Comparison of Retinal Imaging Techniques in Individuals with Pulmonary Artery Hypertension Using Vessel Generation Analysis.

(1) Background: Retinal vascular imaging plays an essential role in diagnosing and managing chronic diseases such as diabetic retinopathy, sickle cell retinopathy, and systemic hypertension. Previously, we have shown that individuals with pulmonary arterial hypertension (PAH), a rare disorder, exhibit unique retinal vascular changes as seen using fluorescein angiography (FA) and that these changes correlate with PAH severity. This study aimed to determine if color fundus (CF) imaging could garner identical retinal information as previously seen using FA images in individuals with PAH. (2) Methods: VESGEN, computer software which provides detailed vascular patterns, was used to compare manual segmentations of FA to CF imaging in PAH subjects (n = 9) followed by deep learning (DL) processing of CF imaging to increase the speed of analysis and facilitate a noninvasive clinical translation. (3) Results: When manual segmentation of FA and CF images were compared using VESGEN analysis, both showed identical tortuosity and vessel area density measures. This remained true even when separating images based on arterial trees only. However, this was not observed with microvessels. DL segmentation when compared to manual segmentation of CF images showed similarities in vascular structure as defined by fractal dimension. Similarities were lost for tortuosity and vessel area density when comparing manual CF imaging to DL imaging. (4) Conclusions: Noninvasive imaging such as CF can be used with VESGEN to provide an accurate and safe assessment of retinal vascular changes in individuals with PAH. In addition to providing insight into possible future clinical translational use.

Retinal vessel changes in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is classically considered an isolated small vessel vasculopathy of the lungs with peripheral pulmonary vascular obliteration. Systemic manifestations of PAH are increasingly acknowledged, but data remain limited. We hypothesized that retinal vascular changes occur in PAH. PAH subjects underwent retinal fluorescein angiography (FA) and routine disease severity measures were collected from the medical record. FA studies were analyzed using VESsel GENerational Analysis (VESGEN), a noninvasive, user-interactive computer software that assigns branching generation to large and small vessels. FAs from controls (n = 8) and PAH subjects (n = 9) were compared. The tortuosity of retinal arteries was higher in PAH subjects compared to unmatched controls (1.17, 95% confidence interval: [1.14, 1.20] in PAH vs. 1.13, 95% CI: [1.12, 1.14] in controls, p = 0.01). Venous tortuosity was higher and more variable in PAH (1.17, 95% CI: [1.14, 1.20]) compared to controls (1.13, 95% CI: [1.12, 1.15]), p = 0.02. PAH subjects without connective tissue disease had the highest degree of retinal tortuosity relative to controls (arterial, p = 0.01; venous, p = 0.03). Younger PAH subjects had greater retinal arterial tortuosity, which attenuated with age and was not observed in controls. Retinal vascular parameters correlated with some clinical measures of disease in PAH subjects. In conclusion, PAH subjects exhibit higher retinal vascular tortuosity. Retinal vascular changes may track with pulmonary vascular disease progression. Use of FA and VESGEN may facilitate early, noninvasive detection of PAH.

Vascular Patterning as Integrative Readout of Complex Molecular and Physiological Signaling by VESsel GENeration Analysis.

The molecular signaling cascades that regulate angiogenesis and microvascular remodeling are fundamental to normal development, healthy physiology, and pathologies such as inflammation and cancer. Yet quantifying such complex, fractally branching vascular patterns remains difficult. We review application of NASA's globally available, freely downloadable VESsel GENeration (VESGEN) Analysis software to numerous examples of 2D vascular trees, networks, and tree-network composites. Upon input of a binary vascular image, automated output includes informative vascular maps and quantification of parameters such as tortuosity, fractal dimension, vessel diameter, area, length, number, and branch point. Previous research has demonstrated that cytokines and therapeutics such as vascular endothelial growth factor, basic fibroblast growth factor (fibroblast growth factor-2), transforming growth factor-beta-1, and steroid triamcinolone acetonide specify unique "fingerprint" or "biomarker" vascular patterns that integrate dominant signaling with physiological response. In vivo experimental examples described here include vascular response to keratinocyte growth factor, a novel vessel tortuosity factor; angiogenic inhibition in humanized tumor xenografts by the anti-angiogenesis drug leronlimab; intestinal vascular inflammation with probiotic protection by Saccharomyces boulardii, and a workflow programming of vascular architecture for 3D bioprinting of regenerative tissues from 2D images. Microvascular remodeling in the human retina is described for astronaut risks in microgravity, vessel tortuosity in diabetic retinopathy, and venous occlusive disease.