LDL-apheresis depletes apoE-HDL and pre-β1-HDL in familial hypercholesterolemia: relevance to atheroprotection

Abstract

Subnormal HDL-cholesterol (HDL-C) and apolipoprotein (apo)AI levels are characteristic of familial hypercholesterolemia (FH), reflecting perturbed intravascular metabolism with compositional anomalies in HDL particles, including apoE enrichment. Does LDL-apheresis, which reduces HDL-cholesterol, apoAI, and apoE by adsorption, induce selective changes in HDL subpopulations, with relevance to atheroprotection? Five HDL subpopulations were fractionated from pre- and post-LDL-apheresis plasmas of normotriglyceridemic FH subjects (n = 11) on regular LDL-apheresis (>2 years). Apheresis lowered both plasma apoE (-62%) and apoAI (-16%) levels, with preferential, genotype-independent reduction in apoE. The mass ratio of HDL2:HDL3 was lowered from ~1:1 to 0.72:1 by apheresis, reflecting selective removal of HDL2 mass (80% of total HDL adsorbed). Pre-LDL-apheresis, HDL2 subpopulations were markedly enriched in apoE, consistent with ~1 copy of apoE per 4 HDL particles. Large amounts (50-66%) of apoE-HDL were removed by apheresis, preferentially in the HDL2b subfraction (-50%); minor absolute amounts of apoE-HDL were removed from HDL3 subfractions. Furthermore, pre-β1-HDL particle levels were subnormal following removal (-53%) upon apheresis, suggesting that cellular cholesterol efflux may be defective in the immediate postapheresis period. In LDL-receptor (LDL-R) deficiency, LDL-apheresis may enhance flux through the reverse cholesterol transport pathway and equally attenuate potential biglycan-mediated deposition of apoE-HDL in the arterial matrix.

Fig. 1.

Bar graphs showing (A) apoE concentration in total HDL (n = 11), (B) apoE concentration in each density gradient HDL subfraction (n = 8), and (C) apoE:apoAI ratio in each density gradient HDL subfraction (n = 8) in normolipidemic subjects (dashed bar, n = 6), in FH patients before (open bar) and after (closed bar) LDL-apheresis. Values are means ± SEM. ***P < 0.001, **0.001 < P < 0.01, and *0.01 < P < 0.05 versus before LDL-apheresis.

Fig. 2.

Bar graph showing the plasma concentrations of HDL subspecies in FH patients (n = 11) before (open bar) and after (closed bar) LDL-apheresis. HDL2b (d = 1.063-1.091 g/ml); HDL2a (d = 1.091-1.110 g/ml); HDL3a (d = 1.110-1.133 g/ml); HDL3b (d = 1.133-1.156 g/ml); HDL3c (d = 1.156-1.179 g/ml). Insert: Bar graph showing the reduction in absolute mass concentration HDL subspecies after LDL-apheresis in FH patients (n = 11). Values are means ± SEM. ***P < 0.001, **0.001 < P < 0.01 and *0.01 < P < 0.05 versus before LDL-apheresis.

Fig. 3.

Bar graph showing the plasma concentrations of pre-β1-HDL in normolipidemic subjects (dashed bar; n = 25), in FH patients (n = 10) before (open bar) and after (closed bar) LDL-apheresis. Values are means ± SEM. ***P < 0.001, *0.01 < P < 0.05.

Fig. 4.

Bar graphs demonstrating the changes in HDL proteome upon apheresis. A: Relative changes in the HDL proteome FH patients (n = 10) after apheresis. Bars in red reached a statistical significance change (P < 0.05). B: Absolute levels (peak areas) preapheresis (open bars) and postapheresis (black bars) of the statistically significant changes (Bonferroni corrected). *P < 0.05, **P < 0.001.