Genetic mutations in genes encoding the LDLR (LDL receptor), APOB (apolipoprotein B-100), or PCSK9 (proprotein convertase subtilysin kexin 9) account for at least 80% of autosomal dominant hypercholesterolemia (1). Familial hypercholesterolemia (FH) is characterized by a selective increase of LDL particles in plasma, resulting in cholesterol deposition in the arteries, tendons, and skin xanthomas, arcus cornea, thereby increasing the risk of premature coronary heart disease (2).
In addition to elevated plasma LDL cholesterol (LDL-C) levels, the low HDL cholesterol (HDL-C) phenotype frequently observed in FH patients may also contribute to premature atherosclerosis (3, 4). Indeed, epidemiological studies have demonstrated that an increase of 1 mg/dl in plasma HDL-C concentration yields a 2% to 3% reduction in cardiovascular risk (5). HDL particles possess multiple anti-atherogenic functions, in particular those related to the reverse cholesterol transport (RCT) pathway, the physiological process by which excess cholesterol is removed from peripheral tissues and transported back to the liver for biliary excretion. Indeed, this pathway represents the primary mechanism by which HDL protects against atherosclerosis and by which it may induce plaque regression (6). In this context, we have recently demonstrated that the atheroprotective RCT pathway is defective in FH patients as a result of functional anomalies of HDL particles that alter their capacity to mediate key steps of RCT. Such anomalies contribute significantly to accelerating atherosclerosis in FH patients (7).
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The treatment of FH includes a low-lipid diet with PUFAs and more vegetables and fruits, a lipid-lowering therapy with a statin, and, if necessary, an intestinal cholesterol absorption inhibitor such as ezetimibe (8, 9). Such pharmacological therapies are in some cases not sufficient to reduce LDL-C to the therapeutic goal (10). Thus, the latter FH patients need to undergo LDL apheresis sessions every 2 or 3 weeks. Indeed, LDL apheresis represents a method of choice, in addition to drug therapy, to reduce cardiovascular risk in severe FH patients by dramatically reducing atherogenic LDL particle levels (11). Various LDL apheresis techniques are currently used: immunoadsorption, dextran sulfate-cellulose adsorption, heparin extracorporal LDL precipitation system, and the direct adsorption of lipoprotein (DALI®) system (Fresenius Medical Care; Germany) using hemoperfusion (12). These different techniques facilitate reduction in all classes of apoB-containing lipoprotein particles, including VLDL, LDL, and lipoprotein [a] (Lp[a]) (up to 70%) and significantly contribute to enhancing the impact of diet and drug therapy on the progression of coronary artery disease(11). However, the LDL apheresis procedure also results in a significant decrease in plasma HDL-C levels (9%-25%), depending on the LDL apheresis system (13). This effect reflects preferential reduction in plasma levels of large HDL2 subfractions (−30%) and, to a lesser extent, in the smaller HDL3 particles (−20%) (14). In the present study, we evaluated the consequences of LDL apheresis on the efficacy of the RCT pathway in FH patients by assessing the ability of HDL particles to mediate free cholesterol efflux from macrophages, CETP-mediated cholesteryl ester (CE) transfer from HDL to apoB-containing lipoproteins, and hepatic HDL-CE delivery.
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