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W2 10 - Atherosclerosis Flashcards

1
Q

What can atherosclerosis lead to?

A

Ischaemic heart disease, stroke, abdominal aortic aneurysm, gut ischaemia, peripheral vascular disease

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2
Q

Constituitional multi-factorial factors of atherosclerosis

A

Genetic abnormalities
Family history
Increasing age
Male gender

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3
Q

Modifiable factors causing atherosclerosis

A

Hyperlipidaemia, hypertension, cigarette smoking, diabetes, inflammation

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4
Q

How does atherosclerosis occur - what is the ‘response-to-injury’ hypothesis?

A

Atherosclerosis arises due to endothelial injury on a background of hypercholesterolaemia

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5
Q

What are the 4 stages of atherosclerosis pathogenesis?

A

Endothelial injury
Endothelial dysfunction
Inflammation
Repair

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6
Q

Give causes of endothelial injury

A

Turbulent blood flow (most important)
Hypercholesterolaemia
Toxins from cigarettes
Homocysteine
Viruses
Inflammation

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7
Q

How does turbulent blood flow explain the distribution of the disease atherosclerosis?

A

Atherosclerosis isn’t evenly distributed in blood vessels. Tends to occur at particular points. Arabises at Ostia, branch points and curvature of vessels (area of turbulence, which can damage the endothelium lining this areas contributing to development of atherosclerosis).

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8
Q

Where does atherosclerosis arise from (areas of turbulent flow)?

A

Ostia of infrarenal aorta, coronary arteries, internal carotid arteries, circle of willis

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9
Q

What does endothelial injury result in?

A

Increased permeability and altered expression of endothelial cell surface molecules

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10
Q

Endothelial dysfunction occurs. What does increased permeability and altered expression of endothelial cell surface molecules lead to? (Pg89)

A

Increase permeability leads to accumulation of oxidised LDL and cholesterol crystals in the intima
Altered expression of adhesion molecules by endothelial cells leads to localised inflammation and platelet adhesion

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11
Q

What does inflammation stage lead to in atherosclerosis?

A

Recruits macrophages to engulf oxidised LDL and cholesterol crystals. This triggers:
- activation of inflammasome/IL1 signalling and further inflammation
- production of ROS that causes further LDL oxidation
(Pg89 image)

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12
Q

What happens in the repair stage of atherosclerosis?

A

Smooth muscle cells are recruited to the intima by growth factors (PDGF, FGF, TGF-a), which produce collagen and other ECM proteins. (Pg89 image)

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13
Q

What are the 3 components of an atherosclerotic plaque? (Pg90)

A

Cells: smooth muscle cells, macrophages, lymphocytes
Extracellular matrix
Lipid

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14
Q

PAGE90 IMAGE OF ATHEROSCLEROTIC PLAQUE COMPONENTS

A

Fibrous cap - smooth muscle cells, macrophages, foam cells, lymphocytes, collagen, elastin, proteoglycans, neovascularisation
Necrotic centre - cell debris, cholesterol crystals, foam cells, calcium

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15
Q

What are the consequences of atherosclerosis?

A

Critical stenosis
Thrombosis - thrombus forming on plaque can cause stenosis or complete occlusion
Aneurysm formation

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16
Q

What is critical stenosis?

A

Occurs when the atherosclerotic plaque obstructs blood flow to the organs to the extent that oxygen delivery/supply can’t meet the demand of the organ.
(in coronary arteries it occurs at about 70% occlusion)

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17
Q

What does critical stenosis result in?

A

Cardiac ischaemia (stable angina)

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18
Q

How can a thrombus form over an atherosclerotic plaque?

A

In a stable plaque there is a lipid core in the middle with fibrous cap over top. Fibrous cap prevents the thrombogenic lipid core from being exposed to the haemostatic substances present in the blood. If this ruptures, the lipid cortriade is exposed to these substances, and a thrombus forms on top of the atherosclerotic plaque.

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19
Q

What factors increase risk of plaque rupture?

A

Plaque structure - a thin fibrous cap, large lipid core, inflammation
Extrinsic factors - hypertension, adrenergic stimulation

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20
Q

What is an aneurysm?

A

The abnormal dilation of a blood vessel

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21
Q

How do atherosclerotic plaques increase risk of aneurysm?

A

Aneurysm forms due to damage to the media. Damage can be mediated by pressure from the necrotic core, ischaemia or inflammation. These changes can damage the smooth muscle cells and weaken the integrity of the wall of the vessel. Under high arterial pressures as the media becomes weakened, the diameter of the vessel increased, leading to the formation of an aneurysm.

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22
Q

Where are plaques in relation to the layers of the blood vessels?

A

Plaque is in the intima of the blood vessel. Media is beneath, adventitia is beneath this.

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23
Q

What are the 4 clinical syndromes of ischaemic heart disease?

A

Angina pectoris
Acute myocardial infarction
Chronic ischaemic heart disease
Sudden cardiac death

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24
Q

What is the pathogenesis of stable angina?

A

Occlusion of coronary artery lumen by >70% = critical stenosis
Perfusion to cardio myocytes cannot meet demand at times of exertion
Causes pain on exertion, relieved by rest

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25
What is the pathogenesis of unstable angina?
Plaque disruption, thrombosis, vasospasm Causing increasingly frequent pain at rest
26
What is acute myocardial infarction!
Necrosis of heart muscle resulting from ischaemia (following coronary artery disease)
27
What is the pathogenesis of acute myocardial infarction?
Generally mediated by plaque rupture, thrombosis and vasospasm causes complete occlusion of a coronary artery. Loss of aerobic glycolysis, decreased ATP and accumulation of lactic acid causes cytoplasmic swelling of cardiac myocytes (reversible injury). Na/K ATPase pumps cease working properly. Cells will start swelling up due to osmosis of fluid. Progresses to ischaemic necrosis in 20-40>8<$ unless perfusion is re-established.
28
How does acute myocardial infarction progress?
Necrosis begins in the subendocardial region and spreads outwards to become transmural. Pg93 image.
29
When do transmural infarcts occur?
Transmural infarcts happen when there is complete occlusion of one of the coronary arteries
30
Transmural infarcts - what will occlusion of the left anterior descending branch cause?
Necrosis of the anterior part of the heart
31
Transmural infarcts - what will occlusion of the left circumflex branch?
Will affect the free wall of the left ventricle
32
Transmural infarcts - what will occlusion of the posterior descending branch of right coronary artery?
Will affect the posterior part of the heart and the interventricular septum
33
Why might non-transmural infarcts occur?
- transient or partial obstruction - global hypotension, during severe hypotension episode - disease to the small vessels
34
Non-transmural infarct - what will a transient or partial obstruction cause?
Will preferentially effect the subendocardial zone. May be a pattern of subendocardial necrosis, with sparing of the epicardial region.
35
Non-transmural infarcts - what will global hypotension cause!
Circumferential subendocardial infarct
36
What is the myocardial response to infarction after 1-3days? (Pg94 table)
Necrosis elicits an acute inflammatory response through damage-associated molecular patterns (DAMPs)
37
What is the myocardial response to infarction after 3-10days? (Pg94 table)
Phagocytosis of damaged cells, granulation tissue formation, compensatory hypertrophy of residual myocytes, neutrophils migrate to the area.
38
What is the myocardial response to infarction after 10-14days? (Pg94 table)
Angiogenesis and collagen deposition (scarring)
39
What is the myocardial response to infarction after 2-8 weeks and then more than 2 months? (Pg94 table)
2-8 weeks - increased collagen deposition >2months - complete collagenous scar
40
Why do myocytes have no capacity for regeneration?
Because they are permanent cells
41
Describe the morphological changes after a few hours, days and end result of a myocardial infarction (IMG OG95)
Few hours - mottling in wall of left ventricle (early necrosis and vascular changes not visible) Few days - vascular changes more marked, forming a hyperaemic border where acute inflammatory response occurs and dilatation of RBCs occurs. Some haemorrhage from damaged vessels. Soft centre where necrotic cells are dying away. End result - scar formation, white scar tissue replacing area of damage
42
Contractile dysfunction is a complication of myocardial infarction. What are consequences of this?
Hypotension Pulmonary congestion/oedema Cardiogenic shock
43
What are some complications of myocardial infarction?
Contractile dysfunction Papillary muscle dysfunction Myocardial rupture Arrhythmias Pericarditis Ventricular aneurysm Mural thrombus Chronic ischaemic heart disease
44
What are papillary muscles?
Anchored to the valves of the heart
45
Papillary muscle dysfunction is a complication of myocardial infarction. What are consequences of this?
Mitral regurgitation Mitral valve insufficiency
46
What is myocardial rupture?
When necrosis becomes very extensive causing a hole in the heart from the ventricle through into the pericardial space, so blood leaks directly out of the heart.
47
Myocardial rupture is a complication of myocardial infarction. What are consequences of this?
Cardiac tamponade Ventricular septal defect
48
Arrhythmias are a complication of myocardial infarction. What are consequences of this?
Heart block Bradycardia Supraventricular tachycardia Ventricular tachycardia Ventricular fibrillation
49
Why does pericarditis occur from an MI?
MI will induce inflammation in the surrounding pericardium = pericarditis
50
Pericarditis is a complication of myocardial infarction. What are consequences of this?
Gradually resolves
51
How can ventricular aneurysm form after MI?
After MI the myocardium weakens due to necrosis and scar formation. Pressure during contraction can lead to dilation and aneurysm formation in the ventricles
52
Ventricular aneurysm is a complication of myocardial infarction. What are consequences of this?
Mural thrombi, arrhythmias and heart failure
53
How can mural thrombus occur in the absence of ventricular aneurysm?
Changes in the endothelium and contractile function of the myocardium can cause stasis of blood, predisposing to the development of thrombus
54
Mural thrombus is a complication of myocardial infarction. What are consequences of this?
Left-sided thrombo-embolism
55
Chronic ischaemic heart disease is a complication of myocardial infarction. What are consequences of this?
Progressive late heart failure
56
What is the pathogenesis of chronic ischaemic heart disease?
Failure of residual myocyte hypertrophy to compensate for effects of MI OR Severe obstructive coronary artery disease without frank infarction
57
What is sudden cardiac death!
Sudden death from an arrhythmia in individuals with underlying structural heart disease
58
Pathogenesis of sudden cardiac death (table pg96)
Most cases are due to the result of electrical irritability of the myocardium following longstanding changes
59
What are the functional consequences of valve disease?
Stenosis Regurgitation
60
How does valve disease cause stenosis?
Failure of a valve to open completely, obstructs forward flow of blood. Due to the abnormality of the valve cusp.
61
How does valve disease cause regurgitation?
Failure of a valve to close completely, causing back flow of blood. Due to the abnormality of the valve cusp or their supporting structures.
62
Which side valvular heart disease is more common?
Left
63
What are the 4 basic aetiological mechanisms for valvular heart disease?
Degenerative valve disease (calcification or myxomatous) Rheumatic valve disease Infective endocarditis Secondary valve disease
64
What is the pathogenesis of calcification degeneration?
1. Valve injury (to endothelial cells) due to repetitive mechanical stress and factors such as hyperlipiaemia and hypertension 2. Inflammation 3. Calcification (so forms a hard firm deposit in valve) (Similar to atherosclerosis)
65
What is the structure of a normal valve? (PG98)
Lined by endothelial cells Fibrous layer Looser region with more loose connective tissue - spongiosa
66
What is the structure of a calcified aortic valve? (PG98)
Calcification occurs in the fibrosa layer Area of calcification is associated with inflammatory cells
67
What people are more likely to develop significant calcification?
People with a bicuspid aortic valve (reason unknown)
68
Morphology of calcification degeneration
Pg99 image
69
What does myxomatous mean?
A deposit that is soft, valves become expanded loose and boggy
70
Aetiology of myxomatous degeneration
Primary - cause unknown Secondary - following MI, insult to heart etc
71
What is the pathogenesis of myxomatous degeneration?
Defective connective tissue synthesis resulting in thinning and fragmentation of the atrialis and fibrosa and expansion of the spongiosa. Deposition of abnormal ECM material within the valve, leading to its dysfunction.
72
Key mechanisms in myxomatous degeneration
Activation of valve interstitial cells to myofibroblasts MMOs driving collagen and elastin fragmentation TGF-b promoting cell proliferation and myofibroblast differentiation
73
What is the end result of myxomatous degeneration?
Expansion and remodelling of the ECM within the valve. Leaves a swollen valve leaflet which loses its structural integrity and becomes looser and more floppy.
74
What causes rheumatic valve disease?
Caused by group A streptococcal (GAS) infection
75
What type of a reaction is rheumatic valve disease?
Type II (mediated by antibodies) or Type IV (mediated by T cells) hypersensitivity reaction to bacterial antigens Caused by cross-reactivity of antibody and T cells to host antigens in different organs
76
Describe the pathogenesis of rheumatic valve disease - PG101 IMG
Bacterium infects the pharyngeal epithelium. Appropriate adaptive immune response, including a B cell response to make antibodies. Activation of T cells promotes inflammatory response to clear infection. Disease occurs because these antibodies and T cells generated to respond to the bacteria can cross-react with a number of different sites and antigens in the body.
77
How does cross-reaction of antibodies and T cells with the antigens cause valve damage?
This elicits an inflammatory response, accumulating inflammatory cells within the valve itself. This will elicit tissue damage, and fibrosis as the process heals, destroying the structure of the valves. This can lead to regurgitation or stenosis.
78
What is infective endocarditis?
Infection of the lining of the heart
79
What are sources of bacteraemia?
Oral, eg following dental procedure or tooth abscess Skin infection Gastrointestinal Intravenous drug use
80
What are host risk factors for infective endocarditis?
Diabetes Alcohol abuse Malignancy Immunodeficiency
81
Why does infective endocarditis not occur in healthy valves?
In healthy valves, bacteria wouldn’t normally interact with the endothelium lining the valve
82
Describe the pathogenesis of infective endocarditis
If a defect or pre-existing valvular disease, bacteria can start to accumulate and lodge in the valve. Over time bacteria proliferates on the valve surface, making it prone to more accumulation due to their poor blood supply. Once at a particular size, fragments can dislodge and disseminate, embolism and spread to other parts of the body, seeding infection.
83
What is wrong in secondary valve disease?
No problem with the valve, problem with surrounding structures
84
What are some mitral valve causes of secondary valve disease?
Rupture of papillary muscles Papillary muscle dysfunction Rupture of chordae tendinae Left ventricular enlargement
85
What are some aortic valve consequences of secondary valve disease?
Degenerative aortic dilatation Rheumatoid arthritis Ankylosing spondylitis Marfan syndrome Syphilis
86
What are the most commonest causes of mitral stenosis, mitral regurgitation, aortic stenosis and aortic regurgitation?
Mitral stenosis - rheumatic heart disease Mitral regurgitation - myxomatous degeneration Aortic stenosis - calcific degeneration Aortic regurgitation - degenerative aortic dilation

Human Diseases (75 decks)

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