Apolipoprotein E4 (apoE4) is a positively charged proinflammatory apolipoprotein bound to high-density lipoprotein (HDL) cholesterol and remnant lipoproteins. ApoE4 is associated with an increased risk of cardiovascular and cerebrovascular disease. Low-density lipoprotein (LDL) apheresis, a therapy for patients with familial hypercholesterolemia, removes apolipoprotein B and other positively charged plasma proteins but negatively charged proteins such as HDL cholesterol are generally spared. Despite their negative charge, LDL apheresis still removes 10% to 15% of HDL cholesterol, in particular, inflammatory HDL cholesterol. Patients with familial hypercholesterolemia have increased plasma levels of apoE4 and apoE4-bound HDL cholesterol. We tested the hypothesis that LDL apheresis would reduce the plasma levels of apoE4. We analyzed the plasma apoE4 levels using enzyme-linked immunosorbent assay immediately before and after LDL apheresis in 10 patients with familial hypercholesterolemia who had tested positive for the apoE4 isoform. After one treatment, the mean plasma apoE4 levels had been reduced by 39%, LDL cholesterol by 75%, triglycerides by 38%, and HDL cholesterol by 18%. The change in HDL cholesterol was significantly related to the apoE4 baseline values (r = −0.83, p = 0.001) and apoE4 levels after apheresis (r = 0.816, p = 0.004). In conclusion, LDL apheresis acutely reduced the plasma levels of apoE4. The mechanism of apoE4 reduction by LDL apheresis might be related to the selective reduction of a particular HDL cholesterol.
Apolipoprotein E (apoE) binds to lipoproteins and serve as an enzyme, cofactor, receptor ligand, and lipid transfer carrier that regulates the metabolism and uptake of lipoproteins in tissue. In plasma, apoE is bound to high-density lipoprotein (HDL) cholesterol and remnant lipoproteins, such as intermediate lipoproteins, very-low-density lipoproteins, and chylomicron remnants. The phenotype of apoE is determined by 3 alleles (e2, e3, e4) that code for 3 different isoforms (E2, E3, E4), which differ from each other by a single amino acid substitution involving cysteine-arginine replacement at position 112 and 158. ApoE4 is the most positively charged isoform, and carriers have a greater risk of developing cardiovascular disease, Alzheimer’s disease, and stroke.
Familial hypercholesterolemia (FH) is one of the most common inherited disorders, with a population frequency as great as 1:70. In addition to elevated low-density lipoprotein (LDL) cholesterol and premature coronary heart disease, FH is associated with decreased levels of HDL cholesterol containing reduced amounts of apoA-I and increased apoE. The apoE4 levels of patients with FH encompasses 50% of the total plasma content of apoE compared to 15% in the normal population.
LDL apheresis is indicated for patients with FH and coronary heart disease and severe hyperlipidemia (LDL cholesterol >200 mg/dl) uncontrolled by maximum treatment with lipid-lowering medications. LDL apheresis devices used in the United States remove LDL cholesterol (60% to 80%) through an attraction of the positively charged plasma proteins such as apolipoprotein B, the atherogenic particle of LDL cholesterol. Despite having a negative surface membrane charge, a small portion (10% to 15%) of HDL cholesterol is removed with LDL apheresis. In the present study, we examined the changes in the plasma levels of apoE4 in patients with FH and its association with HDL cholesterol after one treatment of LDL apheresis.
Methods
Of 30 patients with FH who were undergoing chronic biweekly LDL apheresis at the University of Kansas Atherosclerosis Center and had detectable plasma apoE4 levels, 10 were evaluated for the present study. The patient population was primarily women (n = 8), with a mean age of 55 years. Most patients (n = 9) had experienced a previous vascular event or had undergone a coronary procedure. Lipid-altering therapy included statins (n = 4), ezetimibe (n = 5), and omega-3 fatty acids (n = 7), with 6 patients intolerant to statins.
The LDL apheresis devices used for these patients included the heparin-induced extracorporeal LDL precipitation system (HELP Secura System, Melsungen, Germany) and the dextran sulfate LDL adsorption (Liposorber LA-15 System, Kaneka, Osaka, Japan). The mechanism for the specific removal of lipoproteins by HELP has been attributed to the negatively charged heparin precipitating with the positively charged apoB. The Liposorber LA-15 System exposes the plasma to a column of cellulose beads coated with dextran sulfate cellulose, and the electrostatic polyanionic dextran sulfate ligands bind with the positively charged apoB lipoproteins.
The plasma apoE4 levels were measured using a commercial enzyme-linked immunosorbent assay kit (MBL International, Woburn, Massachusetts). Enzymatic colorimetric test kits (VITROS Chemistry Systems, Ortho-Clinical Diagnostics, Rariton, New Jersey) were used to determine the total cholesterol, triglycerides, and HDL cholesterol.
Data are reported as the mean ± SD, unless otherwise noted. Outcome measures at baseline (immediately before apheresis therapy) and after apheresis treatment were compared using a paired Student’s t test for normally distributed variables and a sign rank test for nonparametric variables, as appropriate. Spearman’s rank correlation coefficients were used to measure the association between changes in apoE4 and changes in total cholesterol, triglyceride, HDL cholesterol, and LDL cholesterol levels. Statistical analyses were performed using the Statistical Package for Social Sciences, version 16 (SPSS, Chicago, Illinois). A 2-tailed α of 0.05 was used to denote statistical significance.
Results
The patients were treated using either the HELP Secura (n = 8) or Liposorber LA-15 (n = 2) system, and each device demonstrated similar reductions of the measured plasma parameters. The treatment was well tolerated by all 10 patients, without any adverse events reported for either system.
LDL apheresis therapy significantly reduced the apoE4 levels by 39% ( Table 1 ). Additionally, marked reductions were noted for LDL cholesterol (−75%), triglycerides (−38%), HDL cholesterol (−18%), and total cholesterol (−54%). The change in HDL cholesterol was significantly related to the apoE4 levels at baseline (r = −0.83, p = 0.001) and apoE4 levels after apheresis (r = 0.816, p = 0.004).
| Parameter | Preapheresis Value | Postapheresis Value | p Value |
|---|---|---|---|
| Apolipoprotein E4 (mg/dl) | 62 ± 11 | 38 ± 10 | <0.001 |
| Low-density lipoprotein (mg/dl) | 246 ± 54 | 89 ± 38 | <0.001 |
| Total cholesterol (mg/dl) | 327 ± 62 | 149 ± 44 | <0.001 |
| Triglycerides (mg/dl) | 204 ± 106 | 116 ± 81 | <0.001 |
| High-density lipoprotein (mg/dl) | 47 ± 13 | 39 ± 10 | <0.001 |
Results
The patients were treated using either the HELP Secura (n = 8) or Liposorber LA-15 (n = 2) system, and each device demonstrated similar reductions of the measured plasma parameters. The treatment was well tolerated by all 10 patients, without any adverse events reported for either system.
LDL apheresis therapy significantly reduced the apoE4 levels by 39% ( Table 1 ). Additionally, marked reductions were noted for LDL cholesterol (−75%), triglycerides (−38%), HDL cholesterol (−18%), and total cholesterol (−54%). The change in HDL cholesterol was significantly related to the apoE4 levels at baseline (r = −0.83, p = 0.001) and apoE4 levels after apheresis (r = 0.816, p = 0.004).
| Parameter | Preapheresis Value | Postapheresis Value | p Value |
|---|---|---|---|
| Apolipoprotein E4 (mg/dl) | 62 ± 11 | 38 ± 10 | <0.001 |
| Low-density lipoprotein (mg/dl) | 246 ± 54 | 89 ± 38 | <0.001 |
| Total cholesterol (mg/dl) | 327 ± 62 | 149 ± 44 | <0.001 |
| Triglycerides (mg/dl) | 204 ± 106 | 116 ± 81 | <0.001 |
| High-density lipoprotein (mg/dl) | 47 ± 13 | 39 ± 10 | <0.001 |
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