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R. Zuckerman; Detecting the Hypoxic Stimulus for Neovascularization in the Retinas of Patients With Diabetic Retinopathy, AMD and CRVO. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5017.
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© ARVO (1962-2015); The Authors (2016-present)
Tissue hypoxia has long been proposed to be the first stage stimulus for neovascularization through the VEGF pathway. Detecting this metabolic stimulus in diabetic patients has proved elusive and animal models have yielded conflicting results. The Biometric Imaging Metabolic Mapper ( IOVS, 46: 4759, 2005; IOVS, 47: 3344, 2006) is the first noninvasive technology capable of probing mitochondrial function in space, time and depth in the living human eye. We therefore searched for the metabolic consequences of diabetes in a clinical study that included diabetic patients ranging from those without frank retinopathy, to those with nonproliferative disease (NPDR) and those with mild proliferative disease (PDR). We also searched for metabolic changes in case studies of patients with AMD and CRVO.
Mitochondrial flavoprotein fluorescence anisotropy was mapped in the temporal retinas of patients with NPDR, mild PDR and age-and gender-matched controls (n=20 in each group, total n=60) as well as 5 patients without frank retinopathy. Patients were staged by color fundus photography, fluorescein angiography, and optical coherence tomography (OCT). Imaging was similarly performed in several patients with AMD and CRVO.
Depression of metabolism prior to new vessel growth of 7.5 +/- 1.1% (mean +/- 1 SEM) in room air and by 11.1 +/- 2.5% during 100% O2 inspiration was revealed in NPDR (P<0.001). Mild PDR revealed massive depression of metabolism (64 +/- 7.5%, P=0.0007). Moreover, capillary dropout was revealed as a widening of frequency histograms of NPDR and PDR patients. One of five diabetic patients (duration of diabetes ≈ 10 yrs) without frank retinopathy showed depression of metabolism in the absence of any visual sign of disease. The mean fluorescence anisotropy of patients with NPDR only equaled that of normal controls breathing room air when NPDR patients were breathed on 100% oxygen. Statistically significant increases in metabolism in the inner retina were observed over photocoagulation burns in PDR. Patients with AMD showed depressed metabolism extending beyond the macula, with profound depression in the parafovea relative to that of the fovea. CRVO accompanied by macular edema was revealed in massive depression of metabolism consistent with OCT and visual fields.
Metabolic mapping provided the first evidence that hypoxia precedes neovascularization in diabetic retinopathy. Metabolic mapping proved to be a highly sensitive, spatially discriminative technique that may be used for early detection, screening, and guiding therapeutic interventions in retinal vascular diseases.
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