Serum Cholesterol Efflux Capacity in Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy

Abstract

Purpose: To investigate serum cholesterol efflux capacity (the ability of the serum to accept cholesterol) and factors that regulate it using nuclear magnetic resonance-quantified measures of lipoprotein particle composition and size and apolipoproteins metrics in patients with age-related macular degeneration (AMD).

Design: Case-control study.

Participants: Four hundred two serum samples from 80 patients with early AMD (eAMD), and 212 patients with neovascular AMD (nAMD), including 80 with typical nAMD (tAMD) and 132 with polypoidal choroidal vasculopathy (PCV), and 110 age- and gender matched control participants.

Methods: Serum from participants showed cholesterol efflux capacity measured using in vitro cell assays and lipoprotein subfractions measured using nuclear magnetic resonance (Nightingale, Ltd). Associations between cholesterol efflux capacity (measured in percentage) and lipid subfractions were investigated in the patients and control participants.

Main outcome measures: Cholesterol efflux capacity and lipid subfractions in control, eAMD, and nAMD. Associations between HDL subfractions and cholesterol efflux capacity.

Results: Cholesterol efflux capacity was higher in patients with eAMD (68.0 ± 11.3% [mean ± standard deviation]) and nAMD (75.9 ± 27.7%) than in the control participants (56.9 ± 16.7%) after adjusting for age, gender, and use of lipid-lowering drug (P < 0.0001). Nuclear magnetic resonance lipidomics demonstrated that the mean diameter of HDL was larger both in eAMD (9.96 ± 0.27 mm [mean ± standard deviation]) and PCV (9.97 ± 0.23 mm) compared with that of the control participants (9.84 ± 0.24 mm; P = 0.0001 for both). Among the 28 HDL subfractions, most of the small, medium, and large HDLs, but none of the 7 extra large HDLs fractions, were associated moderately with cholesterol efflux capacity in eAMD and PCV (R = 0.149-0.277).

Conclusions: Serum cholesterol efflux capacity was increased in eAMD and PCV, but not tAMD, possibly reflecting differential underlying pathophysiologic features of lipid dysregulation in tAMD and PCV. Further studies should be directed toward investigating the diverse biological activities of HDL in AMD, including macular pigment transport, regulation of inflammation, and local cholesterol transport system.

Keywords: AMD, age-related macular degeneration; Age-related macular degeneration; Cholesterol efflux; Drusen; HDL, high-density lipoprotein; LDL, low-density lipoprotein; Lipoprotein; NMR, nuclear magnetic resonance; PCV, polypoidal choroidal vasculopathy; Polypoidal choroidal vasculopathy; RPE, retinal pigment epithelium; RPMI, Roswell Park Memorial Institute; SCES, Singapore Chinese Eye Study; SD, standard deviation; VLDL, very low-density lipoprotein; eAMD, early age-related macular degeneration; nAMD, neovascular age-related macular degeneration; tAMD, typical neovascular age-related macular degeneration.

Figure 1

Bar graph showing cholesterol efflux capacity of control participants and patients with early age-related macular degeneration (AMD), neovascular AMD (nAMD), and polypoidal choroidal vasculopathy (PCV). A multiple linear regression model was used to compare cholesterol efflux capacity of the 3 groups, adjusting the various covariates, including factors affecting cholesterol efflux capacity such as age, gender, and lipid-lowering drug use. The generalized least squares estimation method was used in the multiple linear regression model for the heterogeneity of variance among the 3 groups. ∗P < 0.0083 was considered significant after Bonferroni correction. tAMD = typical neovascular age-related macular degeneration.

Figure 2

Graphs showing the association of metabolic variables in early age-related macular degeneration (eAMD) and polypoidal choroidal vasculopathy (PCV). Each bar represents the association with (A) PCV and (B) eAMD. The size of the bar is the odds ratio, and color refers to effect direction (blue is positive and red is negative) and significance. Dots indicate Bonferroni statistically significant metabolic variables corrected for age, sex, and lipid-lowering drug use (the statistically significance level was i < 0.00022 after Bonferroni correction). Labels describe the properties measured in each lipid subfraction. C = total cholesterol; CE = cholesterol ester; FC = free cholesterol; L = total lipid; P = concentration of particles; PL = phospholipid; TG = triglyceride.

Figure 3

Graph showing Pearson’s correlation (with 95% confidence interval) between cholesterol efflux capacity and high-density lipoprotein (HDL) subfractions. The y-axis shows the coefficiency (r). Most of the small, medium, and large HDLs, but none of the 7 extra-large HDL fractions, were associated moderately with cholesterol efflux capacity. C = total cholesterol; CE = cholesterol ester; FC = free cholesterol; L = total lipid; P = concentration of particles; PL = phospholipid; TG = triglyceride.