Atherosclerosis

  • Atherosclerosisis a common and clinically significant form of arteriosclerosis that involves the inflammatory response and lipid accumulation within the vessel walls.
  • Arteriosclerosis means “hardening of the arteries.”
  • Atherosclerosis is a specific form of arteriosclerosis; it affects the elastic and medium to large muscular arteries.
    — If blood flow through one of these arteries, such as the aorta or carotid arteries, is obstructed, downstream effects can include ischemia and organ failure.
  • Anatomy
  • Three layers of the vessel wall:
    — The tunica intima comprises a thin layer of endothelial cells, which play an active role in the inflammatory response.
    — The tunica media comprises smooth muscle cells, which are responsible for moderation of the vessel lumen via dilation and constriction;
    — The outermost layer is the adventitia.
  • Our histological sample has a large thrombus blocking the lumen.
  • Sample also has a large atherosclerotic plaque that has developed between the tunica media and endothelial layers.
    — Cholesterol crystals create a “cleft”-like appearance.
    — Foam cells are macrophages that have engulfed lipid droplets.
    — Fibrinous cap; as we’ll see, the integrity of this cap determines the stability of the plaque, and, therefore, its clinical consequences.
  • We also have a gross image with a large atherosclerotic plaque at the bifurcation of common carotid artery.

PATHOGENESIS OF PLAQUE FORMATION

  1. Plaque formation is triggered by endothelial injury and response; recall that endothelial activation involves the release of cytokines, chemokines, coagulation factors, and other pro-inflammatory molecules.
    — Injury triggers increased permeability and subsequent recruitment of leukocytes and platelets, which migrate into the intima. Injury can include a variety of forces including hemodynamic stress, inflammation, bacteria, viruses, etc.
  2. Macrophage activation and smooth muscle cell recruitment forms fatty streaks within the intima.
    — Intima is now crowded by macrophages and smooth muscle cells; these cells and other inflammatory molecules were recruited by cytokines released as part of endothelial activation.
    — The active smooth muscle cells proliferate and synthesize extracellular matrix proteins; importantly, collagen is deposited.
    — The smooth muscle cells and macrophages engulf lipid droplets, trapping them in the intima; consequently, indicate that the macrophages become the foam cells we identified in our histological samples.
  3. Fibrofatty plaque formation results in a mature atheroma; be aware that not all fatty streaks progress to this stage.
    — Plaque comprises a fibrous cap and necrotic core:
    The cap comprises smooth muscle cells, collagen fibers, and other proteins.
    The necrotic core comprises extracellular lipids, intracellular lipids housed in foam cells and smooth muscle cells, T lymphocytes, and cellular debris.
    — The potential for the plaque to become thrombotic or break free and embolize depends in large part on the composition and resulting stability of the fibrous cap, and the hemodynamic stresses that act on it.
    Smooth muscle cells in the cap promote collagen deposition, and, therefore, stability; but, inflammatory cells, which are also present, promote cap degradation. Thus, their relative proportions determine plaque vulnerability.

TRIGGERS, MAINTENANCE, AND CLINICAL CONSEQUENCES OF ATHEROSCLEROSIS

  • Key culprits of endothelial injury that ultimately lead to plaque formation include hemodynamic disturbances and hypercholesterolemia.
    — Hemodynamic disturbances that produce turbulent flow increase the risk of plaque formation.
    Thus, plaques commonly form where arteries bifurcate, such as where the common carotid artery splits to form internal and external branches – refer to our gross image in the blue box. Another common site of formation is along the posterior wall of the abdominal aorta, which is also subject to turbulent stresses.
    — Hypercholesterolemia is characterized by high levels of cholesterol in the blood; recall that cholesterol is synthesized by the liver and ingested in the diet, and is transported in the blood as lipoprotein complexes.
    Chronic hypercholesterolemia damages endothelial cells and impairs the vasodilator activity of nitric oxide.
    Additionally, LDLs, which are the lipoproteins complexes that deliver cholesterol to the peripheral tissues, accumulate within the intima of the arteries; indeed, as we saw in the histological sample and our diagrams, cholesterol is a major component of atherosclerotic plaques. Within the plaques, cholesterol has toxic and pro-inflammatory effects that damage the vessel and promote plaque growth.
    — Thus, risk factors for atherosclerosis include family history (via polygenic mechanisms) and other conditions, such as diabetes mellitus, that induce hypercholesterolemia.
  • Review hyperlipidemia, which contributes to atherosclerosis.
  • Statins are often prescribed to lower cholesterol levels, as they reduce its production by the liver.
    — Other risk factors for atherosclerosis include cigarette smoking and age.
  • Role of macrophages and chronic inflammation in atherosclerosis
    — Recall that chronic inflammation occurs when tissue injury and repair attempts overlap.
    — Accumulation of macrophages, cholesterol crystals, and other substances within the vessel wall triggers the inflammatory response.
    In turn, cytokines, particularly IL-1, are released and recruit additional immune cells, including macrophages and T lymphocytes, which promotes a positive feedback cycle of inflammation.
    — Thus, inflammatory conditions are now considered a risk factor for atherosclerosis; clinical assessment may include measurement of C-reactive proteins, which are markers of inflammation that have been associated with atherosclerosis.
    Research to assess the effectiveness of anti-inflammatory therapies in atherosclerosis is ongoing.
  • Significant clinical consequences of atherosclerosis
    — Coronary artery disease (CAD) and heart attack; stroke; aortic aneurysm; and, peripheral vascular disease (PVD).
    — Vessel occlusion and/or aneurysm are responsible for these complications: we show in a histological sample that plaque formation can dangerously narrow or even completely obstruct blood flow (aka, stenosis); write that obstruction of blood flow can lead to ischemia and organ failure.
    — Aneurysm occurs when the vessel wall bulges outward; we show in a histological sample that fatty materials and debris can migrate between the tunics of the vessel wall, leading to dissection (aka, separation).
    From the patient’s perspective, dissection is experienced as a painful tearing sensation; ultimately, mural remodeling and wall weakening can allow vessel rupture and bleeding.
    — We also show an image of a necrotic foot, the result of peripheral vascular disease.

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