Atherosclerosis
- Characterised by intimal lesions called atheromas or fibrofatty plaques
- These protrude into and obstruct the vessel lumen and weaken the underlying media
- The American Heart Association classification divides atherosclerosis into 6 types;
- Type I – initial lesion of isolated macrophage foam cells
- Type II – fatty streak, mainly intracellular lipid accumulation
- Type III  – type II changes plus small extracellular lipid deposits
- Type IV – atheroma lesion, type II change plus core of extracellular lipid
- Type V – fibroatheroma
- Type VI – complicated lesion with surface defect
- Type I – initial lesion of isolated macrophage foam cells
- Fatty streaks are the earliest lesions, composed of lipid filled foam cells
- They are not raised and don’t disrupt blood flow
- They begin as small (<1mm) multiple yellow flat spots and coalesce to form larger lesions
- They appear from before the age of 1 and are present in all children by the age of 10
- Fatty streaks are related to the known risk factors for atherosclerosis, support the hypothesis that they are the precursors of atherosclerotic plaques
- However they often occur in vascular areas where atheroma is uncommon and in individuals in populations which are unlikely to get atheromas therefore although they may be the precursors of atherosclerotic plaques, not all fatty streaks will become so
- Atherosclerotic plaques generally affect elastic arteries (e.g. aorta, carotid and iliac arteries) and large and medium sized muscular arteries (e.g. coronary and popliteal arteries)
- Symptomatic disease can involve the vessels of the heart, brain, kidneys and lower extremities
- Major consequences of artherosclerosis;
- MI
- Cerebral infarction
- Aortic aneurisms
- Peripheral vascular disease
- Mesenteric occlusion
- In smaller vessels, atheroma can occlude vessels causing ischaemic injury
- Plaques can undergo disruption and precipitate thrombi which can further obstruct blood flow
- In large arteries they can encroach on the media, weakening the vessel wall causing aneurisms which may rupture
- Atheromas may be friable and shed emboli into the distant circulation
Morphology
- The key processes are intimal thickening and lipid accumulation
- An atheroma consists of a raised focal lesion derived from the intima with a soft yellow core of lipid covered by a firm, white fibrous cap
- They vary and size and sometimes coalesce to form larger masses
- They usually involve only partial circumference of the vessel
- They are focal and patchy at first and then become more numerous and diffuse as disease progresses
- Abdominal aorta is more commonly involved that the thoracic and lesions tend to be prominent around the ostia of major branches
- After the abdominal aorta the most commonly affected vessels in order are, coronary arteries, popliteal arteries, internal carotid arteries and the vessels of the circle of Willis
- Atherosclerotic plaques generally have 3 principle components;
·       Cells – smooth muscle cells, macrophages and other leukocytes
·       ECM – collagen, elastic fibers and proteoglycans
·       Lipid – extracellular and intracellular
- The fibrous cap is composed of SMC and relatively dense ECM
- Beneath and at the shoulder is a cellular area consisting of macrophages, SMC and T cells
- Deep to the fibrous cap is a necrotic core containing a disorganized mass of lipid, cholesterol, dead cell debris, foam cells and fibrin
- Foam cells are large lipid laden cells that derive predominantly from macrophages but SMCs can also take up lipid to become foam cells
- Finally, particularly around the periphery of the lesion, there is neovascularisation
- Plaques continue to change and remodel and can often calcify
- The advanced lesion of atherosclerosis is a risk of the following pathological events which have clinical significance;
o      Focal rupture, ulceration or erosion of the luminal surface resulting in exposure of highly thrombogenic substances which induce thrombus formation or can be released into the bloodstream as microemboli
o      Haemorrhage into a plaque especially in the coronary arteries, may be due to rupture of the fibrous cap or of the thin walled vessels which vascularise the plaque. The resulting haematoma may expand or rupture the plaque
o      Superimposed thrombus usually occurs on disrupted lesions and may occlude the lumen. Thrombi may heal and become incorporated thereby enlarging the plaque
o      Aneurismal dilation due to weakening of the vessel media
Epidemiology and risk factors
- The risk factors that predispose to artherosclerosis have been identified by a number of prospective studies, most notably the
Framingham study and the Multiple Risk Factor Intervention Trial. These risk factors include; - Age – between 40 and 60 the incidence of MI rises 5 fold
- Sex – M>F, until after the menopause, probably due to a decrease in oestrogen.
- Genetics – most likely familial predisposition in polygenic. They may relate to other risk factors such as hypertension and diabetes or to derangements in lipid metabolism resulting in excessively high blood lipid levels
- The four major risk factors potentially controllable are;
- Hyperlipidaemia – hypercholesterolaemia, particularly associated with a high LDL and low HDL
- Hypertension – both systolic and diastolic levels are important in increasing risk
- Cigarette smoking
- Diabetes mellitus
- Other factors
- Hyperhomocystinaemia
- Caused by low folate and Vit B intake
- In patients with homocystinurua, an inborn error of metabolism resulting in high levels of homocysteine and urinary homocysteine
- Markers of haemostatic function e.g. elevated plasminogen activator inhibitor-1 and inflammation e.g. CRP
- Lipoprotein Lp(a) is an altered form of LDL that has been linked to coronary and cerebrovascular disease
- Hyperhomocystinaemia
- There is a protective role for a moderate intake of alcohol
- Multiple risk factors have a multiplicative effect
Pathogenesis
- ‘Response to injury’ hypothesis considers artherosclerosis to be a chronic inflammatory response of the arterial wall initiated by injury to the endothelium. The lesion is sustained by interactions between modified lipoproteins, macrophages, T cells and the normal constituents of the vessel wall
- Central to this hypothesis are the following;
- Chronic endothelial injury, resulting in endothelial dysfunction causing increased permeability, leukocyte adhesion and thrombotic potential
- Accumulation of lipoproteins, mainly LDL within the vessel wall
- Modification of the lipoproteins by oxidation
- Adhesion of blood monocytes to the endothelium, followed by their migration into the intima and their transformation into macrophages and foam cells
- Adhesion of platelets
- Release of factors from activated platelets, macrophages or vascular cells that cause migration of SMC from the media into the intima
- Proliferation of SMC in the intima and elaboration of the extracellular matrix leading to accumulation of collagen and proteoglycans
- Enhanced accumulation of lipids both intracellularly and extracellularly
Causes of endothelial dysfunction;
- Haemodynamic disturbances – turbulent flow
- Cigarette smoke
- Homocysteine
- Infectious agents
- Inflammatory cytokines e.g. TNF
Role of inflammation
- Upregulation of endothelial adhesion molecules VCAM which binds monocytes and T cells
- After adhering to the endothelial cell, monocytes migrate between the cells stimulated by chemokines and transform into macrophages that engulf oxidized LDL
- Macrophages contribute to the growth of the lesion by;
- Producing IL-1 and TNF which increases adhesion of leukocytes
- Produce chemokines e.g. MCP-!
- Produce reactive oxygen specifies which cause oxidation of the LDL in the lesion
- Produce growth factors which stimulate SMC proliferation
- CD4 and CD8 T cells are recruited by chemoattractants and produce IFNγ and TNFβ which stimulates macrophages, SMC and endothelial cells
Role of lipids
- The mechanisms by which hyperlipidaemia contributes to atherogenesis include;
- Impairement of EC function through increased production of oxygen free radicals that deactivate NO, the major endothelial relaxing factor
- With chronic hyperlipidaemia, lipoproteins accumulate within the intima at sites of increased endothelial permeability
- Oxidized lipid generated by free radicals generated in macrophages or EC is ingested by macrophages via the scavenger receptor distinct from the LDL receptor thus forming foam cells
- It increases monocyte accumulation in lesions
- Stimulates release of growth factors and cytokines
- Cytotoxic to EC and SMC
Role of smooth muscle cells
- SMC migrate from the media to the intima, where they proliferate and deposit ECM components, converting a fatty streak into a fibrofatty atheroma, thus contributing to the progressive growth of the atherosclerotic lesion
- Growth factors that have been implicated in the proliferation of SMC;
- PDGF
- FGF
- TGF-α
- SMC may also take up oxidized lipids to form foam cells
Other factors in atherogenesis
- Oligoclonalitiy of lesions – plaques may be equivalent to benign neoplastic lesions
- Infection – Chlamydia pneumoniae