The retina presents a distinct, non-invasive, and in vivo means of visualizing the vasculature and neural tissues of the human body. It functions as a window into overall health. The retinal nerve fibers are an extension of the axons in the central nervous system (CNS), and the retinal ganglion cells (RGCs) exhibit the typical characteristics of CNS neurons (1). The retinal blood vessels not only reflect the features and regulatory mechanisms of blood vessels throughout the body but also act as indicators of general wellbeing (2).

In the last few decades, research provided evidence of RGC degeneration and damage to the retinal nerve fiber layer (RNFL) in Alzheimer’s disease (AD), a neurodegenerative disorder (3). Additionally, pathological changes were found in the retinal vasculature in cases of stroke (cerebral hemorrhage and infarction) (4). Insights from numerous current studies have also confirmed the correlation between retinal images and the risks of dementia and stroke, which are related to neural and vascular abnormalities, respectively (5, 6). These studies have laid the groundwork for using retinal images to evaluate and predict systemic diseases.

Optical coherence tomography (OCT) offers cross-sectional details of the retina and choroid, while OCT angiography (OCTA) visualizes the vasculature and structure within specific single layers. These technologies can serve as biomarkers for neuronal pathways because of their detailed imaging of RGCs, the RNFL, the inner plexiform layer (IPL), and other neural layer structures (7). Meanwhile, CFP and OCTA can be used for studying vascular pathways (8). Various artificial intelligence methods have been developed to facilitate the use of retinal imaging in the diagnosis and quantitative analysis of both retinal disease (9–12) and systemic diseases (13–16).

OCTA studies investigating superficial vascular density in the eyes of patients with diabetes but no signs of diabetic retinopathy have yielded mixed results. While some studies observed decreased superficial vascular density in diabetic patients without retinopathy (17, 18), others observed no change in density (19, 20). In contrast, investigations into deep vascular density in the eyes of patients with diabetes without signs of diabetic retinopathy, compared to healthy controls, have yielded more consistent findings. Notably, in the majority of studies, a reduction in deep vascular density was reported in diabetic patients without retinopathy (21, 22).

Research efforts exploring the influence of systemic hypertension on OCTA parameters have also yielded somewhat inconsistent findings. Although the majority of studies indicate notable decreases in the superficial vascular density among hypertensive patients (23, 24), some did not observe a significant decrease (25).

Consistent findings from multiple studies indicate that obese adults, even those without diabetes or hypertension, exhibit decreased vascular density of the deep retinal layer (26). Wang et al. studied the association between retinal thickness and fundus blood flow density in chest pain patients with dyslipidemia. They found that the dyslipidemia group had significantly lower superficial vascular density in the inferior and temporal retinal regions than the control group, indicating a potential connection between dyslipidemia and retinal microvascular changes (27).

In this study, unlike previous studies, we focused on investigating differences in retinal structure and function on OCTA between healthy subjects and those with early-stage cardiovascular-kidney-metabolic syndrome. Cardiovascular-kidney-metabolic (CKM) health, first proposed by the American Heart Association, encompasses the clinical manifestations resulting from the pathophysiological interactions among metabolic risk factors, such as obesity and diabetes, chronic kidney disease, and the cardiovascular system (28). A CKM health framework has been proposed to facilitate early detection of suboptimal CKM health to enable timely intervention and slow disease progression (29). In the current study, we focused on early-stage CKM syndrome subjects. Specifically, early-stage CKM syndrome was defined by the presence of prediabetes, diabetes, or hypertension and any signs of abnormal levels of key metabolic and cardiovascular blood indicators, including glucose, triglyceride, total cholesterol, HDL, LDL, and uric acid. We aimed to identify whether OCTA imaging biomarkers can be used as an evaluation tool for predicting early CKM syndrome.

This study demonstrates that early-stage CKM syndrome is associated with widespread retinal structural and vascular changes. To our knowledge, this is the first study that examines the relationship between CKM syndrome and retinal structure and function. The most consistent findings were reduced retinal thickness and vascular density across multiple macular regions, particularly in the superior and temporal regions. These findings align with prior research linking systemic health to retinal microvascular dysfunction (1, 2). Given that aging is associated with vessel density reduction (31) and thickness reduction (32) and that men tend to exhibit lower vessel density (33). We further performed a multivariate analysis to adjust for confounding factors such as age and gender. The multivariate analysis highlighted the outer temporal region thickness and the outer and inner superior vascular density as potential independent biomarkers, even after adjusting for age and gender, suggesting that OCTA can detect early retinal changes even in asymptomatic individuals.

Research on superficial vascular density in diabetes patients without signs of diabetic retinopathy has produced mixed results, with some studies reporting decreased vascular density (9, 34), while others found no significant changes (10, 35). Studies on deep vascular density showed more consistent results of decreased vascular density. In our study, we observed significantly reduced retinal thickness and vessel density across almost all ETDRS regions. Furthermore, we observed a gradient change from normal to prediabetes to diabetes, highlighting the dose-dependent impact of glycemic dysregulation on retinal structure and function.

Research on the effect of systemic hypertension on OCTA parameters has led to somewhat conflicting results. Although the majority of studies have reported a significant reduction in hypertensive patients (23, 24) in both superficial and deep vascular density, some reported non-significant change (25). In our study, we observed a similar trend that almost all ETDRS regions showed a significant reduction in thickness and vascular density.

Retinal structure and function changes vary according to the lipid profile. Low HDL, a marker of impaired lipid metabolism, was associated with focal retinal thinning (outer superior) and vascular loss (outer superior, outer temporal, inner temporal, and inner inferior), potentially reflecting endothelial injury caused by dyslipidemia, which is consistent with Wang’s study (27), who also reported significantly reduced superficial vascular density in the inferior and temporal regions of patients in the dyslipidemia group. In our study, we further categorized dyslipidemia into four subgroups and found that abnormal HDL and triglyceride groups showed more significant changes in thickness and vessel density, while abnormal LDL and total cholesterol groups showed no significant change. Further studies are needed to elucidate the different effects of lipid substances on retinal function.

Yang et al. found that high uric acid level was associated with lower vessel density in men (36). However, in our study, we observed somewhat contradictory results, with vessel density showing an increasing trend in the dysuricemia group, although most quadrants were not statistically significant. This unexpected increase in vascular density with dysuricemia may indicate compensatory vasodilation, though further research is needed to clarify this relationship.

In our study, after adjusting for age and gender, the only significant changes in retinal thickness and vascular density were observed in the temporal and superior regions. A study by Lin et al. revealed that the temporal and superior regions are more vulnerable in patients with type 2 diabetes (37). Similar findings were also reported in the literature for the severity of diabetic retinopathy, where total thickness in the temporal and superior regions showed the most prominent change related to DR severity (38). A histologic study conducted by Kern et al., in an animal model of diabetes mellitus (DM), found that vascular disorders were more common in the superior temporal retina compared to the inferior nasal retina (39). One possible explanation for this phenomenon is that the temporal side of the retina usually has the lowest vessel density among the four quadrants because it lies furthest away from the optic disc region and thus is more susceptible to ischemia or hypoxia.

Retinal alterations in early-stage CKM likely result from systemic processes such as inflammation, oxidative stress, and endothelial dysfunction, which affect both neural and vascular tissues. The retina, as an extension of the central nervous system, is highly susceptible to metabolic stress, making OCTA’s ability to visualize both structural (thickness) and functional (vascular density) changes critical for early detection of systemic health decline. Therefore, OCTA-derived biomarkers may serve as non-invasive tools to assess suboptimal CKM health, particularly in populations at risk for diabetes or hypertension. The identification of retinal regions, such as outer nasal and outer superior, as key sites of change could guide targeted screening strategies. However, longitudinal studies are needed to validate these markers for predicting future cardiovascular or metabolic events.

Early-stage CKM syndrome is associated with detectable retinal structural and vascular changes via OCTA, particularly in the macular region. These findings support OCTA as a promising tool for evaluating systemic health status, with potential for early intervention in the early stages of metabolic and cardiovascular disease.