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Cardiovascular & Respiratory Medicine > Atherosclerosis > Flashcards

Atherosclerosis Flashcards

1
Q

What are the modifiable risk factors for atherosclerosis?

A
  1. Smoking
  2. Lipids intake
  3. Blood pressure
  4. Diabetes
  5. Obesity
  6. Sedentary lifestyle
  7. Hypertension
  8. High cholesterol
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2
Q

What are the non-modifiable risk factors for atherosclerosis?

A
  1. Age
  2. Sex
  3. Genetic background
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3
Q

Describe the changes in epidemiology of atherosclerosis that have been seen 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
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4
Q

If the risk factors are general, why is atherosclerosis focal?

A
  1. Plaques/ stenosis tend to form at the “bends” of vessels- cause inflammation
  2. Bends of vessels= VORTEX:
    - systolic flow generates long lasting vortexes
    - This is where/ why a plaque is formed
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5
Q

What are the main cell types involved in atherosclerosis?

A
  1. Vascular endothelial cells: barrier function and recruits leukocytes
  2. Platelets: thrombosis
  3. Monocyte- macrophages
  4. Vascular smooth muscle cells
  5. T lymphocytes
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6
Q

What is the role of vascular endothelial cells in athersclerosis?

A
  • Barrier function (e.g. to lipoproteins)
  • Leukocyte recruitment
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7
Q

What is the role of platelets in athersclerosis?

A
  • Thrombus generation
  • Cytokine and growth factor release
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8
Q

What is the role of monocyte-macrophages in athersclerosis?

A
  • Foam cell formation (accumulate fat from cells)
  • Cytokine and growth factor release
  • Major source of free radicals (highly reactive- used to kill bacteria, but in contact with macrophages converts fat to dangerous form)
  • Metalloproteinases (degrade collage; weaken plaques)
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9
Q

What is the role of vascular smooth muscle cells in athersclerosis?

A
  • Migration and proliferation
  • Collagen synthesis (strengthens the plaque- stabilises= myocardial infarction)
  • Remodelling & fibrous cap formation
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10
Q

What is the role of T lymphocytes in athersclerosis?

A
  • Macrophage activation- CD4 Th1
  • Macrophage de-activation- CD4 Treg
  • VSMC death- CD8 CTL (kills smooth muscle cells)
  • B-Cell/ Antibody help- CD4 Th2
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11
Q

is the formation of atherosclerosis as active process? why/ why not?

A

Yes: involves INFLAMMATION (not just fat depositing on artery walls with no reaction)
- CANTOS Trial showed that atherosclerosis has an inflammatory basis
- Patients at high risk of atherosclerosis complications injected with antibodies to Interleukin -1 (IL-1) (stimulates inflammatory response)
- Fewer major adverse cardiovascular events (MACE) mostly stroke and heart attacks in treated patients

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12
Q

What is the role of lipids in atherosclerosis?

A

Multiple mechanisms including cholesterol crystal formation connect lipids and inflammation in atherosclerosis:
- Cholesterol crystal formation= less heart attacks/ strokes
- Cholesterol gets absorbed by macrophages
- forms crystals after build up
- Crystals release IL-1
- The cholesterol crystals induce physical injury in the plaque core, promoting cell apoptosis and triggering an increased inflammatory response

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13
Q

describe the role/ importance of macrophages in atherosclerosis

A
  • White blood cells can injure host tissue if they are activated excessively or inappropriately!
  • In atherosclerosis, the main inflammatory cells are macrophages, which are derived from blood monocytes
  • Macrophage subtypes are regulated by combinations of transcription factors binding to regulatory sequences on DNA. However, we do not yet understand the regulation!
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14
Q

What are the 2 types of macrophages involved in atherosclerosis?

A
  1. Inflammatory macrophaes:
    - Adapted to kill microorganisms (germs)
  2. Non-inflammatory and resident macrophages:
    - Normally homeostatic functions (mediate tight control of tissue metabolites (e.g. in alveolar/ osteocytes in bones)– may be parenchymal
    - Alveolar resident macrophages - surfactant lipid homeostasis
    - Spleen - iron homeostasis (regulate iron)
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15
Q

What is the “J curve” in terms of LDL in atherosclerosis?

A

This curve shows that those with higher blood pressure and/or cholesterol levels, closer to the top of the curve, are more likely to die from CVD. The curve also shows that those at the lowest end of the curve (with very low blood pressure and/or low cholesterol levels) also have higher CVD mortality.

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16
Q

How does LDL affect your risk of cardiovascular diseases?

A

LDL= “Low density lipoprotein”
‘Bad’ cholesterol - Synthesised in liver.
Carries cholesterol from liver to rest of the body including arteries.
- not completely bad (we need some of it)
- Only becomes bad by the action of free radical enzymes + aggregation at bends)
- Higher LDL= higher level of CVDs

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17
Q

How does HDL affect your risk of cardiovascular diseases?

A

HDL= “High density lipoprotein”
Good’ cholesterol
Carries cholesterol from ‘peripheral tissues’ including arteries back to liver (=“reverse cholesterol transport”)
- Lower HDL= higher level of CVDs

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18
Q

How do oxidised LDL(s) and modified LDL(s) affect your risk of cardiovascular diseases?

A
  • Chemical and physical modifications of LDL by free radicals, enzymes, aggregation
  • Families of highly inflammatory and toxic forms of LDL found in vessel walls.
  • Increases risk of CVDs
19
Q

Describe the structure of an LDL

A
  1. Have a docking molecule “molecular addresses for fat delivery”- used to dock onto specific protein sites
  2. Inner core= triglycerides and phospholipids= cargo fat for fuel
  3. Lipid monolayer (like cell membrane) but one molecule thick- separating fats from water on the outside
  4. Highly inflammatory
  5. Made up of cholesterol and phospholipids
20
Q

Describe the mechanism by which LDL can become trapped in the subendothelium, and what this can cause?

A
  1. LDLs leak through the endothelial barrier –likely due to endothelial activation in areas of vortex.
  2. LDL is trapped by binding to sticky matrix carbohydrates (proteoglycans) in the sub-endothelial layer and becomes susceptible to modification (oxidation/ burning)
  3. Best studied modification is oxidation – free radical attack from activated macrophages
  4. LDL becomes oxidatively modified by free radicals. Oxidised LDL is phagocytosed by macrophages and are then known as “foam cells”. These cells stimulate chronic inflammation
21
Q

What is familial hyperlipidemia?

A
  • Autosomal genetic disease (main form dominant with gene dosage)
  • Causes massively elevated cholesterol (>~20 mmol/L). (effective ‘normal’ ~1-5 mmol/L)
  • It’s caused by a genetic mutation that means your liver fails to clear LDL from blood.
  • Causes Xanthomas and early atherosclerosis; if untreated fatal myocardial infarction before age 20
22
Q

What are some symtpoms/ presentations of familial hyperlipidemia/ hypercholesterolemia?

A

Xanthoma: certain fats build up under the surface of the skin. Xanthomas are raised, waxy-appearing, frequently yellowish-colored skin lesions.

Foam cells: (macrophages within xanthoma)- appear as raised red lesions on the skin

23
Q

What are the 2 types of receptors found that can be found on LDL?

A
  1. LDL receptor
  2. Scavenger receptor
24
Q

What is the role of the LDL receptor?

A

(LDL receptors are present on the cell membranes of liver cells (hepatocytes) and other cells throughout the body- expression negatively regulated by intracellular cholesterol)
- Pick up LDLs circulating in the bloodstream and transport them into the cell.
- Once inside the cell, the LDL is broken down to release cholesterol.
- The cholesterol is then used by the cell, stored, or removed from the body
- Excess cholesterol in the cells suppresses the formation of new LDL receptors
- so the intake of cholesterol in the form of LDL into the cells decreases
- In LDLR-negative patients, macrophages accumulate cholesterol

25
Q

What is the role of scavenger receptors?

A

“hoover up chemically modified LDL”- abnormal form of LDL not under any neg feedback (continue)
- Macrophages in atherosclerotic lesions have been shown to express ≥6 structurally different scavenger receptors for uptake of modified forms of low-density lipoproteins (LDLs)
- Although the removal of modified LDLs would seem beneficial, the pathways following scavenger receptor uptake that metabolize the modified lipoproteins appear to become overwhelmed
- leading to the accumulation of cholesterol-laden macrophages and establishment of a chronic inflammatory setting
- Now known that scavenger receptors are a family of pathogen receptors that ‘accidentally’ bind OxLDL.
- There are 2 types of macrophages scavenger receptors that are used to internalise Ox-LDL

26
Q

What are the 2 types of scavanger recptors found on macrophages?

A
  1. Macrophage scavenger receptor A:
    Known as CD204
    Binds to oxidised LDL
    Binds to Gram-positive bacteria like Staphylococci & Streptococci
    Binds to dead cells
  2. Macrophage scavenger receptor B:
    Known as CD36
    Binds to oxidised LDL
    Binds to malaria parasites
    Binds to dead cells
27
Q

What are the 2 possible outcomes of Ox-LDL uptake via macrophage scavenger receptors?

A

Arterial Ox-LDL deposits (after internalised & activated by macrophaes) can lead to either:

  1. Activation of ‘bug-detector’ pathways= INFLAMMATION
  2. Safe clearance, reverse cholesterol transport= HOMEOSTASIS

Can be dominated by either (usually in balance)

28
Q

Describe the mechanism of action of HMG-CoA reducatase inhibitors

A
  • Cholesterol synthesis is also negatively regulated by cellular cholesterol. Led to the discovery of HMG-CoA reductase inhibitors (= “statins”) for lowering plasma cholesterol.
  • Decreases liver cholesterol synthesis
29
Q

Describe the mechanism of action of PCSK9 inhibitors

A
  • PCSK9 degrades LDLR (increases cholesterol levels)
  • LDLR removes cholesterol from blood and allows it to suppress cholesterol biosynthesis
  • PCSK9-deficient humans are protected from cardiovascular disease
  • PCSK9 inhibitors are now in use for severe or statin-resistant hyperlipidemia:
  • Antibodies
  • Antisense
  • Si-RNA
30
Q

How do macrophages generate free radicals that further oxidise lipoproteins?

A

Macrophages have oxidative enzymes that can modify native LDL:
a) NADPH Oxidase, for example superoxide O2- (dangerous- can interact with + mutate DNA/ proteins= death of cells)
b) Myeloperoxidase (esp found in macrophages in vessel walls), for example, HOCl hypochlorous acid (bleach) from ROS + Cl-, HONOO Peroxynitrite (causes extreme tissue damage)
c) Generation of H2O2

31
Q

Describe the mechanism by which foam cells are formed by macrophages

A

Macrophages accumulate modified LDLs to become enlarged foam cells

32
Q

What microscopic features are seen when macrophages change to foam cells?

A
  1. Cholesterol crystals (long/ jaggered- triggers macrophages to secrete inflammatory mediators)
  2. Zone of sick and dying foam cells
  3. Fat globules (triglycerides insoluble in water)
  4. Foam cell debris (dead toxic stuff)
33
Q

What cytokine mediators are released by macrophages to recruit monocytes

A

Cytokines – protein immune hormones that activate endothelial cell adhesion molecules
- Interleukin-1 – triggers eg 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

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.

Immunosuppression a big problem as a side effect
Positive feedback loop / vicious cycle leading to self-perpetuating inflammation

34
Q

Describe the wound healing role of macrophages in atherosclerosis

A

Macrophages release growth factors that recruit VSMC (vascular smooth muscle cells) and stimulate them to migrate, survive, proliferate and deposit extracellular matrix e.g. structurally strong collagen
- “Platelet derived growth factor” and “Transforming growth factor beta” change the VSMCs from contractile to synthetic
- Contractile VSMCs had higher contractile filaments but decreased matrix deposition genes
- Wheras synthetic VSMCs have lower contractile filaments and increased matrix deposition genes

35
Q

What are the specific effects of the growth factors: “Platelet derived growth factor” and “Transforming growth factor beta”

A

Platelet derived growth factor:
Vascular smooth muscle cell chemotaxis
Vascular smooth muscle cell survival
Vascular smooth muscle cell division (mitosis)

Transforming growth factor beta:
Increased collagen synthesis
Matrix deposition

36
Q

How do macrophages with plaques degrade tissues?

A
  • Express proteinases (Metalloproteinases (=MMPs))
  • Family of ~28 homologous enzymes.
  • Activate each other by proteolysis.
  • Degrade collagen.
  • Catalytic mechanism based on Zn.
37
Q

What complications can be caused if a macrophage with a plaque ruptures?

A

Blood coagulation at the site of rupture may lead to an occlusive thrombus and cessation of blood flow:
1. Occlusive thrombus
2. All macrophage contents (e.g. factors) spill out + react with blood= trigger clot formation= myocardial infarction

38
Q

What are the characteristics of vulnerable and stable plaques?

A
  1. Large soft eccentric lipid-rich necrotic core
  2. Increased VSMC apoptosis
  3. Reduced VSMC & collagen content
  4. Thin fibrous cap
  5. Infiltrate of activated macrophages expressing MMPs
39
Q

What sites are commonly affected by thrombosis/ myocardial infarction in atherosclerosis?

A
  • Thrombus occluding left anterior descending coronary artery (supplies the left wall & septum)
  • Anteroseptal myocardial infarction
  • ECG – ST-segment elevation anterior leads (T-wave inversion seen later); also a VE (doesn’t let action potential get through quickly= reentrant tachycardia= reduced co-ordination/ control- AP just goes round and round= cardial arreats)
40
Q

What can lead to macrophage apoptosis following athersclerosis?

A
  1. OxLDL derived metabolites are toxic eg 7-keto-cholesterol.
  2. Macrophage foam cells have protective systems that maintain survival in face of toxic lipid loading
  3. Once overwhelmed, macrophages die via apoptosis
  4. Release macrophage tissue factors and toxic lipids into the ‘central death zone’ called lipid necrotic core
  5. Thrombogenic and toxic material accumulates, walled off, until plaque rupture causes it to meet blood
41
Q

Summarise the macrophage functions in atherosclerosis

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
  • Release macrophage tissue factors and toxic lipids into the ‘central death zone’ called lipid necrotic core
  • Initiate death of vascular smooth muscle cells
42
Q

What are the signs and symptoms of athersclerosis?

A

Death of the downstream tissues (heart and brain)
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

43
Q

What is Nuclear Factor Kappa B (NFkB)?

A

(Transcription Factor) A “Master regulator” of inflammation; predominant non-redundant highly connected network hub (connects + integrates many inflammatory stimuli/ different roles of macrophages)

  1. NF-kappa-B directs multiple genes in concert:
    - Multiple different inflammatory stimuli including IL-1 and cholesterol crystals
    - Coregulation of multiple different inflammatory genes (also include IL-1)
  2. Switches on numerous inflammatory genes
    - Matrix metalloproteinases
    - Inducible nitric oxide synthase
    - Interleukin-1
44
Q

What factors can activate NFkB?

A

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

Cardiovascular & Respiratory Medicine (14 decks)

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