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Pathology > Atherosclerosis > Flashcards

Atherosclerosis Flashcards

1
Q

What is atherosclerosis?

A

Atherosclerosis is the accumulation of fibrolipid plaques in systemic (as opposed to pulmonary) arteries.

It causes a huge amount of illness by reducing the blood flow in important areas e.g. myocardial infarction in the heart.

Could lead to occlusion of vessels

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2
Q

Definition of atherosclerosis

A

Disease characterized by the formation of atherosclerotic plaques in the intima of large and medium-sized arteries, e.g. coronary arteries

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3
Q

What is the time course for atherosclerosis?

A

birth - no atherosclerosis
* late teenage/early 20s - fatty streaks in aorta, may not
progress to established atherosclerosis
* 30s/40s/50s - development of established atherosclerotic
plaques
* 40s-80s - complications of atherosclerotic plaques e.g.
thrombosis, intraplaque haemorrhage

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4
Q

What are the risk factors for atherosclerosis?

A
  • hypertension
  • hyperlipidaemia
  • cigarette smoking
  • poorly-controlled diabetes mellitus
    Hypercholesterolemia - most important factor
    Males
    Age
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5
Q

What is the pathogenesis of atherosclerosis?

A

Endothelial Damage theory:
* endothelial cells are delicate
* easily damaged by cigarette smoke, shearing forces at arterial divisions, hyperlipdaemia, glycosylation products
* cumulative damage leads to endothelial ulceration, microthrombi, eventual development of established atherosclerotic plaques

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6
Q

What are the complications of atherosclerosis?

A

If an atherosclerotic plaque
completely blocks an artery (usually by superadded thrombosis or haemorrhage within the plaque) then no blood will flow to the organ supplied by that artery and (unless
there is a second arterial supply which is unusual in the
body) the organ will die (infarct).

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7
Q

What happens if an atherosclerotic plaque breaks off?

A

It can travel downstream to block smaller vessels (embolism).
This may cause small infarcts distal to the main atherosclerotic plaque and over time these cumulative effect of these small infarcts can be significant.

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8
Q

Where does atherosclerosis happen mostly?

A

Occurs in high pressure vessels – pulmonary arteries, relatively low pressure, high pressure in aorta – lots of atherosclerosis

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9
Q

What happens if atherosclerosis occurs in the aorta?

A

It can cause an aortic aneurysm leading to death

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10
Q

How does atherosclerosis form?

A

1.Endothelial cell dysfunction (lots of cholesterol damages wall)
2.High levels of LDL in the blood will begin to accumulate in the arterial wall
3.Macrophages are attracted to the site of damage and take up lipid to form foam cells (inflammatory response)
4.Formation of a fatty streak (earliest stage of plaque)
5.The activated macrophages will release lots of their own products - cytokines and growth factors
6.Smooth muscle proliferation (to intima) around the lipid core and formation of a fibrous cap (collagen)

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11
Q

What are some other features of atherosclerosis ?

A

Often asymptomatic
The accumulation of lipid, macrophages and smooth muscle cells in intimal plaques
Can cause life-threatening damage if a thrombus forms on a disrupted plaque

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12
Q

What type of disease can atherosclerosis cause?

A

Cerebral infarction
Carotid atheroma, leading to TIAs
MI
Aortic aneurysm (can cause sudden death)
Peripheral vascular disease
Gangrene

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13
Q

which is the best-known risk factor for coronary artery disease

A

Age

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14
Q

What are the risk factors for atherosclerosis?

A

Age
Tobacco Smoking
High Serum Cholesterol – LDL gets into artery walls – taken up by macrophages and make vessel wall bigger and bigger
Obesity
Diabetes
Hypertension
Family History

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15
Q

How does tobacco cause atherosclerosis?

A

Damages the inner layer of arteries – damages endothelium – nicotine kills endothelium – cells die

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16
Q

How does obesity cause atherosclerosis?

A

Whole body inflammation – fat cells harbour inflammatory cells

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17
Q

How does diabetes cause atherosclerosis?

A

change in glucose damages vessels – unstable glucose damages vessel

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18
Q

How does hypertension cause atherosclerosis?

A

repeated damage to blood vessel by high blood flow

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19
Q

What are the key cell types of endothelial cells?

A

endothelial cells, smooth muscle cells, macrophages, fibroblasts

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20
Q

What are the arterial wall layers?

A

Endothelium, tunica media, tunica intima, adventitia

21
Q

How are atherosclerotic plaques distributed?

A

Focally distributed – some areas of normality – not the whole vessel usually

22
Q

What is atherosclerotic plaque distribution based on?

A

HAEMODYNAMIC FACTORS

Changes in flow/turbulence (eg at bifurcations) cause the artery to alter endothelial cell function.

Wall thickness is also changed leading to neointima. Altered gene expression in the key cell types is key.

23
Q

What is a neointima?

A

new intimal layer

24
Q

What is the structure of an atherosclerotic plaque?

A

Lipid
Necrotic core
Connective tissue
Fibrous “cap”

25
Q

What will an atherosclerotic plaque eventually cause?

A

Eventually the plaque will either occlude the vessel lumen resulting in a restriction of blood flow (angina), or it may “rupture” (thrombus formation – death).

26
Q

What happens in disease?

A

Medial thinning – tunica media in orange – in disease it thins

27
Q

How does atherosclerosis occur?

A

Initiated by an injury to the endothelial cells which leads to endothelial dysfunction.

Signals sent to circulating leukocytes which then accumulate and migrate into the vessel wall.

Inflammation ensues

28
Q

Libby movie

A

Look back at the recording of fundamentals of atherogenesis lecture

29
Q

What causes inflammation in the arterial wall?

A

LDL - can pass in and out of the arterial wall
in excess it accumulates in arterial wall, and undergoes oxidation and glycation.

Endothelial dysfunction - response to injury hypothesis (27 flashcard)

30
Q

What are chemoattractants?

A

chemicals that attract leukocytes

31
Q

What is the stimulus for adhesion for leukocytes?

A

Once inflammation is initiated, chemoattractants are released from endothelium and send signals to leukocytes.

Chemoattractants are released from site of injury and a concentration-gradient is produced.

32
Q

What are some inflammatory constituents found in plaques?

A

IL-1
IL-6
IL-8
IFN-g
TGF-b
MCP-1
c-reactive protein

33
Q

Leukocyte recruitment to vessel walls

A

Same as diapedesis basically, extravasion

34
Q

Progression of atherosclerosis steps:

A
  1. Fatty streaks
  2. Intermediate lesions
  3. Fibrous Plaques or Advanced Lesions
  4. Plaque Rupture
  5. Plaque Erosion – more prominent in women
35
Q

What happens in 1. Fatty streaks?

A

Earliest lesion of atherosclerosis

Appear at a very early age (<10 years)

Consist of aggregations of lipid–laden macrophages and T lymphocytes within the intimal layer of the vessel wall

Mainly inflammatory cells in fatty streaks

36
Q

What happens in 2. Intermediate lesions?

A

Composed layers of:
Lipid laden macrophages (foam cells)
Vascular smooth muscle cells
T lymphocytes
Adhesion and aggregation of platelets to vessel wall
Isolated pools of extracellular lipid

37
Q

What happens in 3. Fibrous Plaques or Advanced Lesions?

A

Impedes blood flow

Prone to rupture
Covered by dense fibrous cap made of ECM proteins including collagen (strength) and elastin (flexibility) laid down by SMC that overlies lipid core and necrotic debris

May be calcified

Contains: smooth muscle cells, macrophages and foam cells and T lymphocytes

Might have some angina

38
Q

What happens in 4. Plaque rupture?

A

Plaques constantly grow and recede. Dynamic

Fibrous cap has to be resorbed and redeposited in order to be maintained.

If balance shifted eg in favour of inflammatory conditions (increased enzyme activity), the cap becomes weak and the plaque ruptures.

Basement membrane, collagen, and necrotic tissue exposure as well as haemorrhage of vessels within the plaque

Thrombus (clot) formation and vessel occlusion

39
Q

How do we detect plaque rupture?

A

We detect plaque rupture by ECG.

40
Q

What happens in 5.plaque erosion (more common in women)?

A

Second most prevalent cause of coronary thrombosis

Lesions tend to be small ‘early lesions’

A thickened fibrous cap may lead to collagen triggering thrombosis rather than tissue factor (as in plaque rupture)

A platelet-rich clot may overlie the luminal surface.

There is usually a small lipid core

Plaque erosion could be cause of Heart attack

41
Q

Differences between plaque rupture and plaque erosion?

A

Ruptured plaque has a large lipid core with abundant inflammatory cells

Eroded plaques have a small lipid core, disrupted endothelium, more fibrous tissue and a larger lumen.

42
Q

What is a red thrombus?

A

rbcs and fibrin

43
Q

What is a white thrombus?

A

Platelets and fibrinogen

44
Q

What is a Neutrophil extracellular traps?

A

extruded DNA, and enzymes which cause cell activation and cytokine release.

Involved in plaque erosion and rupture

45
Q

Timeline of atherogenesis?

A

Healthy vasculature - Selectin and adhesion molecules, LDL
Endothelial activation - Leukocyte adhesion, rolling and migration then cytokine release and leukocyte recruitment
Early lesion - Platelet adhesion and activation
Advanced lesion - VSMC migration and proliferation then Fibrous cap and foam cell accumulation
Atherothrombosis - Plaque activation and aggregation, plaque rupture and thrombosis

46
Q

What are the treamtents of Coronary Heart disease?

A

PCI - Percutaneous Coronary Intervention

2 million + procedures / year worldwide

More than 90% of patients require stent implantation

Restenosis was a major limitation, no longer though due to drug eluting stents

47
Q

What are coronary statements used in patients today made of?

A

Metal - titanium

48
Q

Summary of atherosclerosis?

A

Atherosclerotic lesions are dynamic - changing with age and health status

Environmental factors are key, including genetics

Molecular mechanisms in plaques are becoming known and can be targeted with drugs.

Major cell types involved in atherogenesis are endothelium, macrophages, smooth muscle cells and platelets
I
nflammation is critical in the plaque life cycle

Stents plus medical therapies have been hugely successful treatments built upon knowledge of the fundamental biology of the vessel wall

Pathology (7 decks)

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