Metabolic factors influence CNV activity in neovascular AMD – insights from the BIOMAC study

Abstract

Purpose : To identify candidate systemic metabolic factors which may modulate CNV activity and thereby influence the treatment demand with intravitreal anti-VEGF injections (IAI) in subjects with neovascular AMD.

Methods : Cohort study on 46 patients with neovascular AMD, treated with anti-VEGF injections. The cohort was stratified by treatment need. One group (N=25) received regular IAI at intervals of 6 weeks or less, while still having signs of CNV activity (high frequency group – HF). The second stratum (N=21) included subjects with a treatment interval of 10 weeks or longer and having no signs of CNV activity (low frequency group – LF). Full ophthalmological profiling was performed and EDTA blood samples were collected. Metabolic factors were analyzed using Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS). Welch’s two sample t-test was performed on natural log-transformed data for statistical analysis. Metabolites reaching a p<0.05 were considered for further analysis as potential candidates.

Results : Both strata were well balanced regarding age (HF 78.4±8.14; LF 79.7±7.00 years), gender (HF 40% LF 61.9% female) and BCVA (HF 61.4±15.7; LF 65.0±12.4). Due to the group definition, central retinal thickness differed between HF and LF (HF 352.2±98.0 vs. LF 274.8±45.7μm. 34/899 biochemicals were differently regulated between HF and LF. 24 are up- and 10 are down-regulated in HF. Most of the upregulated metabolites belong to the lipid pathway (54%). Key candidates up-regulated in HF: sarcosine (95% CI HF 1.05-1.25; LF 0.74-1.08; ratio LF/HF 0.79; p=0.0024) and retinol (95% CI HF 1.03-2.06; LF 0.58-1.53; ratio LF/HF 0.68; p=0.0494). Key candidates down-regulated in HF: Glutathione, reduced (GSH) (95% CI HF 0.70-1.09; LF 0.99-1.54; ratio LF/HF 1.42; p=0.0296), 2,3-diphosphoglycerate (2,3-BPG) (95% CI HF 0.80-0.98; LF 0.94-1.10; ratio LF/HF 1.15; p=0.0181) and theanine (95% CI HF 0.28-0.47; LF 0.47-1.25; ratio LF/HF 2.29; p=0.0203).

Conclusions : nAMD subjects with higher and lower treatment need differed in several metabolic factors. Metabolites such as sarcosine and retinol, were elevated in the HF group and have pro-angiogenic potential. GSH, 2,3-BPG and theanine were increased in the LF cohort and may inhibit angiogenesis. In summary, systemic metabolic factors may influence treatment need through modulation of CNV activity.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.