Use of Indocyanine Green Angiography for Real-Time ...

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In this study, we investigated the DC characteristics and quantitatively evaluated the UWF ICGA images in patients with DM. To the best of our knowledge, this is the first UWF ICGA qualitative and quantitative analysis according to DR severity. We demonstrated that hypofluorescent spots and choroidal hyperpermeability were frequent UWF ICGA findings in patients with DC, and the &#;salt and pepper&#; pattern, choroidal artery tortuosity, late choroidal non-perfusion, inverted inflow phenomenon were more common in patients with advanced DR. Notably, quantitative image analysis revealed that CVD and CFD were increased according to the DR stage, which was consistent with the increase in SFCT.

Diabetic choroidopathy was first described by Hidayat and Fine, which included choriocapillaris dropout, basement membrane thickening, and choroidal neovascularization in patients with advanced DM on light microscopy5. Another histopathologic study, reported the diabetic choroid was characterized by choriocapillaris degeneration, which included increased alkaline phosphatase activity and extravascular migration of polymorphonuclear leukocytes7. These histopathologic studies revealed that DM could affect the choroidal circulation.

With the development of ICGA imaging technology, there have been studies that identified and defined DM.

Weinberger and Gaton were the first ones to report the ICGA findings of patients with NPDR20. They employed conventional 50-degree ICGA imaging and reported a late phase &#;salt and pepper&#; pattern and hypofluorescence spots, which is the characteristic pattern of choroidal changes in NPDR. In our study, we discovered a &#;salt and pepper&#; pattern is more frequent in advanced NPDR and PDR eyes than in early NPDR or no DR eyes (Table 2). The &#;salt and pepper&#; pattern of selective CC filling indicates focal choroidal ischemia20. Therefore, DR severity may exacerbate choroidal vascular damage. Only 60&#;80% of the small fluorescein molecules are bound to plasma proteins and thus leak through the fenestrated choriocapillaris, causing &#;background staining.&#; Unlike fluorescein, up to 98% of ICG molecules are bound to plasma proteins and do not leak through the fenestrated choriocapillaris. Therefore, the hyperfluorescence appearance of ICGA could be interpreted as a breakdown of the CC or a small choroidal vessel and subsequent leakage of the ICG molecule. Meanwhile, in control eyes, choroidal hyperpermeability and hypofluorescent spots were detected (Table 2). Thus, choroidal vascular leakage on ICGA is not a characteristic feature of DC.

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In the early phases of ICGA, the choroidal artery was detected as a radial linear contrast enhancement pointing posteriorly (Fig. 1b,c). The choroidal artery exhibits corkscrew-like tortuosity around the posterior pole area, particularly in advanced NPDR and PDR eyes (Table 2, Fig. 1c,f). In PDR eyes, an inverted inflow phenomenon was observed, in which retinal arteries started to fill before choroidal perfusion (Fig. 1b,e). Previous studies employing doppler imaging indicated that as DR severity increased, choroidal blood flow decreased and choroidal vascular resistance increased25,26,27. Thus, these two ICGA findings could be attributed to increased choroidal vascular resistance. This has the potential to be used as a characteristic qualitative ICGA finding of DC. However, due to the cross-sectional design of this study, we could not determine whether these findings appear in a chronological order with DC progression.

MA is defined as a saccular expansion of the capillary wall, which is primarily detected in the retina but also in other organs such as the kidneys and hearts of diabetic patients. These MAs cause endothelial hypercellularity and selective pericyte loss, resulting in vascular wall weakness28. An early ICGA imaging study detected MA; however, it did not ensure that it was true choroidal MA or early choroidal neovascularization as described in the pathological examination20. In our study, we confirmed that all MAs observed in ICGA were also apparent in FA (Fig. 3). However, the number of MA in ICGA was lower than that in FA (Fig. 3). This is thought to be due to the size of the MA being large enough for the protein-bound indocyanine green molecule to pass through and then be detected by ICGA20.

Previous SFCT or subfoveal CVI studies using OCT imaging only show a limited portion of the choroid in the posterior pole. The findings of OCT studies remain controversial. Both choroidal thinning and thickening have been reported13,29,30,31. The ocular therapy for DR is an important factor to consider when interpreting these findings. Both intravitreal anti-VEGF injection and panretinal photocoagulation induce a choroidal thinning32. This consideration could be avoided only treatment-naïve patients with DM were targeted. According to the DR severity, our findings demonstrated a significant increase in CVD and SFCT (Figs. 4a and 5a). Interestingly, only Haller&#;s layer, not Sattler&#;s layer, shows significant thickening as DR severity increases in the SFCT sub-layer analysis (Fig. 5c,b, respectively). According to these findings, choroidal vessels dilated as DC progressed, which is thought to be due to the dilation of Haller&#;s layer. Given that the ICGA image did not show CC vasculature, dilation of choroidal vasculature in DC was mainly responsible for the change in medium- to large-sized choroidal vessels. Perivascular cells express different morphologies and functions along with vascular trees33. Veins are covered by vascular smooth muscle cells (VSMC), which are substantially less dense than arteries33. In addition, in recent studies, veins were found to exhibit NG2 and platelet-derived growth factor receptor beta (PDGFRβ) expressing pericytes34,35. In hyperglycemia, protein kinase C-delta (PKC-δ) upregulation inhibits the PDGF/PDGFRβ-Αkt pathway, reducing pericyte survival and inducing pericyte apoptosis36,37. Therefore, reduced pericyte coverage or changes in pericyte characters may cause changes in CVD and choroidal thickness in DC.

A fractal is a geometric pattern that allows the description of objects that branch repeatedly38. The fractal dimension (Df) represents the complexity of the branching pattern of the vasculature, and it is a ratio with no counting units. The reduction in retinal vascular Df indicates early vascular changes in DR39,40. In this study, CVD and CFD were significantly higher in advanced DR eyes than in early or no DR eyes (Fig. 4b). Given that no choroidal neovascularization was observed in the qualitative evaluation, the simultaneous increase in CVD and CFD indicates that choroidal vessels dilate and tortuosity increases at the same time. Based on the findings of a Doppler hemodynamic study, the increase in CFD can be interpreted as a cause or effect of an increase in choroidal vascular resistance26. The gradual increase in CFD based on DR stages and choroidal artery tortuosity in advanced DR (Table 2) indicates that choroidal vascular resistance increases with DR severity degree. The choroidal vessels have VSMC coverage that is denser in choroidal arteries33. In DM, hyperglycemia inhibits VSMC apoptosis while enhancing VSMC proliferation41,42. Transforming growth factor-beta (TGFβ) is upregulated in diabetic endothelial cells, promoting Smad2/3 signaling in perivascular cells and mesenchymal cell differentiation into VSMC43,44. TGFβ1 also induces VSMC phenotypic switch to contractile phenotype45. These microvascular mural cell phenotypic changes could be explained by a gradual increase in CFD by the DR stage and an increase in choroidal vascular resistance in DC.

DME was caused by a local effect of VEGF and pro-inflammatory cytokines synthesized by the retina46. Based on the presence or absence of DME, subgroup analysis revealed significantly high CFD, SFCT, and Haller&#;s layer thickness in the DME group. These findings demonstrate how localized retinal inflammation and VEGF activity in DR affect choroidal vasculature. Based on these findings, CFD with SFCT, particularly Haller&#;s layer thickness, could be used as a biomarker for treatment response monitoring of DME.

This study has several limitations. First, the retinal vasculature was not subtracted from the image analysis process. This may result in underestimation of fractal dimension and vascular density in advanced DR with retinal non-perfusion. Second, because images were used without stereographic projection, peripheral CVD may be overestimated. Third, because the UWF ICGA detects mainly medium- to large-sized choroidal vessels, choriocapillaris cannot be analyzed in this study. Fourth, renal function, which has a significant effect on choroidal thickness, was not considered. Finally, because the choroidal vascular disease is ambiguous, the possibility of co-existing choroidal diseases such as pachychoroid spectrum disease cannot be entirely excluded.

In conclusion, we revealed that diabetes induces choroidal vascular dilation and increases choroidal vascular complexity through UWF ICGA analysis. An advanced diabetic choroidopathy had a characteristic UWF ICGA pattern, including the &#;salt and pepper&#; pattern, inverted inflow phenomenon, late choroidal non-perfusion, and choroidal artery tortuosity, indicating choroidal inflammation and increased vascular resistance. Future longitudinal studies should focus on DC clinical staging and its therapeutic applications.

Use of Indocyanine Green AngiographyIndocyanine Green Angiography for Real-Time ...

Qualitative and quantitative evaluation of diabetic ...