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Atherosclerosis Flashcards

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1
Q

What is atherosclerosis?

A

Chronic inflammation resulting from interaction between lipoproteins, macrophages, T cells and normal arterial wall elements.
This develops plaques that damage the major arteries and leads to cardiovascular disease.

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2
Q

What are the types of atherosclerosis?

A

Acute coronary syndromes
Cerebrovascular disease
Peripheral vascular disease.

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3
Q

What are acute coronary syndromes?

A

Stable and unstable angina
Stable - can continue daily life but exertion causes breathlessness and tight chest.
Unstable - excessive stenosis, feels symptoms without exertion. Requires intervention by stenting or angioplasty.
This can lead to myocardial infarction.

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4
Q

What is cerebrovascular disease?

A

Strokes
Transient ischaemic attacks (TIAs)
Linked to carotid artery blockage - thrombi form at the plaque and dislodge, go to secondary sites in the brain.

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5
Q

What is peripheral vascular disease?

A

Intermittent claudication - narrowing or blockage in arteries in legs. Causes pain, discolouration and loss of function.
Renal failure - promotes oxidative stress and plaque formation.

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6
Q

Where does atherosclerosis occur?

A

Large arteries, not veins.
Especially at bifurcations, as there is turbulent flow, which causes the endothelium to express different molecules and tight junctions become leaky.
All large arteries are affected but especially important are lesions in: coronary arteries, carotid arteries, renal arteries, femoral arteries.

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7
Q

What is coronary atherosclerosis?

A

The vessels in the heart are narrowed or blocked.
This causes extreme chest pain and an elevated ST wave on ECG.

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8
Q

What is stable plaque phenotype?

A

The lipid core of the atheroma is walled off by a thick fibrous cap formed by extracellular matrix components.
The smooth muscle cells drive ECM protein production.
The stable plaque is asymptomatic.

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9
Q

What is vulnerable plaque phenotype?

A

The fibrous cap thins.
The plaque can rupture, which exposes plaque lipids and tissue factor to blood components, initiates coagulation cascade, platelet adherence and thrombosis.
The thrombus blocks blood flow, and causes myocardial infarction.
The thrombi can be cleaved and lodges in a secondary vascular bed which causes transient ischaemic attack.

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10
Q

How do you prevent vulnerable plaque?

A

Modifiable risk factors - exercise and diet changes.
Non-modifiable risk factors - genetics related to predisposition of vulnerable plaque phenotype.

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11
Q

What are macrophage foam cells?

A

The major cell types in plaques.
Foam cells assimilate (eat) lipids, using a range of expressed receptors.

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12
Q

What are the cell types in atherosclerotic plaques?

A

Endothelial cells - gatekeepers of vessels.
Smooth muscle cells - in medial layer, for structure and vascular tone of blood vessels.
Platelets
Macrophages
CD4 helper T cells.

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13
Q

What are platelets?

A

Form haemostatic plugs.
Communicate with other immune cells - macrophages and T cells to drive inflammatory mechanisms.

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14
Q

What are T helper cells in atherosclerotic plaques?

A

CD4 TH cells are adaptive immune cells.
They communicate with macrophages to promote their activity.
This drives pro-inflammatory function, which can exacerbate the local plaque environment.

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15
Q

What is the structure of an artery wall?

A

Endothelium - single cell barrier of vessel wall, separates the intima from the blood.
Intima
Internal elastic lamina (borders media)
Media - contains smooth muscle cells.
External elastic lamina (borders media)
Adventitia
Vaso vasorum
see picture

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16
Q

What is the role of the adventitia in atherosclerosis?

A

Forms ectopic lymphoid structures as the plaque develops.
This is rich in T cells.
Other immune cells from plaques drain into the lymphatics in the adventitia, then drain into lymph node.

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17
Q

What are vaso vasorum?

A

These are blood vessels that supply large blood vessels.
Neovascularisation - formation of new blood vessels that can supply the plaque.

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18
Q

How is the endothelium activated?

A

Turbulent flow - exposes the endothelium to new factors.
Excessive pro-inflammatory cytokines - IL-1, TNF-a, oxLDL, LPS.
The endothelium begins expressing adhesin molecules.

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19
Q

What is endothelium adhesin molecule expression?

A

Expresses adhesin molecules - ICAM-1, VCAM, E-selectin, P-selectin.
These allow circulating white cells e.g. monocytes to interact with the blood vessel walls.
The immune cells slow down and adhere to the endothelial cells, then migrate to the subendothelial space in the intima.
The monocytes mature into macrophages which begins plaque development.

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20
Q

What are the mediators released by endothelial cells?

A

Vasodilators - nitric oxide, prostaglandin I2 (PGI2).
Vasoconstrictors - endothelin, angiotensin II.
Anti-thrombotic factors - tissue plasminogen activator (tPA), PGI2).
Prothrombotic factors - thromboxane A2, Plasminogen Activator inhibitor-1 (PAI-1).

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21
Q

What is nitric oxide?

A

When produced by endothelial cells, it is protective through acting as a vasodilator, which reduces blood pressure.
When produced from inducible nitric oxide synthase from macrophages, it contributes to LDL oxidation, which is involved in plaque formation.

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22
Q

What are platelets?

A

Small cytoplasmic fragments of megakaryocytes.
Essential for endothelial cell repair.
Essential role in haemostasis - forming haemostatic plugs.
Life span of 8-10 days in circulation.

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23
Q

How do platelets communicate with white blood cells?

A

Platelets shed material into vesicles, which can then go to white blood cells such as monocytes.
The cargo is taken up by monocytes, and can drive the development into foam like macrophages.
These foam cells generate inflammatory mediators and drives the development of plaques.

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24
Q

What do platelets do?

A

Adhere to sub-endothelium via collagen receptors, which are exposed when the endothelium is damaged.
Tissue factor is also exposed, and can be recognised by platelets which then start to form thrombi.
Secrete important SMC growth factors e.g. PDGF.
Secretes vasoactive mediators e.g. TxA2, 5HT.

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25
What are vascular smooth muscle cells?
VSMCs provide muscular arteries with elasticity. Mediate vasodilation and vasoconstriction. Regulate blood pressure.
26
What is smooth muscle differentiation?
SMCs can become synthetic and contractile SMCS, which produce elastin and collagen for the ECM. The ECM proteins form the fibrous cap, which prevents the plaque from becoming vulnerable through walling off. Macrophage-induced SMC apoptosis is seen in vulnerable plaques.
27
How are monocytes recruited to endothelium?
The endothelium produces chemotactic molecules which attract the monocytes. The monocytes then tether on the endothelial wall, and roll along through interaction of P-selectin glycoprotein ligand 1 (PSGL-1) with endothelial selecting. The monocytes become firmly adhered to the endothelial cells through integrin interaction with endothelial cells, and then enter the subendothelial space - diapedesis.
28
What are the chemotactic molecules?
The oxidised LDL (oxLDL) can induce expression of chemotactic molecules by the endothelial cells. e.g. monocyte chemotactic protein 1 (MCP-1), which attracts the monocyte to the endothelium.
29
What do monocytes do in the subendothelial space?
Macrophage colony stimulating factor (M-CSF) drives monocyte differentiation into macrophages. At first macrophages remove cytotoxic and proinflammatory oxLDL particles or apoptotic cells. But progressive accumulation of macrophages and their uptake of oxLDL leads to development of atherosclerotic lesions.
30
What is cholesterol accumulation in macrophages?
Macrophages upregulate scavenger receptors SR-A and CD36 which facilitates uptake oxLDL into macrophages, lipids accumulate and macrophages develop into foam cells. Foam cells are the major constituent found in fatty streak atheroma plaques.
31
What are macrophages?
Macrophages differentiate from recruited monocytes. Accumulate modified LDL via Scavenger Receptors (SRs). Macrophage foam cells are the main cell type in fatty streak lesions. Secrete inflammatory mediators e.g. IL-1, TNF-a, LTB4, Chemokines. Secretes growth factors e.g. M-CSF, PDGF, FGFs.
32
What are the growth factors that macrophages secete?
M-CSF = monocyte colony secreting factor. PDGF - platelet derived growth factor. FGF - fibroblast growth factor
33
How do macrophages cause plaque rupture?
Matrix metalloproteinases (MMPs) degrade extracellular matrix components - fibronectin, laminin, collagen, elastin. This weakens the fibrous cap which protects the necrotic core. Tissue inhibitor of metalloproteinases (TIMPs) can reduce this, but there needs to be a balance between TIMP and MMP to avoid going from a stable to a vulnerable plaque.
34
How do macrophages affect smooth muscle cells?
Macrophages can trigger apoptosis in SMCs, by activating Fas apoptotic pathway, and secreting TNFa and nitric oxide. Can also decrease collagen synthesis without SMC death e.g. through macrophage decreasing its secretion of TGFB which deprives SMCS of this TGF-B needed for collagen biosynthesis.
35
What is the effect of the necrotic core?
The necrotic core contributes to inflammation, thrombosis, proteolytic plaque breakdown and physical stress on the fibrous cap which leads to thinning. Necrotic cores arise from apoptosis of advanced lesional macrophages and defective phagocytic clearance - efferocytosis of apoptotic macrophages in advanced plaques. Macrophage apoptosis does not trigger plaque necrosis, but when apoptotic macrophages are not sufficiently cleared by efferocytosis it does.
36
What is CD68?
A protein expressed on macrophages. When staining for CD68 and for collagen, the region enriched with macrophages is absent of collagen. This shows the macrophages lead to breakdown of collagen. See picture.
37
What is the transition from simple fatty steak to a complex lesion?
This is characterised by immigration of smooth muscle cells from the media to the intimal/subendothelial space. The SMCs proliferate and take up oxLDLs, which contributes to foam cell formation. TH2 cytokine IL-4 has antagonists effects on atherogenic IFN-y activity.
38
What else furthers the progression of atherogenesis?
There is continued monocyte recruitment. Intra plaque microvessels develop from the adventitia and supplies blood to the plaque. Fibro fatty plaques protrude into the artery lumen and cause stenosis (narrowing). The endothelium forms gaps, which are plugged by platelets, but thrombi can dislodge and cause secondary CVD complications.
39
What is the antiatherogenic effects of T cells in lesions?
Lesional T cells are activated and express Th1 and Th2 cytokines. TH1 IFN-y reduces scavenger receptor expression on macrophages, decreases collagen synthesis and inhibits SMC proliferation.
40
What are the atherogenic effects of T cells in lesions?
T cells mainly have an atherogenic effect. IFN-y stimulates macrophage production of proinflammatory cytokines, and increased expression of MHC II. This increases the accumulation of macrophages within lesions, and enhances their ability to present antigens to T cells to cause inflammation.
41
What are the potential fates of fibro-fatty plaques?
Ulceration - exposes endothelium. Thrombosis Vasospasm - causes vasoconstriction, which can cause ischaemia. Embolism - dislodged thrombi and go into pulmonary circulation, fatal Plaque haemorrhage - bleeding into plaque. Aneurysm - local dilation Artery rupture, especially in cerebral arteries.
42
What are the plasma components in atherogenesis?
Lipoproteins Coagulation cascade components. Acute phase reactants - C-reactive protein (CRP) and Complement components Oxidants and anti-oxidants.
43
What are coagulation cascade components?
Damaged endothelial cells express tissue factor, which activates Factor X. Factor X converts prothrombin to thrombin, which activates fibrinogen to fibrin and platelets. Fibrin forms a stable mesh to reinforce the platelet plug and form a thrombus.
44
What is c-reactive protein?
Reduces nitric oxide in endothelial cells which reduces vasodilation. Upregulates adhesion molecules - VCAM-1 and ICAM-1, which facilitates monocyte adhesion and migration. Enhances uptake of oxLDL by macrophages to form foam cells. Stimulates SMCs to proliferate. Increases expression of MMPs, which degrade the fibrous cap.
45
What are plasma oxidants?
Reactive oxygen species oxidises LDL to oxLDL which is taken up by macrophages to form foam cells. Impairs nitric oxide vasodilation. Stimulate MMPs. Activate transcription factors for expression of adhesion molecules and cytokines for immune cell recruitment.
46
What is the classification of lipoproteins?
Based on density: Chylomicrons Very low density lipoprotein (VLDL) Intermediate density lipoprotein (IDL) Low density lipoprotein (LDL) High density lipoprotein (HDL)
47
What are the features of lipoproteins?
VLDL, IDL and LDL are pro-atherogenic. HDL is anti-atherogenic - reverse cholesterol transport and anti-oxidant properties.
48
What are VLDLs?
VLDL particles contain apolipoprotein B-100 and apolipoprotein E, synthesised in the liver and function to transport fatty acids to adipose tissue and muscle. After triglyceride removal from peripheral tissues, some of the VLDL are metabolised to LDL by further removal of triglycerides and apolipoproteins.
49
What is LDL?
LDL is needed to transport cholesterol to peripheral tissues, but increased levels are associated with increased risk of CVD. Circulating levels of LDL are determined by its rate of uptake through hepatic LDL receptors.
50
How can LDL cholesterol be modified?
Can be decreased by medical intervention - statins, bile acid sequestrants. Lifestyle changes - diet, exercise, plant stanols.
51
What are statins?
Lower circulating cholesterol levels by inhibiting HMG CoA reductase, the rate limiting enzyme required for endogenous cholesterol biosynthesis. Decrease in intracellular cholesterol leads to activation of SREBP transcription factors, which stimulate transcription of LDLR gene. So there is upregulation of LDLR and enhanced clearance from plasma degradation of LDL, reducing its circulating levels.
52
How can LDL be modified?
Can be decreased by medical intervention - statins, bile acid sequestrants. Lifestyle changes - diet, exercise, plant stanols.
53
What is HDL cholesterol?
Low plasma HDL is associated with increased risk of CVD. Mediates reverse cholesterol transport. Important source of anti-oxidants.
54
What are the major components of HDL?
ApoA1, ApoE Reduces inflammation and thrombosis Promotes cholesterol efflux.
55
What are the components of dysfunctional HDL?
ApoCIII, Lp-PLA2, SAA1. Reduced cholesterol efflux. Increased inflammation Increased thrombosis.
56
What are modifiable risk factors for Coronary heart disease?
High plasma LDL cholesterol. Hypertension Physical inactivity/ obesity, BMI >30 Smoking Diabetes
57
What are non-modifiable risk factors for CHD?
Personal history of CHD. Family history of CHD. Advanced age Gender
58
What are genetic causes of high LDL levels?
Familial hypercholesterolaemia - Impaired LDLR, which causes cholesterol accumulation. Defective apoB - which circulates LDL. Increases risk of developing CVD
59
What are genetic causes of low HDL?
Tangier disease - defective ABC1 transporter, which transports cholesterol from cells into HDL, esterified and exchanged for triglycerides. ApoA1 deficiency, major component for HDL Increases risk for CVD.
60
What are genetic causes of lowered CVD risk?
Low LDL-C levels - PSCK9 loss of function PSCK9 is involved in recycling of LDLR, for cholesterol uptake.
61
What is the LDL receptor?
When receptor binds LDL, receptor becomes internalised with the cargo. The endosome fuses with lysosome and breaks away the LDL and metabolises it into cholesterol. This cholesterol can then be used for endogenous synthesis pathways - cell membrane, hormones, bile acids. Receptor recycled back onto surface and re-expressed on plasma membrane.
62
What is the defective LDLR in familial hypercholesterolaemia?
Proportion of outside of receptor is intact. But the intracellular portion doesn’t have a domain, the receptors fail to internalise LDL, which causes excessive accumulation of LDL in circulation.
63
What are genetic variations contributing to CVD risk factors?
ApoE, causes high LDL. Low HDL levels, caused by Hepatic lipase, ApoA1, CETP, LPL. Coagulation deficiency, caused by fibrinogen B, PAI-1, factor VIII. High blood pressure, by angiotensin converting enzyme.
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