• Atherosclerosis is a disease of blood vessels which develops over years and involves the progressive development of a fibrofatty lesion, termed an atheromatous plaque, within the vascular wall. The clinical consequences of atherosclerosis largely depend on the location of the affected vasculature and whether the lesion causes slow, progressive narrowing or catastrophic occlusive thrombosis of the vessel. In developed countries, the clinical sequelae of atherosclerosis are the most common cause of death and disability. While the pathogenesis of atherosclerosis has been studied for years, only in the past decade has it become clear that immune inflammatory processes are responsible for much of atherosclerotic pathology.
  • Overview
    • A large number of epidemiological studies have now identified a variety of risk factors for atherosclerotic plaque development and are categorized into those which can be modified by an individual and those which cannot.
  • Unmodifiable Factors
    • Male Gender: Women are protected from clinical events during reproductive years; however, risks equalize following menopause
    • Increased Age: Atherosclerosis is largely clinically silent until the elder years
    • Genetics: A few clearly familial cases can be traced to Familial Hypercholesterolemia or homocystinuria; otherwise, hereditary association is likely genetically complex
  • Modifiable Risk Factors
  • Overview
    • Although extensively studied, our understanding of atherosclerotic pathogenesis is still growing and will likely undergo significant refinement in the future. The initiating injury in atherosclerosis appears to be deposition of LDL lipid particles and their subsequent oxidation in the tunica intima. Intimal deposition of oxidized LDL likely then initiates a pathogenic sequence which results in progressive and chronic inflammation of the vascular wall together with activation of wound healing processes. Chronic inflammation, wound healing, and further deposition of lipids result in progressive expansion of the plaque which can significantly narrow the artery or render the plaque prone to rupture and thus initiation of a catastrophic arterial thrombosis.
  • Lipid Deposition
    • Atherosclerotic plaques appear to begin as "Fatty Streaks" which represent focal accumulations of lipids in the vascular tunica intima. The nature of the deposited lipids appears to be largely LDL particles which following deposition become oxidized, thus generating "Oxidized-LDL" particles. Why LDL particles begin to deposit in the vascular intima is still begin understood, although increased levels of plasma LDL observed as hyperlipidemia clearly contribute.
  • Immune Cell Recruitment
    • The presence of intimal Oxidized LDL appears to initiate recruitment of immune cells into the vascular wall possibly by enhancing endothelial expression of leukocyte adhesion molecules. Once recruited, immune cells likely elaborate a variety of cytokines which promote further leukocytic recruitment. Macrophages and lymphocytes, especially B-cells and T-cells, are the primary leukocytes recruited into the vascular wall. Consequently, the inflammatory infiltrate of atherosclerosis largely follows the pattern of chronic inflammation.
  • Endothelial Dysfunction
    • A contributing factor to leukocyte recruitment may be "Endothelial Dysfunction" which is a generic term referring to a derangement in the normal functioning of endothelial cells. Endothelial dysfunction is a global phenomenon, affecting all vasculature, and appears to be induced by some of the risk factors associated with Atherosclerosis such as smoking, hypertension, and Diabetes Mellitus - Type II. Whatever the cause, endothelial dysfunction may enhance the recruitment of leukocytes to fatty streaks initiated by intimal oxidized LDL deposition.
  • Foam Cell Formation
    • Macrophages recruited into the fatty streak phagocytose the deposited oxidized LDL but appear to lack sufficient capacity to efflux the internalized lipids. Because the intracellular lipids give these macrophages a "foamy" appearance, they are termed "Foam Cells". Foam Cells elaborate a variety of inflammatory cytokines but also appear to undergo necrotic death within the plaque. Over time, the accumulation of dead foam cells results in the development of a "Necrotic Core" within the atherosclerotic plaque.
  • Matrix Formation
    • As the atherosclerotic plaque grows, vascular smooth muscle cells migrate into the lesion, likely from the tunica media, proliferate, and begin elaborating extracellular matrix. Development of the fibrous component of the plaque indicates a late stage in its evolution and likely represents attempts at wound healing during the process of chronic inflammation.
  • Evolution
    • The above processes of lipid deposition, chronic inflammation, and matrix formation can continue for decades and ultimately result in slow expansion of the plaque. Initially, expansion of the plaque does not occur at the expense of the vascular luminal diameter and instead causes the vessel wall to remodel in such a way that the lumen remains at its normal patency. For some patients, however, the plaque eventually begins to expand inwardly, reducing the luminal diameter and thus resulting in arterial stenosis which can manifest clinically as downstream tissue hypoperfusion.
    • In these patients the plaque is generally highly stable and does not rupture; consequently, the atheroma comes to clinical attention due to the signs and symptomology of tissue ischemia and can be treated effectively. In other patients, atheromas never reduce luminal diameter and instead tend to develop highly thin and rupture-prone fibrous caps. In these patients the atheroma is largely clinically silent until its catastrophic rupture which releases enormous amounts of pro-thrombotic material into the vascular lumen. This precipitates a sudden, occlusive or near-occlusive thrombosis of the involved vasculature and thus comes to attention as a medical emergency.
Clinical Consequences
  • Overview
    • Atherosclerosis is clinically silent until there is sufficient stenosis or catastrophic occlusive thrombosis of vasculature. Certain vessels appear to be especially prone to development of atherosclerosis and the clinical consequences of the disease largely depend on where lesions are formed. Below we list vessels which are particularly predisposed and whose involvement forms the basis of most atherosclerotic clinical consequences.
  • Prone Vessels