_______________________________________ Hyperlipidemias and Atherosclerotic Cardiovascular Disease
Effective lipid management has been shown to slow the progression of atherosclerosis and lower incident morbidity and mortality of ASCVD [17; 18; 19; 20; 21; 22; 23]. As a result, early diagnosis and appropriate clinical management of hyperlipidemias has become a public health priority in the primary and secondary prevention of ASCVD [24]. Guidelines for management of hyperlipidemias focus not only on the administration of lipid-lowering drugs but also the implementation of lifestyle changes [24]. Together, these interventions assist with patient adherence and improve clinical outcomes [22; 23]. This approach requires collaboration among all members of the multidisciplinary team of healthcare providers, including physicians, nurses, pharmacists, dietitians, counselors, and physiotherapists [9; 25]. ETIOLOGY OF ATHEROSCLEROSIS Atherosclerosis results from a chronic inflammatory process that targets medium- and large-sized arteries. This process begins in childhood and progresses slowly with age. However, the condition is rapidly accelerated by a variety of genetic and environmental factors, and hyperlipidemia is a major risk factor in the pathogenesis and progression of atherosclerosis [12; 14; 26; 27]. An elevated concentration of LDL is a major cause of atherosclerosis and increased ASCVD [14; 17; 18; 19; 20; 21; 22]. The causative role of hyperlipidemia has been supported by the finding that decreasing the plasma levels of LDL and triglycerides has a beneficial effect on primary and secondary prevention of ASCVD by reversing, to some extent, the underlying pathology of atherosclerosis [23]. Atherosclerotic vascular disease develops in three progressive stages: fatty streak formation, plaque formation, and plaque disruption [12; 27; 28; 29; 30; 31]. FATTY STREAK FORMATION Fatty streaks are flat yellow discolorations on the arterial inner (i.e., luminal) surface that neither protrude into the lumen nor disrupt blood flow. The precise mechanisms responsible for the formation of fatty streaks are unclear but endothelial dysfunction is accepted as the primary event in atherogenesis. Physical stressors (e.g., turbulent blood flow at branching points) as well as chemical stressors (e.g., hyperlipidemia, cigarette smoking) alter endothelial cell functions in a complex and interdependent process. This results in: • Impairment of the role of endothelial cells as a barrier, allowing for the abnormal accumulation of lipids in the sub-endothelial layer and their subsequent transformation (oxidation) • Release of pro-inflammatory cytokines (e.g., interleukin 1 [IL-1] and tissue necrosis factor- α [TNF- α ])
• Release of cell surface adhesion molecules that attract leukocytes (e.g., leukocyte adhesion molecules [LAM], monocyte chemotactic protein 1 [MCP-1], intercellular adhesion molecule 1 [ICAM-1]) • Decreased availability of vasodilator compounds such as nitric oxide and prostacyclin • Stimulation of prothrombotic effect and platelet aggregation Together, physical and chemical stressors promote endothelial dysfunction and trigger the initial sub-endothelial accumulation and transformation of oxidized LDL. Initially, oxidized LDL acts as a proinflammatory mediator to attract circulating leukocytes (e.g., monocytes and T-lymphocytes) to the sub- endothelium. Second, dysfunctional endothelial cells and modified smooth muscle cells secrete macrophage-stimulating factors that lead to the expression of scavenger receptors or acetyl-LDL receptors on the surface of macrophages and smooth muscle cells [28]. These scavenger receptors selectively bind to oxidized LDL, enabling phagocytosis by macrophages and transformed smooth muscle cells, which gradually become lipid-laden and are known as foam cells. Increased numbers of foam cells and extracellular lipids account for the appearance of fatty streaks [12; 27; 28; 29; 31]. PLAQUE FORMATION As atherogenesis progresses, arterial fatty streaks increase in size as a result of continuing infiltration by smooth muscle cells, which migrate from the underlying muscular layer and accumulate oxidized LDL, and infiltration by T-lymphocytes, which synthesize and release inflammatory cytokines. These changes increase the number of foam cells and exacerbate local inflammation. In time, extracellular accumulation of LDL, collagen, elastic fibers, and calcium deposits contribute to the formation of larger and thicker atherosclerotic vascular plaques. Histology shows that atherosclerotic plaques consist of a large lipid core surrounded by a fibrous cap. After decades of development, the enlarging plaque exhibits signs of a chronic inflammatory process within the vessel wall [28]. The arterial wall undergoes a restructuring process that initially grows outward and preserves the lumen diameter. At this stage of development, the condition is asymptomatic and undetectable by angiographic studies. As time progresses, larger plaques start to protrude into the lumen and partially disrupt blood flow. Disruption of laminar blood flow also inhibits the expression of superoxide dismutase, a powerful antioxidant, further contributing to oxidation of LDL. This more advanced stage is associated with symptoms of ischemia and may be detected by angiography [12; 27; 28; 29; 31; 32].
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