Theme 2 - Genetic and environmental cause of disease: Part 1 Flashcards
1
Q
What is an atheroma?
A
Intimal lesion that protrudes into a vessel wall. It consists of a raised lesion with a soft core of lipid and is covered by a fibrous capsule
2
Q
What does the fibrous cap of an atheroma consist of?
A
Smooth muscle cells, macrophages, foam cells, lymphocytes, collagen, elastin
3
Q
What does the necrotic centre of an atheroma consist of?
A
Cell debris, cholesterol crystals, foam cells, calcium
4
Q
What are foam cells?
A
Lipid macrophages that contain cholesterol
5
Q
What is the inner most and middle layer of an artery?
A
inner most - endothelium
middle - smooth muscle
6
Q
Which vessels are commonly affected by atheroma?
A
- bifurcations (sites of turbulent flow)
- abdominal aorta
- coronary arteries
- popliteal arteries
- carotid vessels
7
Q
What are the 9 risk factors for HDL?
A
- age
- male gender
- family history
- genetic abnormalities
- hyperlipidaemia (LDL:HDL)
- hypertension
- cigarette smoking
- diabetes
- C-reactive proteins
8
Q
How does atherosclerosis start?
A
-chronic inflammatory response to damage or injury to the inner layer of an artery
9
Q
What can cause damage to the inner layer of an artery?
A
- High BP
- high cholesterol
- an irritant, such as nicotine
- certain diseases e.g diabetes
10
Q
What is the response to injury hypothesis?
A
- Chronic endothelial injury
- Endothelial dysfunction (e.g increased permeability, leukocyte adhesion) and emigration
- Smooth muscle emigration from media to intima. Macrophage activation
- Macrophages and smooth muscle cells engulf lipid
- Smooth muscle proliferation, collagen and other ECM deposition, extracellular lipid
11
Q
What are the two events leading up to atherosclerosis?
A
- Fatty streak
- earliest lesion
- composed of lipid filled foamy macrophages
- begin as minute flat yellow spots that coalesce into streaks
- not all fatty streaks are destined to progress to atheromatous plaques - Atherosclerotic plaque
- intimal thickening and lipid accumulation
- thrombus on plaque appears red
12
Q
What are the sequelae of atherosclerosis?
A
- Rupture, ulceration or erosion
- haemorrhage into plaque
- atheroembolism
- aneurysm formation
13
Q
What is a thrombus?
A
- A solid mass of blood constituents formed within the vascular system
- a blood clot inside a vein or artery
14
Q
What is the sequence of events from an initial lesion to a complicated lesion?
A
- Initial lesion
- Fatty streak
- Intermediate lesion
- Atheroma
- Fibroatheroma
- Complicated lesion
15
Q
What is stasis and turbulence?
A
both abnormal blood flow
stasis - reduced blood flow
turbulence - increased flow
16
Q
What are the 3 causes of thrombosis?
A
Vircows triad
- abnormal blood flow
- endothelial injury
- hypercoagulability
17
Q
What is coagulation?
A
Blood clotting
18
Q
What is claudication?
A
pain on walking due to reduced blood flow to the legs
19
Q
What are the differences between arterial thrombosis and venous thrombosis?
Think about mechanism, location, diseases, composition, treatment
A
Arterial thrombosis:
- typically from rupture of atheromatous plaque
- left heart chambers, arteries
- ishaemic stroke, claudication
- mainly platelets
- anti-platelet agents (clopidogrel)
Venous thrombosis:
- typically from combination of factors from Virchow triad
- muscle and valves of veins
- DVT, PE
- mainly fibrin
- anticoagulants (heparin, warfarin)
20
Q
What is polycythemia?
A
Increase in number of red blood cells in the body. Increase in number causes blood to be thicker, which can cause clots
21
Q
What are the differences between clots and thrombus ?
A
Clots:
- platelets not involved
- occurs outside vessel
- red
- gelatinous
- not attached to vessel wall
Thrombus:
- platelets involved
- occurs only inside vessel
- red (venous), pale (arterial)
- firm
- attached to vessel wall
22
Q
What is an embolus?
A
- A thrombus that breaks loose and travels from one location in the body to another
- becomes lodged in a vessel and blocks its lumen
- most common is a PE derived from DVT
23
Q
What are some sequelae of thrombosis?
A
- occlusion of vessel- causing ischaemia or infarction
- dissolution
- incorporation into vessel wall
- recanalisation
- embolisation
24
Q
What is hypoxia?
A
When the oxygen supply to tissues is impaired. Other metabolites e.g glucose are still available
25
What is ischaemia?
- the interruption / disturbance of blood flow to cells and tissues
- this reduces oxygen supply AND metabolites
26
What is individual cell death in ischaemic injury called?
necrosis
27
What is infarction?
Ischaemia (inadequate blood supply) leading to cell death (necrosis)
28
What are the mechanisms of ischaemic cell injury?
- decrease ATP
- increase lactate
- failure of Na pump --> accumulation of Na+
- membrane damage
- leakage of intracellular proteins (creatine kinase, troponin, transaminases)
- failure of Ca pump --> accumulation of Ca2+
- decrease protein synthesis
29
So how can we detect ischaemia?
- lactate levels
| - intracelular proteins
30
What are the 6 causes of ischaemia?
1. Vascular occlusion (atherosclerosis, thrombosis, embolism, hyper viscosity)
2. Vasospasm
3. Vascular damage
4. Extrinsic compression e.g tumour
5. Mechanical interruption e.g torsion
6. Hypoperfusion e.g cardiac failure
31
Why does the nature of the blood supply have an impact on the outcome of ischaemia?
-an alternative blood supply means less damage
-tissues with dual vascular supply are generally resistant to infarction
e.g lungs: pulmonary and bronchial veins
liver: hepatic artery and portal veins
Kidneys, spleen, testes have one artery to supply the region and are hence more vulnerable to infarction
32
What factor decides whether ischaemia causes reversible or irreversible cell injury?
duration of ischaemia
33
Why does a slower rate of developing vascular occlusion make it less likely to infarct tissue?
Allows time for development of alternative perfusion pathways (collateral supply)
34
What are the 5 variables that affect whether ischaemia is reversible or irreversible?
1. nature of blood supply
2. duration of ischaemia
3. rate of vascular occlusion
4. tissue vulnerability
5. blood oxygen content
35
What are the two types of necrosis seen in ischaemia?
1. Coagulative necrosis
| 2. Liquefactive / colliquative necrosis
36
How does coagulative necrosis work?
- denaturation of enzymes means they are unable to break down cell structure
- basic outline of cell is preserved for a few days (eosinophillic 'ghost cells')
- tissue remains firm
37
How does liquefactive necrosis work?
- mode of injury is enzyme digestion
- cells complete digested and broken down within hours
- tissue is liquified which creates a cavity or cyst within the brain
38
What colour are infarcts in organs with a single blood supply?
white
39
What colour are infarcts in organs with a dual blood supply?
red
40
What are the order of processes in irreversible cell injury?
1. Biochemical alteration --> cell death
2. Ultrastructural changes
3. Light microscopic changes
4. Gross morphologic changes
41
Why would there be yellowing of a myocyte undergoing coagulative necrosis?
neutrophil infiltration
42
How do you treat ischaemia clinically?
therapeutic repercussion of ischaemia
43
How might repercussion augment tissue damage?
- generation of reactive oxygen species by sudden repercussion of ischaemic tissue
- heart might be salvaged but not function correctly
44
what is the commonest cause of ischaemia?
vascular occlusion
45
What is shock?
- A state of reduced systemic tissue perfusion due to cardiovascular collapse / reduced mean artery pressure
- This hypo perfusion leads to ischaemia, multi-organ failure and eventually death
46
What are the 3 types of shock?
1. Hypovolaemic
2. Cardiogenic
3. Distributive
47
How does hypovolaemic shock occur?
- intravascular fluid loss
- decreased venous return to heart (pre load)
- decreased stroke volume
- decreased cardiac output
48
How does patient compensate for hypovolaemic shock?
- increase heart rate
| - patient will become tachycardic to increase MAP
49
What are the causes of hypovolaemic shock?
- haemorrhage (trauma, GI bleeding, fractures)
| - non-haemorrhagic fluid loss (diarrhoea, vomiting, burns)
50
How does cardiogenic shock occur?
-cardiac pump failure
51
How do we compensate during cariogenic shock?
MAP drops so we increase total peripheral resistance through the sympathetic nervous system to compensate
52
What are the 4 types of cardiogenic shock?
1. myopathic (heart muscle failure)
2. arrhythmia related
3. mechanical
4. extra-cardiac (anything outside the heart that impairs cardiac filing e.g PE)
53
What is distributive shock caused by?
-decrease SVR due to severe vasodilation
54
What are the subtypes of distributive shock?
septic shock, anaphylactic shock, neurogenic shock, toxic shock syndrome
55
What criteria is used to decide if patient has a PE?
Wells criteria
56
What causes a swollen, tender leg?
- outflow blocked
- increased hydrostatic pressure
- collateral blood flow
57
What are the other symptoms of PAD?
- hair loss on legs and feet
- numbness/ weakness in legs
- ulcers on feet that don't heal
- shiny skin
- erectile dysfunction
- changing skin colour on legs e.g blue
- gangrene
58
What is ischaemic heart disease?
- inadequate blood supply to myocardium
- decrease coronary blood flow
- myocardial hypertrophy
59
What are the majority of cases of IHD caused by?
a reduction in coronary blood flow due to obstruction of the coronary arteries by atheroma
60
What is the NIH Framingham risk score calculation?
risk assessment tool for estimating your 10-year risk of having a heart attack
61
What are 2 other risk calculators ?
- SCORE
| - QRISK3
62
What is angina pectoris?
paroxysmal attacks of chest pain - constricting, squeezing, choking
Typically 2 patterns:
-typical/stable
-crescendo/unstable
63
What is acute ischaemia?
atheroma + acute thrombosis/ haemorrhage
64
Explain the gross morphology of an MI
<24 hr: normal
1-2 days: pale, oedematous, myocyte necrosis
3-4 days: yellow with haemorrhage edge
1-3 weeks: red-grey to grey white, pale, thin
3-6 weeks: dense fibrous scar
65
What is a subendocardial myocardium?
- A subendocardial infarct results in necrosis exclusively involving the innermost aspect of the myocardium
- relatively poorly perfused under normal conditions
- can infarct without any acute coronary occlusion
66
What are the symptoms of an MI?
- pain or discomfort in chest
- light headedness, nausea or vomiting
- jaw, neck or back pain
- discomfort or pain in arm or shoulder
- shortness of breath
67
What are the blood markers of cardiac myocyte damage?
- troponins T&I
- creatin kinase MB
- myoglobin
- lactate dehydrogenase isoenzyme 1
- aspartate transaminase
68
What are the treatments for an MI?
1. M.O.N.A: Morphine, oxygen, nitrates, aspirin
2. Reperfusion: PCI (Percutaenous coronary intervention)
3. Thrombolysis - dissolving thrombolysis
4. Balloon angioplasty
5. coronary bypass grafting
69
What is familial hypercholesterolaemia?
- mutation in genes involved in cholesterol metabolism
| - commenest are low density lipoprotein receptor gene and apolipoprotein B
70
What are the pathophysiological causes of congestive heart failure?
- decreased myocardial contractility
- increase afterload
- decrease cardiac compliance
- volume overload
- large increase in pre load
- decrease pre load
71
What are the two main causes of left heart failure?
- decreased cardiac output
| - pulmonary congestion
72
What is the main causes of right heart failure?
congestion of peripheral tissues
73
What is the most useful non-invasive test in assessment of left ventricular function?
echocardiography
74
What is ascites?
build up of fluid in the abdomen - clinical feature of severe congestive heart failure
75
What happens in atherosclerosis?
- endothelial injury
- lipids and macrophages leak into BV
- macrophages eat fat cells and lipids forming foamy cells
- fibrous cap is formed - gets bigger, narrowing lumen of BV
- blood struggle going through and getting to tissue
