Atherosclerosis

• Atheroma:

  • Condition characterised by the focal accumulation of lipid in the intima of arteries (Greek: porridge)
  • When a patient has multiple atheroma lesions it is said to be generalised atheroma
  • In generalised atheroma many of the lesions in the arterial wall will become fibrotic and often calcify
• Atherosclerosis:

  • Atheroma causing hardening of arteries
  • Sclerosis process = a fibrotic process of mineralisation, deposition of calcium salts, that causes the arteries to physically harden
• Risk factors for atherosclerosis:

  • Age
  • Males
  • Smoking
  • Hypertension
  • Diabetes mellitus
  • Raised levels of LDL (low-density lipoproteins) - cholesterol blood levels
  • Family history
  • There are genetic disorders where raised levels of LDL result from genetic abnormalities
• Risk factors for atherosclerosis - smoking:

  • Carbon monoxide in the blood stream is able to damage the endothelial cells that line the arteries
  • These cells are v sensitive and a small amount of damage to them may be a very important early event in the development of the atheromatous lesion
• Risk factors for atherosclerosis - hypertension:

  • In health, when blood is pulsating through an artery, there's a v fine layer of liquid serum just above the endothelial cells that line the artery's internal surface
  • Blood cells, like platelets, don't normally contact the endothelium
  • Hypertension can create a sort of 'turbulence', which would result in the blood cells touching the endothelium
• Risk factors for atherosclerosis - raised levels of LDL (low-density lipoproteins) - cholesterol blood levels:

  • Low density lipoproteins are generally referred to as cholesterol
  • High density lipoproteins bind to the low density lipoproteins and take them to the liver for further processing
  • But raised levels of LDL can result in the formation of atheromatous/atherosclerotic lesions
• Pre-disposing factors (they all correlate with the prevalence of atherosclerosis):

  • Obesity
  • Lack of exercise
  • Low socio-economic status
• Development of atherosclerosis:

  • An atheromatous lesion goes through 3 stages in its evolution:
  • Fatty streak
  • Fibrolipid plaque
  • Complicated lesion
  • In any one artery, there may be a combination of all these lesions; not all fatty streaks go on to develop into fibrolipid plaques or complicated lesions (fatty streaks can even be quite prevalent in young individuals)
• Normal blood vessel structure:

  • LHS: histological section that has been stained to show elastic fibres. Muscular artery at top. Peripheral nerve to the right. Vein at the bottom. Vein is much larger than other 2 and has a much thinner vessel wall than the artery.

  
• Normal blood vessel structure:

  • RHS: histological section showing the detail of the artery wall. 2 types of arteries: elastic and muscular. This image shows a muscular artery. It has an internal elastic lamina, and an external elasticated lamina on the outer part of the vessel, in between the tunica media and the tunica adventitia. In a muscular artery, the tunica media is composed of smooth muscle cells, in an elastic artery elastic tissue is found throughout the arterial wall between the internal and external elastic lamellae.

  
• Normal blood vessel structure:

  • RHS: The endothelial lining isn't shown here, but it's a v thin layer (1 cell thick) of cuboidal cells that provides a smooth surface for the lining of the artery.

  
• Fatty streak - 1st lesion:

  • Endothelial damage - the first event in the formation of a fatty streak
  • Permeability - the endothelial damage leads to permeability, allowing lipids to enter the intima of the artery
  • Monocyte adhesion - endothelial damage also leads to the possibility of monocyte adhesion to the endothelium so that monocytes can find their way in along with low density lipoproteins (LDL)
  • Entry of LDLs
  • Foamy macrophages - these are macrophages which have taken up LDLs, but can't digest the fat, so they simply fill up with fatty droplets and sit there in the intima

  
• Monocytes adhere to the damaged endothelium and then they can migrate through the endothelium into the intima by a process called diapedesis. This is the movement of a white blood cell through the vessel wall.

  Top RHS: Artery with a v large fatty streak in the process of becoming a fibrolipid plaque

  
• The monocytes are the precursor cells of macrophages and they are often stimulated by cytokines to differentiate into macrophages. In the fatty streak, in addition to the monocytes, we also find lymphocytes (particularly T lymphocytes). The T lymphocytes secrete cytokines and it's the cytokines that stimulate the monocytes to differentiate into macrophages.

  
• At the same time, the increased permeability of the endothelium allows LDLs (yellow globules in this diagram) to be taken up by the macrophages. As this happens, the macrophage's cytoplasm expands to give a foamy cell - a large cytoplasmic bag filled with lipid globules and the nucleus, which is pressed to the side of the cell so it can hardly be seen. That is the fatty streak.

  
• Some fatty streaks will evolve into fibrolipid plaques - this occurs when the T cells, which are the drivers, release cytokines that stimulate the smooth muscle cells of the media to come through the internal elastic lamina, migrate into the plaque and will take up some LDL (since they are somewhat phagocytic) - they will make the plaque become more prominent and elevated.

  
• Fibrolipid plaque:

  • Elevated lesion bulging into the lumen
  • Smooth muscle cells, migration, proliferation - smooth muscle cells migrate up to the surface of the intima - they are followed by fibroblasts and there is cell proliferation
  • More lipid uptake
  • Production of collagen - part of a kind of repair process for the artery - the repair is causing damage though, as is often the way in chronic inflammatory diseases
  • The lymphocytes produce the cytokines which drive the process
• Fibrolipid plaque:

  • Sometimes the macrophages break down in a fibrolipid plaque and we get the formation of a lipid lake (yellow blob in middle) - might see some of the cholesterol crystallising out too - crystals dissolve in histological preparations though, so cholesterol clefts are left behind
• Fibrolipid plaque:

  • Lesion that has a lipid lake with a fibrous cap over the surface
  • At this stage the endothelial lining is still intact in the fibrolipid plaque, but it's bulging into the lumen, giving the opportunity for blood cells (like platelets) to impact on the surface of the fibrolipid plaque

  
• Complicated lesion follows impaction of platelets onto the surface, leading to thrombosis - happens when fibrolipid plaque becomes ulcerated - endothelial cells stripped away and lost, platelets impact on surface -> causes clotting cascade to happen -> lump of thrombus blood coagulation forming on the surface of the plaque (may sit over the lipid lake) - calcification may happen (calcium salts deposited in tissue) - further fibrosis may weaken the artery wall - the cap over the atheromatous plaque may breach to form a fissure -> lipid comes out into the lumen -> may trigger more thrombosis.
• A complicated lesion is the formation of a coagulated mass of blood constituents within a vessel.
• Complicated lesion:

  • Occlusion - can occlude the whole artery
  • Ulceration
  • Thrombus formation
  • Haemorrhage into plaques
  • Plaque fissuring and rupture
  • Embolism - material from a complicated lesion can undergo embolism (it can break off from the lesion or the thrombus over the surface) and can then be passively transported in the blood to other sites
  • Calcification
  • Aneurysm formation - caused by weakening of the wall

  
• LHS = early atheromatous plaque in an elastic artery (know it's elastic; elastic tissue throughout the thickness of the wall between the intima).

  Bulge into lumen = fibro-fatty plaque

  RHS = LDL stained red so foamy cells can be seen easily in fibrolipid plaque

  
• Example of how atheroma can have a serious clinical consequence - particularly when it affects the left coronary artery.

  
• Early atheroma has lipid in the centre of the lesion, macrophages, a lipid lake and a fibrous cap forming - early atheromatous lesion can go in 2 directions in the coronary artery

  • Stabilised plaque = small lipid pool, thick fibrous cap - lumen is narrowed but still preserved
  • Vulnerable plaque = large lipid pool, thin fibrous cap and many inflammatory cells (lots of lymphocytes and macrophages in the vulnerable plaque) - may get thrombosis over the surface with rupture of the plaque through the fissure

  
• Once we get the complicated lesion (bottom central picture) then there are 2 ways that that can go:

  • Plaque may heal - very reduced lumen with extensive fibrosis - patient will have angina pectoralis because the amount of oxygen that can get through the narrowed artery isn't sufficient to meet the needs of the heart muscle, so on exertion there will be chest pain as a result of a deprivation of nutrients to the heart muscle
  • Plaque doesn't heal - complete blockage of the artery leading to acute myocardial infarction (death of the heart muscle - heart attack)

  
• • LHS = coronary artery showing early atheromatous plaque - yellowish lipid pool in the wall of the artery at the bottom of the arterial lumen
  • Middle = early thrombosis over the lesion - beginning to get formation of a complex lesion - brown material = blood constituents that have turned brown because of fixation - partially obstructs lumen
  • RHS = complicated lesion with thrombosis that's entirely blocking lumen of coronary artery

  
• Distribution of atherosclerosis:

  • Can affect any large or medium size artery
  • More often widespread than localised
  • Tends to occur at bifurcations of arteries
  • Significant clinical effects seen in coronary arteries and cerebral arteries
  • Commonly seen in aorta (effects here related to aneurysms)
  • Seen in mesenteric arteries - can lead to bowel ischaemia - and femoral arteries - can lead to problems in legs
• Consequences of atherosclerosis:

  • Ischaemic heart disease
  • Cerebral ischaemia and infarction - cause of one type of common stroke
  • Aortic aneurysm - most common consequence of atheroma in aorta
  • Small bowel ischaemia and infarction - occurs when mesenteric arteries are blocked
  • Peripheral vascular disease - when femoral arteries are blocked
• Consequences of atherosclerosis - ischaemic heart disease:

  • Angina pectoralis - occurs if the disease narrows the coronary artery - on exercise pain develops in chest and may radiate down left arm - resolves as the individual rests - happens because insufficient oxygen and nutrients can get to the heart muscle to satisfy its needs during exercise
  • Myocardial infarction - where the heart muscle dies as a consequence of ischaemia
  • Heart failure - angina pectoralis and myocardial infarction may lead to this in time
• Consequences of atherosclerosis - peripheral vascular disease:

  • When femoral arteries are blocked
  • Intermittent claudication - when pain in the legs develops in exercise because insufficient oxygen and glucose can get to muscles in legs
  • Gangrene - happens after ischaemia of digits and subsequent infection
• Management of atherosclerosis - lifestyle:

  • Healthy eating and exercising, non-smoking
  • Modification of lifestyle is the best way to manage it; prevention is always better than treatment
• Management of atherosclerosis - medical:

  • Cholesterol medications
  • Anti-platelet medications
  • Beta-blocker medications
  • Angiotensin-converting enzyme (ACE) inhibitors
  • Calcium channel blockers
  • Diuretics
  • Fibrinolysins
  • Can be given to dissolve thrombi
  • Often used to  produce a clinical improvement where we have a complicated lesion with a big thrombus blocking an artery to dissolve the blood clot
• Management of atherosclerosis - surgical:

  • Angioplasty - the surgical modification of arteries
  • Endarterectomy - internal lining with all its atheromatous plaques is removed - allows vessel to be re-endothelialised and blood flow to be re-established along a smooth internal lumen
• Management of atherosclerosis - surgical:

  • Stent - device placed in coronary artery to widen it and re-establish blood flow
  • Bypass - if the artery is too blocked to place a stent or the atheroma is near the origin of the coronary artery then vessels will be taken from the legs and grafted on to the coronary artery to provide extra blood supply to the heart muscle