Hyperlipidemias and Atherosclerotic Cardiovascular Disease ________________________________________
Intermediate-Density Lipoproteins IDLs, also known as VLDL remnants, are created when circulating VLDL and chylomicrons are hydrolyzed by the enzyme lipoprotein lipase, releasing free fatty acids and producing chylomicron remnants in addition to IDL particles. IDLs have a short half-life (less than 30 minutes) and undergo liver absorption by selective uptake mainly by binding to the LDL receptor, with Apo B-100 and Apo E as required cofactors. Genetic variants of Apo E are responsible for low binding to the LDL receptor, which results in high concentrations of circulating VLDL and IDL, a condition clinically known as type III hyperlipoproteinemia [14; 75]. Low-Density Lipoproteins LDLs play a central role in atherogenesis and are often called “bad cholesterol.” The discovery of the LDL receptor by Goldstein and Brown and their work elucidating its role in cholesterol homeostasis is one of the most important advances in cardiovascular research. Their studies have been a major contribution to the understanding of the mechanisms underlying hyperlipidemias [72]. The proatherogenic role of LDL on the release of pro-inflammatory cytokines (e.g., IL-1, TNF- α ) and adhesion molecules (e.g., LAM, ICAM-1) is well established. LDLs are the product of VLDL and IDL metabolism by lipoprotein lipase. LDL is the most cholesterol-rich of all lipoproteins, and even in healthy individuals, LDLs carry two- thirds of the circulating cholesterol [14]. LDL has a half-life of 1.5 to 2 days, which accounts for a plasma concentration higher than VLDL and IDL [14; 46; 53; 57]. There are several subtypes, also known as subfractions, of LDL, and it has been proposed that smaller, denser LDL particles are more atherogenic than larger and less dense LDL. However, research suggests that the use of clinically available LDL subfractions to estimate the risk of ASCVD is premature [76; 77; 78]. Plasma clearance of LDL is primarily mediated by the LDL receptor expressed on the cell surface. Although LDL receptors are expressed in various cell types, approximately 75% of all LDL receptors are expressed in hepatocytes [79]. The uptake of LDL in hepatocytes is mediated by the interaction between the LDL receptor and Apo B-100 (the only apoprotein expressed in LDL), which acts as a ligand at the LDL receptor. This selective and highly effective mechanism accounts for the extraction of approximately 75% of all LDL from plasma [80]. Hepatic LDL receptors are downregulated by the high delivery of cholesterol by chylomicrons or dietary saturated fat and upregulated by decreased cholesterol and saturated fat intake [46; 81]. The crucial role of LDL in atherogenesis results from it being oxidized in the arterial subendothelium. Oxidized LDL has a high affinity for the scavenger receptor expressed in macrophages undergoing endocytosis, which leads to intracellular accumulation and the transformation of lipid-rich macrophages into foam cells.
Genetic mutations of either the LDL receptor or Apo B-100 alter the effectiveness of the binding and increase the plasma concentration of LDL. Familial hypercholesterolemia and familial defective Apo B-100 are examples of clinical conditions that result from these genetic mutations [82; 83]. Homozygotes for familial hypercholesterolemia inherit two mutant LDL receptor genes and present with a 6- to 10-fold elevation in plasma LDL from birth. These patients suffer from advanced CHD starting in early childhood [72; 84]. The expression of LDL receptors in the liver is also regulated by the intracellular enzyme HMG-CoA reductase. Inhibition of HMG-CoA reductase, for example by the administration of statins, not only results in direct inhibition of the intracellular synthesis of cholesterol but indirectly increases the expression of LDL receptors and therefore promotes the LDL-receptor- mediated removal of circulating cholesterol. The LDL receptor is also relevant from a clinical perspective because both thyroid hormones and estrogens stimulate its expression in the liver [80; 85]. Consequently, deficiencies of these hormones decrease the availability of LDL receptors and result in increased concentrations of circulating LDL and increased risk of ASCVD [14; 80]. Lipoprotein(a) Elevated plasma subtype lipoprotein(a) levels are an independent, causal risk factor for ASCVD and calcific aortic stenosis [12; 27; 31; 46; 47]. Lipoprotein(a) has a similar lipid composition to more typical LDL but has a higher protein content [86]. The atherogenic role of lipoprotein(a) relates to its unique molecular properties and results in the inhibition of fibrinolysis, enhanced capacity to traverse the arterial endothelium, and low affinity for the LDL-receptor- mediated clearance from circulation [47]. Lipoprotein(a) is a major carrier of oxidized phospholipids, and thus a key mediator of atherosclerotic vascular disease; it also exhibits platelet activating and pro-inflammatory properties that further contribute to atherogenesis [87]. Unlike LDL, the level of lipoprotein(a) is 70% to 90% genetically determined; as of 2025, there are no approved pharmacotherapies that specifically target this lipoprotein. Evidence has emerged that in patients with coronary atherosclerosis, elevated levels of apoprotein(a) are associated with a heightened degree of plaque instability, raising the risk of myocardial infarction. Using sophisticated imaging techniques and arterial ultrasound to study coronary lesions in patients following recent myocardial infarction, investigators examined the relationships of total cholesterol, triglycerides, and lipoproteins to pancoronary atherosclerosis (e.g., plaque volume, core lipid burden) and the presence of focal vulnerable plaques. Using multivariable analysis, they found that elevated LDL, non-HDL, and total cholesterol were strongly associated with lipid deposition and plaque burden in the coronary tree, but not with the presence of focal vulnerable plaque. Conversely, lipoprotein(a) was strongly associated
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