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Biology of Disease CH0576

Ischaemic Heart Disease(Coronary Artery Disease)

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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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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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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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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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Aetiology & Risk Factors

• Modifiable risk factors:– Hypertension– Cigarette smoking– Hypercholesterolaemia– Diabetes mellitus– Obesity– Physical inactivity– Psychosocial factors (e.g. stress)

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Modifiable Risk Factors

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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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Aetiology & Risk Factors

• Conditions that decrease oxygen delivery to the heart:-

– Anaemia

– Hypotension

– Carbon monoxide poisoning

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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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Commonest Sites of Coronary Artery Occlusion

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Atheroma Stages in Aorta

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Sites of MI & Vessel Involvement

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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