- Atherosclerosis is a progressive disorder and primarily an inflammatory disease
- It is caused by atheroma’s and marked by the narrowing of arteries by the hardening done by plaques
- Atheroma is the flaky material made up of lipids (cholesterol and lipid), macrophages, calcified lesions and fibrous tissue that are present nearest the lumen of an artery
- Atherosclerosis begins with damage to the endothelium wall of the arterial wall
- Damage to the endothelial wall causes an inflammatory response where there is recruitment of white blood cells
- White blood cells enter the vessel behind the endothelial lining and absorb saturated fats and cholesterol from circulating LDLs.
- This causes the development of the atheroma behind the endothelium, narrowing the lumen of the arteriole vessel.
- As this develops the atheroma can become calcified and loses elasticity to form a plaque.
The term of Atherosclerosis is of ancient Greek origin where “athero” refers to mush and “sclerosis” means the hardening. Atherosclerosis is a complex disorder that refers to the hardening of the arteries due to the accumulation of lipids (particularly cholesterol). It describes the build-up of plaques also known as fatty deposits in the inside of arteries that cause the disorder to be progressive as it can either block the artery or increase the chance of an artery being blocked.
This process can begin very early on in your life and cause no harm. It can continue throughout your lifetime however, most people are not aware they have it until later on (middle age). If the plaques begin to get bigger they are able to narrow the blood vessel and obstruct blood flow, which can cause further complications; if a blockade occurs in the brain a stroke can strike or tissue/cells can die due to inadequate supply of oxygen (ischemia).
Endothelial damage – Step 1
The first step to the formation of an atherosclerotic plaque (also known as “atheroma”) is damage to the endothelium (tunica intima) lining of an artery (below figure). The endothelium is a very thin layer of cells within the blood vessel wall and the damage is mainly seen in the intima layer of an artery as the artery has a high blood pressure to begin with.
People who are most likely to develop atherosclerosis are those who have a high blood pressure and in their diet have high levels of LDL in their blood.
LDLs (low density lipo-protein) are soluble fatty proteins, that carry cholesterol from the liver to tissues as a safe transport is needed due to it cholesterol’s insolubility. High levels of LDLs cause too much cholesterol to leak out of the bloodstream and become deposited within arterial walls.
The damage can also occur due to a number of other risk factors listed below:
- Tobacco smoke
- High blood pressure
- High cholesterol levels – LDL
- Family history of heart disease
- old age due to the decreasing flexibility of arteries
Once the damage has happened, a lesion begins to occur within the endothelium where lipids and fats begin to become deposited in the arterial wall. It is important to remember this process is not an superficial process as plaques end up having a strong hold within the arterial wall rather than on the arterial wall.
Inflammatory response – Step 2
Endothelial damage to the arterial wall causes chemicals from the blood such as cholesterol to become collected under the damaged endothelium lining forming fatty streaks (Figure 1). Fatty streaks are the first line of warning of atherosclerosis which is able to be visualized without magnification. These fats become oxidised which sends a signal to the immune system.
After the lipids (cholesterol and fatty acids) have started to accumulate, an inflammatory response is triggered. It causes the recruitment of various white blood cells around the body, where white blood cells leave the bloodstream and move into the arterial wall. More precisely, the endothelium cells of the arteries express adhesion molecules which triggers an immune response, via blood circulating monocytes. Monocytes are a type of white blood cell. The migration of monocytes beneath the endothelium causes the monocytes to differentiate (become) macrophages. Macrophages are another important white blood cell of the immune system that are present in response to an infection or the accumulation of damaged/dead cells. They are specialized cells that recognize and engulf target cells. These cells of the immune system attempt to degrade the cholesterol deposits by engulfing the circulating LDLs (see above for LDL definition). Many macrophages die in the process as they have a build-up of cholesterol within them causing them to transform into foam cells (Figure 5). Since more death has occurred this increases more signalling to the immune system (via cytokines) and more macrophages die and become foam cells. This causes a cascade effect in the inflammatory response where platelets come along and form a clot. It shows inflammation is a therapeutic target in atherosclerosis. More cholesterol begins to accumulate and become deposited within the arterial wall. This deposit is also known as an atheroma.
Plaque formation – Step 3
Atheroma’s or plaque build and can cause obstruction to the flow of blood within arteries.
As shown above early atherosclerosis is mainly associated with the recruitment of inflammatory cells due to endothelium (tunica intima) damage. The next step is the formation of plaque (figure below). Fibrous tissue also present within the arterial wall alongside calcium salts become accumulated. This swells up and hardens the plaque making the lumen of the artery very narrow due to reduced elasticity. This causes for the smooth muscle to become exposed where platelets present within the blood form a fibrous “cap” structure over the plaque deposition, sealing it into the arterial wall, further solidifying the plaque. This prevents inappropriate blood clotting (thrombosis) from occurring.
However, as a side it is important to realise plaques are either stable or unstable. The idea behind the stable and unstable plaques comes down to the so-called ‘fibrin cap’ that can either mature on the lesion and become stabilized or be vulnerable and thin which is more prone to rupture :
- The thick fibrous cap comes from the idea of slow growing plaques that expand due to what has been explained above; accumulation of lipids into foams cells and ultimately there is a thickening as the fibrin cap matures.
- In contrast, if the inflammatory conditions predominates changes occur within the tunica media layer to limit the synthesis of new collagen. Plaques can rapidly grow due to an increase in deposition of lipid. These changes thin the fibrous cap causing it to become more susceptible to damage. This increases the vulnerability of the plaque due to the thin fibrin caps that are more prone to rupture. Once damage has occurred to the fatty plaque there is complete blockage of the artery where clotting factors (involved in the blood clotting process) become exposed to the blood leading to thrombosis and ultimately stroke or an myocardial infraction (heart attack).
Raised blood pressure
Plaques present within the arterial wall cause the narrowing of the lumen, making it difficult for the heart to pump blood effectively around the body. This leads to strenuous stress on the heart and blood pressure is raised. This high blood pressure increases the chance of an individual to acquire further atherosclerosis as there is a higher chance that a plaque will form again due to the high blood pressure. This shows there is a positive feedback response in the disease. The general outcome is as follows:
- Reduce in blood flow reducing O2 supply and CO2 removal.
- This causes further damage to the arterial walls where white blood cells become trapped with cholesterol
- This will reduce the concentration gradients around the tissue cells therefore reduces the rate of diffusion
- This reduces the rate of respiration in cells and therefore, reduces ATP in the cells.
- Cells cannot function – the tissue will eventually die leading to ischemia.
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. (Libby 2012) – Libby, P. 2012, ‘Inflammation in atherosclerosis’, Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 32, no. 9, pp. 2045–51.