Pathogenesis and Morphology of Atherosclerosis

Response to Injury Hypothesis

• This hypothesis was first presented by Russell Ross in 1986. Dr. Ross happened to be a dentist (this is turning into a very dento-centric lecture, but please don’t accuse me of being an “anti-dentite”).
• The risk factors discussed above cause repetitive chronic injury to vascular endothelium (not discussed previously were viruses, immune reactions, and toxins that can also cause Atherosclerosis, but do so with far less frequency).
• The injuries caused by these various problems lead to the insudation of LDL through the vascular endothelium and into the tunica intima (remember histology?)
• Reactive oxygen species released by injured endothelium change LDL to oxidized LDL. This is the critical event of Atherosclerosis pathogenesis.
  • Oxidized LDL leads to the up-regulation of adhesion molecules within the vascular endothelium. This in turn promotes the margination, rolling, and diapedesis of circulating macrophages.
• Macrophages that have entered the tunica intima then engulf the LDL present there.
  • They engorge themselves on LDL and they become foam cells. The cytoplasm looks foamy with numerous vacuoles.
  • Oxidized LDL stimulates macrophages to release many factors including:
    • Cytokines like TNF and IL-1.
    • Chemokines cause chemotaxis of new macrophages through the endothelium and into the intima.
• The released chemokines also stimulate smooth muscle from the tunica media to migrate into the intima.
  • These smooth muscle cells proliferate and secrete various components of extracellular matrix (collagen, elastin, proteoglycans, etc.).
    • This extra ECM will contribute to the development and enlargement of the lesion.
  • They also, like macrophages, phagocytose oxidized LDL to become foam cells.

• Some foamy macrophages and smooth muscle cells will die, liberating their lipid contents leading to necrosis as the lesions enlarge.
• HDL will mobilize LDL from the plaques. This is why we want HDL levels high. Without HDL, even low levels of LDL can cause atherosclerosis because there is nothing to remove it once it is incorporated into a lesion.
• Lesions begin in early childhood and progress gradually as an individual ages. Reducing risk factors can help prevent or slow this progression.
  • By the 5^th decade of life, these lesions are fully formed and known as complicated lesions. It is these lesions that cause clinical problems (MI and strokes).

Morphology of Atherosclerosis

• Fatty streaks are the initial lesion. They can be seen in the first decade of life (and as I mentioned earlier, they have been seen in 1 year old babies).
  • They are linear, slightly raised, and yellowish. They form in the same direction as blood flow (which makes sense when you recall that these lesions are formed by LDL forcing its way from the bloodstream through the endothelium into the intima).
  • Fatty streaks are comprised of macrophage foam cells (which are the cause of the yellow color).
  • They are accentuated at the ostia (openings of vessels off of a main one) of vessels due to hemodynamic effects.
• Atheromas or atherosclerotic plaques form from fatty streaks.
  • These are enlarged, coalesced fatty streaks.
  • Referring to these as plaques indicates that they have a slightly raised surface (but more elevated than fatty streaks).
  • Really, atheromas are just fatty streaks on steroids. They’ve got more foam cells, more collagen and extracellular matrix, and more intima in general.
  • There is fragmentation of the internal elastic lamina and pressure atrophy of the media.
    • They don’t just enlarge into the lumen, but weaken the wall of the vessel.
    • This is why one of the complications of Atherosclerosis is aneurysms (more info later)
  • Free lipid and cells of chronic inflammation can be seen on histologic examination.
    • Free lipid can take the form of cholesterol crystals in the intima. During processing to make a slide, these crystals disappear leaving behind cholesterol clefts.
• Advanced atheromas result from further enlargement of the plaque that compromises the lumen of the vessel. Here is where you begin to see symptomatic disease.
  • This leads to greater hemodynamic forces and pressures which cause greater endothelial cell injury, necrosis, erosion, and ulceration.
  • The newly exposed collagen promotes platelet aggregation and accumulation leading to the formation of a fibrin-platelet thrombus.
  • There is a lot of necrotic debris from dead foam cells within the center or core of a fully developed (complicated) atheroma.
    • This debris may calcify, contributing to that “hard gruel” feeling of the plaque upon digital palpation.
  • The advanced atheroma has even more weakening of the vessel walls due to further replacement of normal tissue with collagen.
    • Remember that collagen is rigid and lacks elasticity that is so important to blood vessels. This is one of the underlying problems leading to aneurysm development
  • There is normally a pale fibrous cap of collagen and smooth muscle overlying a yellow core of necrotic debris and lipids.
• There are two main types of atheromas: eccentric and concentric.
  • Concentric atheromas are collagen rich and deposit all around the vessel wall.
    • The large amounts of collagen present make these vessels extremely rigid.
    • Because there is no normal tissue present in the entire circumference of the vessel, vasodilators will not work to improve flow through the affected region.
  • Eccentric atheromas are rich in lipids and necrotic debris and they only involve a portion of the wall.
    • Because there is a portion of the vessel circumference that is normal, vasodilators will improve bloodflow.
• Locations of atherosclerosis in order of descending frequency:
  • Abdominal aorta and iliac arteries are the most frequent sites of Atherosclerosis and also the most frequent sites of aneurysm.
  • Coronary arteries are the next most frequent site of Atherosclerosis.
    • Only the epicardial coronary arteries are involved. No intramyocardial branches are affected.
    • The epicardial coronary arteries are the ones you’re probably most familiar with – the right and left coronary arteries, the left anterior descending artery, and the left circumflex artery.
  • The other locations were not specifically discussed here, but they are the:
    • Popliteal arteries, descending thoracic aorta, internal carotids, and the circle of Willis.

Back to the Circulatory System Index