to the accumulation of cholesterol due to lack of negative feedback

Led to the discovery of HMG-CoA reductase inhibitors (= “statins”) for lowering plasma cholesterol

29
Q

What are macrophage scavenger receptors (MSR)?

A

MSRs are second LDL-receptors that are not under feedback control of cholesterol - these are found in atherosclerotic lesions

30
Q

What are the 2 types of macrophage scavenger receptors?

A

MSR A - known as CD204: binds to gram-positive bacteria (e.g. staphylococci and streptococci) and dead cells

MSR B - known as CD36: binds to malaria parasites and dead cells
binds to oxidised LDL

However, both ALSO bind to oxidised LDL
This triggers the activation of the inflammation pathways
Leads to the recruitment of more inflammatory cells e.g. macrophages

31
Q

What are the functions of activated macrophages?

A

Generate free radicals that further oxidise lipoproteins

Phagocytose modified lipoproteins, & become foam cells

Express cytokine mediators that recruit monocytes

Express chemo-attractants & growth factors for vascular smooth muscle cells

Promote wound healting

Express proteinases that degrade tissue

32
Q

How do macrophages generate free radicals?

A

Macrophages have oxidative enzymes that can modify native LDLs leading to more oxi-LDL formation

e.g. NADPH Oxidase
Myeloperoxidase

Macrophages accumulate modified LDLs to become enlarged foam cells

33
Q

How do macrophages express cytokine mediators to recruit monocytes?

A

Plaque macrophages express many cytokines to recruit monocytes

e.g. IL-1: upregulates molecule VCAM-1 –> leads to upregulation of vascular cell adhesion, mediates tight monocyte binding

Atherosclerosis is reduced in mice without IL-1 or VCAM-1

Also express chemokines (small protein chemoattractants) to monocytes = recruitment of monocyte chemoattractant protein-1 (MCP-1) which bind to monocyte G-protein coupled receptor CCR2

Atherosclerosis is reduced in MCP-1 or CCR2 deficient mice

34
Q

How do macrophages promote wound healing?

A

Release of complementary protein growth factors that recruit vascular smooth muscle cells to stimulate them to proliferate and deposit on the extracellular matrix

35
Q

What chemo-attractants and growth factors do macrophages express?

A

Platelet derived growth factor:

Vascular smooth muscle cell chemotaxis
Vascular smooth muscle cell survival
Vascular smooth muscle cell division

Transforming growth factor beta:

Increased collagen synthesis
Matrix deposition

36
Q

How do macrophages express proteinases that degrade tissue?

A

Metalloproteinases (= MMPs) are a family of around 28 homologous enzymes that degrade tissue by degrading collagen

MMPs activate each other by proteolysis

And MMPs work on a catalytic mechanism based on Zn

37
Q

How does the release of MMPs from macrophages lead to a vulnerable and unstable plaque?

A

So initially, macrophages make smooth muscle cells produce collagen, but at a later stage they also release MMP that break down collagen

This weakens the fibrous cap on the atherosclerosis

38
Q

How can the vulnerable plaque rupture and cause thrombosis?

A

Plaque’s fibrous cap weakens as MMPs degrade the collagen, so the plaque can eventually rupture from blood flow

Ruptured plaque releases necrotic core = platelet activation

Blood coagulation at site of rupture may lead to thrombus = stopping of blood flow

39
Q

What are the characteristics of a vulnerable and unstable plaque?

A

Large soft eccentric lipid-rich necrotic core

Increased vascular smooth muscle cell apoptosis

Reduced vascular smooth muscle cell & collagen content

Thin fibrous cap

Infiltrate of activated macrophages expressing MMPs

40
Q

How does coronary artery thrombosis and MI link together?

A

Thrombus occludes a coronary artery

No blood flow to that region of the heart

Leads to infarction of heart tissue

And eventually death

41
Q

How do macrophages go through apoptosis during atherosclerosis?

A

Oxi-LDL derived metabolites are toxic e.g. 7-keto-cholesterol

Macrophage foam cells have protective systems that maintain survival in face of toxic lipid loading

Once overwhelmed, macrophages die via apoptosis

42
Q

What triggers / leads to macrophage apoptosis?

A

Once protective systems (e.g. HDL) are overwhelmed - macrophages die via apoptosis

43
Q

What do dead macrophages result in?

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

44
Q

What is Nuclear Factor Kappa B (NFkB)?

A

Transcription factor that is the master regulator of inflammation

45
Q

What is the role of NFkB?

A

Activated by numerous inflammatory stimuli:
Scavenger receptors
Toll-like receptors
Cytokine receptors e.g. IL-1

These switch on numerous inflammatory genes:
Including IL-1 itself
Matrix metalloproteinases (MMPs)
Inducible nitric oxide synthase

IL-5 activates kappa B (positive feedback loop)

46
Q

Summary of macrophages in atherosclerosis:

A
  1. Risk factors: smoking, hypertension, diabetes, hyperlipidaemia, location - disturbed flow
  2. Risk factors cause edothelial cells to retract and become permeable
  3. LDL slips through the endothelial lining into the subintimal layer, where it binds to proteoglycans in the matrix
  4. The LDL oxidises to form oxidised LDL (oxLDL)
  5. Endothelial cels become sticky and express VCAM-1, this attaches monocytes to it
  6. Monocytes emigrate into the vessel wall
  7. Monocytes express scavenger receptors - the oxLDL meets these and activates the scavenger receptors
  8. The activation causes the monocytes to differentiate into macrophages and take up oxLDL
  9. The monocytes and macrophages also secrete growth factors to stimulate the SMCs to proliferate, thickening the artery wall and surrounding the plaque
  10. The SMCs therefore make more collagen to strengthen the fibrous cap on the plaque (Stable plaque formation)
  11. Macrophages continue to uptake more oxLDL via scavenger receptors = activates Kappa B to secrete reactive oxygen species (radicals)
  12. This closes a positive feedback loop, as oxygen radicals go on to oxidise more LDL into oxLDL
  13. Kappa B also secretes cytokines which further activates endothelial cells - second viscious cycle
  14. Causes endothelial cells to secrete more chemokines - attracts more monocytes leading to third vicious cycle
  15. Also causes macrophages to secrete MMPs which degrades collagen
  16. Generates weakening of plaque = plaque rupture by degradation of artery wall
  17. Leads to thrombosis as necrotic core in plaque is exposed to the bloods pro-thrombolytic factors and platelets
47
Q

What is atherogenesis?

A

The formation of atherosclerotic plaque in the subintimal layer

48
Q

What triggers atherogenesis?

A

Endothelial dysfunction
Mechanical sheer stresses (HTN)
Biochemical abnormalities (elevated and modified LDL, DM, elevated plasma homocysteine)
Immunological factors (free radicals from smoking)
Inflammation ( infection such as chlamydia, Helicobacter)
Genetic alteration

49
Q

What is the pathophysiology of the fatty streak phase in atherogenesis?

A

Dysfunctional endothelial cells and retention of lipoproteins (LDL, VLDL etc)

Leads to increased expression of monocyte interaction (migration into intimal space)

Other immune cells that mediate the internalization of LDL by macrophages to form foam cells

50
Q

What is the pathophysiology of plaque progression in atherogenesis?

A

Infiltration and proliferation of tunica media smooth muscle cells

Various growth factors e.g. transforming growth factor-β (TGF-β), fibroblast growth factors (FGF), etc)

SMC’s are recruited to the luminal side of the lesion to form a barrier between lesional prothrombotic factors

51
Q

What is the pathophysiology of a stable plaque?

A

Fibrous cap composed of layers of smooth muscle cells ensconced in a substantial extracellular matrix network

It provides an effective barrier preventing plaque rupture

Stable plaques have small necrotic cores

The production of TGF-β by T-regulator cells and macrophages maintains fibrous cap quality by being a potent stimulator of collagen production in smooth muscle cell

52
Q

What is the pathophysiology of an unstable / vulnerable plaque?

A

It is a result of increased and unresolved inflammatory status of core

This unresolved inflammation causes thinning of the fibrous cap

Areas of thin fibrous cap are prone to rupture exposing prothrombotic components to platelets and pro-coagulation factors leading to thrombus formation and clinical events

Y2 - BRS - CVR (21 decks)

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