1. Ischaemic Heart Disease (Coronary Artery Disease)
Biology of Disease CH0576
Ischaemic Heart Disease
(Coronary Artery Disease)
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2. Ischaemic Heart Disease
A collective term to describe a range of conditions characterised by inability of the coronary arteries to deliver adequate O2 to meet the needs of the myocardium.
A number of factors govern the outcome of IHD:
The degree of coronary insufficiency
Rapidity of onset
Degree of collateral circulation
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3. Ischaemic Heart Disease
The possible outcomes being:-
Chronic Ischaemic Heart Disease
Angina Pectoris
Myocardial Infarction
Sudden Death
IHD is by far the commonest form of heart disease in the industrialised world.
It is generally uncommon in the less developed areas of the world.
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4. Aetiology & Risk Factors
A) Atherosclerosis: of the coronary arteries is by far the leading cause of IHD
Several risk factors have been identified for atherosclerosis, these are essentially the risk factors for IHD development.
The risk factors fall into two main groups:
Unmodifiable risk factors
Modifiable risk factors
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5. Aetiology & Risk Factors
Unmodifiable risk factors:
Older age (patients are typically aged 35 – 65 years of age)
Male gender (after the age of 65, the rates of IHD are similar for both sexes)
A family history of premature IHD.
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6. Aetiology & Risk Factors
Modifiable risk factors:
Hypertension
Cigarette smoking
Hypercholesterolaemia
Diabetes mellitus
Obesity
Physical inactivity
Psychosocial factors (e.g. stress)
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7. Modifiable Risk Factors
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8. Aetiology & Risk Factors
B) Other Causes: These include:-
Thromboemboli
Coronary Artery Spasm
Coronary Arteritis
Conditions which increase cardiac work load and oxygen demand:
Tachycardia,
hyperthyroidism,
catecholamine treatment.
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9. Aetiology & Risk Factors
Conditions that decrease oxygen delivery to the heart:-
Anaemia
Hypotension
Carbon monoxide poisoning
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10. Pathogenesis
Irrespective of the eventual clinical outcome, IHD almost always begins with athersclerotic changes in the coronary circulation.
A number of varying theories of the pathogenesis of atherosclerosis have been proposed.
A favoured theory is the ‘response to injury’ theory.
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11. Response to Injury
This hypothesis accommodates all of the various risk factors which have been outlined for IHD.
Key features of the theory include:
The development of focal areas of endothelial injury.
Permeation of lipoproteins into the vessel wall
The lipoproteins are predominantly LDLs and VLDLs.
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12. Response to Injury (key points)
A range of cellular interactions at the site of endothelial injury.
Cells involved in these interactions include
endothelial cells,
smooth muscle cells,
mononuclear phagocytes,
T-lymphocytes.
Proliferation of smooth muscle cells and the proliferation of elements of the extracellular matrix.
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13. Response to Injury
Endothelial Injury: The injury to the endothelial layer in vivo is usually very subtle. Potential sources of injury include:-
Circulating endotoxins
Hypoxia
Products of cigarette smoke
Viruses
Specific endothelial toxins e.g homocysteine
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14. Response to Injury Probably of most importance as damaging events are:
Haemodynamic stresses
The effects of hypercholesterolaemia.
These two damaging events acting together will have a synergistic effect.
Turbulent flow increases endothelial permeability and cell turnover.
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15. Response to Injury
Turbulent flow also increases receptor mediated LDL- endocytosis.
Leucocyte adhesion to endothelium is also increased.
The complex geometry of the arterial system gives rise to local turbulence.
This theory is supported by the increased incidence of plaque formation at specific sites:-
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16. Response to Injury
The mouths of exiting vessels.
Branching points of arteries.
Along the posterior wall of the descending and abdominal aorta.
The concept of the ‘hammer and anvil’
Hyperlipidaemia: The severity of any atherosclerosis has a direct correlation with serum levels of cholesterol or LDL.
Chronic hypercholesterolaemia may initiate endothelial damage itself.
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17. Modified LDLs
Lipoproteins accumulate within the intima of vessel walls at sites of damage.
The lipid within the arterial wall is modified by oxidative mechanisms to yield modified LDLs.
Modified LDLs contribute to the pathogenesis by:
Being readily ingested by macrophages
Being chemotactic for monocytes
Increasing monocyte adhesion
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18. Modified LDLs
They retain macrophages at the site of damage.
They stimulate the release of growth factors and cytokines.
They are cytotoxic to endothelial cells and smooth muscle cells.
They are immunogenic.
It may be possible to confer some protection against AS by the use of anti-oxidants such as Vit E.
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19. Cellular Events Cellular Interactions:
A complex range of cellular interactions, similar to those which occur in chronic inflammation, occur at the site of plaque formation.
Macrophages engulfing lipids become ‘foam cells’.
Smooth muscle cells migrate from the media into the intima and proliferate.
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20. Cellular Interactions
In face of persistent hyperlipidaemia:-
Monocyte adhesion
Subendothelial migration of smooth muscle cells
Accumulation of lipids within macophages and smooth muscle cells, all continue.
Aggregates of these foam cells within the intima become obvious ‘fatty streaks’
These can be evident in the vessels of individuals from an early age.
They are the forerunners of fully formed atheromas.
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21. Cellular Interactions
With further persistent hyperlipidaemia the situation worsens.
Smooth muscle cells proliferate in response to cytokines.
There is collagen and extracellular matrix deposition.
Extracellular lipid accumulates.
The fatty streak is converted into a fibro-fatty atheroma – the atheromatous plaque
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22. Cellular Interactions
The deposition of collagen and other extracellular matrix components produces a distinct ‘fibrous cap’ over the site.
As a consequence the vessel lumen becomes increasingly occluded  ischaemia.
The endothelium above the atheroma is fragile and is prone to ulceration/damage.
Platelet aggregation and thrombosis are initiated at the sites of ulceration  further ischemia.
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23. Pathogenesis
Severe or fatal IHD often involves a >50% decrease in the diameter of at least one of the major coronary arteries.
Most severe narrowing is usually at:-
Proximal 2 cms of the left anterior descending and left circumflex coronary arteries (LAD & LCX).
Proximal and distal thirds of the right coronary artery (RCA)
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24. Pathogenesis
Sudden thrombotic occlusion, due to ulceration or rupture of an atheromatous plaque seems to be the precipitating event of an acute myocardial infarct.
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25. Commonest Sites of Coronary Artery Occlusion
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26. Atheroma Stages in Aorta
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27. Sites of MI & Vessel Involvement
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28. Appearance of Myocardial Infarct (Early)
Lateral MI
Due to blockage of LCX artery
Failure to perform oxidative reaction with NBT
Light area is the infarcted site
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