Adaptation of notes by Professor Kumar
Recall atherosclerosis practical last week. Atherosclerosis is difficult to define. The length of the definition is inversely proportional to how much we know
- Affects large/medium sized arteries (not little arteries, not veins)
- Variety of changes leading to thickening of intima. The intimal thickening is characteristically not symmetrically all the way around the vessel (eccentric, not concentric).
- Mixture of inflammation and fibrosis
- Accumulation of lipids: cholesterol and its esters
- Don't understand what causes it, but we have described a lot of different characteristics of it.
- 1 Definition
- 2 Importance
- 3 Epidemiology
- 4 Lesions of atherosclerosis
- 5 Location
- 6 Inside a plaque
- 7 Rupture of a plaque
- 8 Haemorrhage into a plaque
- 9 Effects of atherosclerosis
- 10 Pathogenesis
- 11 Recommended articles
A complex disease of large and medium-sized arteries, characterised by focal or eccentric thickening of the intima by inflammatory and fibrotic lesions associated with deposition of lipids, especially cholesterol and cholesteryl esters.
Because of ischaemic effects, especially on the heart and brain, which are major health problems in economically developed countries. Ischaemic heart disease alone accounts for approximately 1 in 7 deaths in Australia. Atherosclerosis is less common in Asia, the Middle East, Africa and South America.
- 1 in 4 people will die due to atherosclerosis
Causes of death in Australia
- Cardiovascular disease - 31.7%
- Ischaemic heart disease (almost all of which is atherosclerosis related) - 15.1%
- Cerebrovascular disease (a lot of which is atherosclerosis) - 7.8%
- Malignant neoplasms - 30.2%
- Respiratory disease - 8.3%
- Chronic lower respiratory diseases - 5.0%
- Pneumonia and influenza - 1.7%
- Accidents, poisoning and violence - 6.2%
- Diabetes mellitus - 2.8%
Death rates over the past 100 years
While death rates from cardiovascular disease have declined since the peak around 1970, the health and economic costs of cardiovascular disease still exceed those of any other disease group (approx $6 bn per annum).
- At its peak, in the 60s-70s, things were 2-2.5x worse than they are now
- The decline in death rates does not mean atherosclerosis has diminished
- The predisposing factors (e.g. hyperlipidemia/diet) have not gone away - obesity keeps these high
- Death rates drop due to increasingly better management
- That costs the health care system a lot
- Would do better if we could reduce atherosclerosis in the first place
- 4 of the top 10 highly prescribed drugs on the PBS are statins (related to plasma lipids and cholesterol)
- Prevention is mainly about lifestyle and getting people to change lifestyle is hard
Lesions of atherosclerosis
The earliest grossly detectable lesions are known as fatty streaks. Increasing numbers of these widely distributed, subclinical lesions are detected in individuals aged between 15-35 years. They do not necessarily progress further and may regress completely. [Initial ≈1 mm yellow spot develops into a linear streak. Composed of lipid-laden "foam cells" which are primarily activated macrophages (from adherent monocytes) but may also be derived from smooth muscle cells; also some T-lymphocytes (mostly CD4+ with a Th1 cytokine profile); little extracellular lipid or fibrosis.]
Typical lesions of atherosclerosis are referred to as atheromatous or fibrofatty plaques, which are particularly likely to involve certain vessels.
- Aorta, especially infrarenal abdominal; most striking at branch points, including renal and mesenteric artery ostia
- Coronary arteries
- Carotid and vertebrobasilar arteries
- Iliac, femoral and popliteal arteries.
Upper limb arteries are notably spared, while pulmonary arteries are only involved in the presence of pulmonary hypertension.
[Raised lesions, from 3-15 mm diameter, usually white to yellowish-white. Contain variable amount of extracellular lipid and lipid-laden foam cells; covered by collagenous cap containing smooth muscle cells; may be centrally necrotic. Inflammatory cells prominent at shoulders of plaque; granulation tissue may be noted at the base. Typically disrupt the internal elastic lamina; advanced plaques are associated with atrophy of underlying media and calcification.]
Complicated lesions include ulceration (fissuring or rupture) of plaques, occlusive and non-occlusive thrombosis (which may be related to fissuring or to endothelial denudation) as well as haemorrhage into plaques. Plaques with a high lipid content are much more prone to fissure or rupture, because of their mechanical properties and/or because of weakening by degradative enzymes of inflammatory cells. However, lipid-rich vulnerable plaques can undergo at least partial regression, unlike more stable fibrous plaques. Other complications of atherosclerosis include embolism of plaque contents and aneurysmal dilatation of large vessels. Note that thrombi may subsequently organise and recanalise.
- Early - fatty streaks
- Fibrofatty plaques ("plaques" or "atheromas")
- Complicated lesions developing on top of those plaques
- We don't understand how one lesion goes to the next - a problem in our understanding
- Everybody over late teens has fatty streaks. Majority of these do not progress (many regress)
- Most fatty streaks develop at the sites where atherosclerosis doesn't tend to occur (widespread)
- They are 1mm or so in size
- Note in the first picture of the aorta - we see little white dots and streaks. Almost invisible without staining (stained on the left hand side of the aorta for fat).
- Dot like lesion, and the dots become larger and elongated, and become streak-like lesions to run longitudinally along the intima
- Fatty streaks = intracellular (mostly) fat in the intima (above the IEL).
- Cells with intracellular fat are called "foam cells" (mostly macrophages that have engulfed fat, but also resident smooth muscle cells or SMC that have migrated from the media to the intima)
- In the fatty streak, may also see CD4 T cells (don't know why they're there)
- What happens next? It varies, and we can't predict it
- In some vessels, we go on to form fibrofatty plaques/atheromas:
- Note in the picture, patches in the wall of the coronary artery
- Flat, but elevated, lipid-laden lesions
- In histology, we can see a thickened intima, full of lipid vacuoles. In between the lipids, we can see lots of fibrous tissue. IEL is disrupted and unhappy.
- Intimal thickening
- Accumulation of CT
- Accumulation of lipid
- Aortic luminal surface at a later stage. At the bottom edge we can see flat lesions like we saw in the coronary artery. But in most of the rest of the wall, we can see confluence of the atheromas
- Histology: these plaques can get a lot thicker and protrude into the lumen (this is a big deal in small/medium sized vessels, where the lumen is narrowed significantly). As the intima has become a lot thicker, the media has become a lot thinner (this is a feature of later progression of atheromas)
- Mixture is variable: some are very fibrotic, others are more lipid-filled
- number 1 site is the abdominal aorta and its bifurcation. In terms of clinical significance, the #2 site, the coronary arteries and #4/#5 including the carotid and vertebral arteries.
- The aorta is involved in nearly everyone with atherosclerosis, but the other arteries are very important clinically
- Popliteal arteries etc result in morbidity (complications)
- Selective targeting is interesting - upper limb arteries are virtually never involved. Pulmonary arteries are usually not affected, unless there is pulmonary hypertension (hence arterial pressure is important)
- We don't understand why the upper limbs are never involved.
Inside a plaque
- Intima at the top, media at the bottom
- In the middle of many atheromas, there is a necrotic core, which is essentially dead tissue and extracellular lipid.
- Over the top of that is a zone of inflammatory cells and smooth muscle cells
- The endothelium sitting on top of that zone is less functional in terms of its anticoagulant properties
- Inflammation is typically marked at the sides (shoulders) of the plaque
- Fibrous cap varies in thickness (plaque is more mechanically stable where the fibrous cap is thicker). A thin cap is a problem
- Low power plaque shows virtually the same structure
- Higher magnification shows you all the features we see in the stylised diagram. Shoulder is important as it contains inflammatory cells that produce things like matrix metalloproteinases, which break down the fibrous cap, which can reduce the structural integrity of the plaque, enabling it to split
- High power at the base of the plaque. Lipid was forming elongated crystals (hence it was free cholesterol). Around the base of the plaque, we see cellularity and blood vessels forming (hence there is granulation tissue - indicating repair. Hence we have chronic inflammation: inflammation and repair).
- Centre of the plaque is a dead zone, but around it there is chronic inflammation
Section through a coronary artery
- Eccentric thickening
- Note we have a branch point here
- On the right, there is a little thickening. On the left, there is much more thickening. Hence we have eccentric thickening.
- Most of the thickening is lipid-rich
- Note the fibrous cap, large area of calcification at the base, and thick underlying media.
- Small/medium sized arteries: eccentric thickening of the wall reduces luminal size. When the plaque is very thick and has a thin cap, we end up with complications (that are dangerous)
- At this stage, we only have stenosis (which could reduce flow, causing mild ischaemia e.g. angina)
- Much more dangerous is the development of complicated lesions
- Complicated lesions: lipid-rich plaques that are mechanically stable:
- Rupture (more common)
Rupture of a plaque
- When a plaque splits, it exposes the subepithelial CT
- Then you will get a thrombus
- The thrombus may stick on the wall in a large vessel (mural thrombus in the aorta)
- In a small vessel (e.g. coronary artery), occlusion is very likely due to the thrombus. In tissues with no collateral circulation (e.g. heart, brain), this is a big problem
Haemorrhage into a plaque
- This can happen if the plaque ruptures on the surface and blood goes into the plaque
- Alternatively, you can get bleeding from the vessels
- Section: blood entering the plaque from somewhere proximal to our section
- Inside the plaque, we see blood that has entered and clotted: a haematoma.
- This causes the lumen to be hugely reduced
- This results in ischaemic effects just as bad as if there was thrombosis on top of the plaque
- Properties of the plaque:
- Intima gets thicker, full of lipid
- Media gets thinner
- If we look at an aorta section, we notice that the media is extremely thinner than normal
- Then there is relatively little elastic tissue in the aorta
- Then the pressure causes increased size of the vessel
- This leads to an aneurysm, and possible rupture: a big problem
- Rupture of the plaque can release its porridge-like contents to the blood stream. This embolus can go to little vessels and block small vessels e.g. in the brain
- The section indicates one such embolus in the kidney. Note the cholesterol clefts, indicating that it's embolic material from a plaque
Hence the complicated lesions of atherosclerosis include:
- Calcification of the wall
Effects of atherosclerosis
- Ischaemia of any involved vascular bed, which may either be gradually progressive due to stenosis, or episodic and unpredictable when associated with complicated lesions; the latter are especially likely to lead to acute arterial occlusion
- Mortality primarily because of myocardial ischaemia including infarction, cerebral infarction and aneurysm rupture
- Additional morbidity resulting from lower limb vascular disease, renal and mesenteric ischaemia.
- The effects are due to ischaemia due to:
- Progressive narrowing of the vessels (stenosis), and limitation. This has some possibility of collateral circulation and effective interventions.
- Complicated lesion (e.g. thrombosis or haemorrhage), causing abrupt ischaemia. This is much more difficult to manage.
- Complicated lesions don't surface until >40
- Clinical effects include:
- Myocardial infarct
- Cerebral infarct
- Gangrene of extremities
- Abdominal aortic aneurysm
- Coronary artery dissected, shows a thrombus
- Section of a heart, showing myocardial infarction. Down the bottom, we see scarring and thinning (indicating an old MI, with another artery)
- Carotid artery dissected at the neck, at the bifurcation (where you should listen for bruits). Branch points are where atherosclerosis targets. These vessels are important for cerebral disease
- Vertebral artery section. In close up, we can see a vertebral artery in cross section, with a pinhole through the middle (very thickened and occluded). Although the circle of Willis will provide collateral circulation, it's not usually enough to keep brain tissue alive, and often the carotids are affected simultaneously
- Basilar artery sample, shows you displaced artery, with a thrombus inside it.
- Cerebral infarct, is the result of occlusion mentioned above (notice on the left of the sample). This is an area of liquefactive necrosis. Lesion doesn't need to initially be in the brain, but can be in the neck
- Aortic aneurysm
- Second aortic aneurysm showing a lot of thrombus, with laminations
- Thrombosis in the common iliac and external iliac due to atherosclerosis
- Angiogram: lower limb vascular disease (can't exercise, or walk). Rt leg: area of extreme stenosis. Lt leg: femoral artery is fully blocked, but can see some opening up of collateral circulation (profunda femoris artery). This has grave risk of developing gangrene.
- Toe amputation: due to atheroembolism or thromboembolism of digital arteries in the toes.
No single factor has been established as a necessary or sufficient cause, although numerous risk factors are associated with an increased risk of developing atherosclerosis.
- Constitutional: age, gender and genetic factors
- Modifiable: arterial blood pressure, plasma lipoprotein levels (especially increased LDL and VLDL, decreased HDL), smoking, diabetes mellitus
- Other: systemic inflammatory status (as assessed by high-sensitivity CRP), obesity (independently of other factors above), dyslipoproteinaemias, elevated plasma homocysteine, infections, physical activity, personality type
The currently held view of pathogenesis is that the lesions of atherosclerosis represent a specialised form of chronic inflammation, which develops as a response to retention of altered lipoproteins in the arterial intima and other causes of injury to vascular endothelium.
- Not much is understood
- We understand things that predispose to developing atherosclerosis, but not how they work
- Handout shows you sets of risk factors. No single risk factor is either necessary or sufficient
- Note that hypertension increases shear stresses with every heart beat (perhaps this is why branch points are important).
- Interaction between endothelial damage and lots of lipid
- Lipids are oxidised and gobbled up by macrophages, which die, releasing factors that attract more macrophages to keep the cycle going.
[For further information, see Insull W. The pathology of atherosclerosis: plaque development and plaque responses to medical treatment. Am J Med 2009;122:S3-S14; Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis.Nature 2011; 473:317-25.]