Plasmalogens and octanoylcarnitine serve as early warnings for central retinal artery occlusion.

Image of a retina.

Wang C, Li Y, Feng J, Liu H, Wang Y, Wan Y, Zheng M, Li X, Chen T, Xiao X. (2024) Plasmalogens and octanoylcarnitine serve as early warnings for central retinal artery occlusion. Molecular Neurobiology

Central retinal artery occlusion (CRAO) is a form of ophthalmic emergency caused by an interruption of blood flow of the central retinal artery. CRAOs are very serious and result in loss of functional visual acuity or lead to irreversible damage to retinal cells. This can also increase a person’s risk for stroke and myocardial ischemia, which is reduced blood supply to the heart muscles and prevents the ability to receive adequate oxygen. Since this can be such a severe condition and requires quick action to save vision, biomarkers have been a primary focus to increase early detection. To date, biomarker research for CRAO has focused on hematological markers such as neutrophil/lymphocyte ratio, but these are better used to assess the patient’s inflammatory status and is not the best fit for predicting occurrence of CRAO. In comparison, metabolites reflect the metabolic pathways in an exact point in time and therefore are useful as biomarkers, especially in cardiovascular and cerebrovascular diseases. Wang et al were interested in determining biomarkers for risk of CRAO and to use these to better understand the mechanisms behind CRAO.

To determine whether any metabolic biomarkers for risk of CRAO could be identified, blood levels were compared between patients with CRAO and healthy controls using non-targeted metabolomics. All participants were between the ages of 18-75 years, the CRAO patients were diagnosed with the current guideline at the time of onset, and blood was collected within 72 hours of symptom onset. Venous blood was collected prospectively after overnight fasting and arterial blood samples were collected from upstream of the embolization site of the CRAO before thrombolytic intervention was injected. In their analysis, 1259 metabolites were identified, then when screening differential metabolites between the two groups, 54 were found with 27 being upregulated and 27 downregulated in the CRAO group compared to the controls. Using metabolite network mapping, Wang et al detected greater alterations in lipid metabolites in people with CRAO. As well, pathway enrichment analysis demonstrated an enrichment of cholesterol metabolism pathway in the CRAO group. Since the bloodstream is how metabolite waste is removed from organs, comparing arterial blood that enters an organ and the venous blood that leaves the organ can demonstrate the metabolic status of the organ. It was hypothesized that arterial blood from the site of obstruction could reveal more information about the embolus causing CRAO compared to what the venous blood would reveal. Using both blood samples, the authors compared venous blood from the CRAO group and the control group, then selected metabolites that had a similar trend when comparing the arterial blood between the two groups. Choline plasmalogen (PC) 18:0/20:4, PC 18:0/22:6, and octanylcarnitine were all found to be downregulated in the CRAO group.

To further characterize the differences between the CRAO group and the control group, other clinical parameters were analyzed. Of these, high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A1 (ApoA1) which is a major component of HDL particles, were found to be significantly different between CRAO and control with both suggested to be able to predict CRAO occurrence.

Wang et al were interested in whether there were biomarkers associated with the risk of CRAO and whether any associated metabolites could elucidate the mechanisms behind CRAO. As there had been no useful biomarkers for CRAO, and a quick response is required to prevent loss of visual acuity and irreversible damage to retinal cells, identifying biomarkers of risk could be incredibly beneficial. Although previous biomarkers used for CRAO have been representative of systemic inflammation, the embolus in people who experience CRAO is often caused by carotid atherosclerotic plaque, therefore hyperlipidemia biomarkers could be more representative of the risk level. Using non-targeted metabolomics, 3 metabolites including PC 18:0/20:4, PC 18:0/22:6, and octanylcarnitine and 2 blood indexes such as HDL-C and ApoA1 are suggested to be able to predict CRAO occurrence. Interestingly, ApoA1 is a main component of HDL and HDL-C has a beneficial effect on cardiovascular health. HDL can remove cholesterol from peripheral tissues to the liver which stops cholesterol from accumulating in the artery wall and causing an occlusion. High levels of HDL-C have a beneficial effect on cardiovascular health and have been associated with a reduced incidence of CRAO, which supports the findings of this study. As well, plasmalogens were reduced in the patients with CRAO and this could be due to plasmalogens acting as antioxidants. In addition, high levels of plasmalogens are able to inhibit cholesterol synthesis therefore if their levels are low, cholesterol can continue to be produced and eventually accumulate, especially if it is not being cleared due to reduced levels of HDL-C. The authors suggest that further work should look at the typed of embolus patients have and classify the data in that way since this study looked all CRAO patients together. As well, there was a variation between time of onset and time of blood collection which could also alter metabolite levels and standardizing this time in future work would be beneficial.