Anatomic, genetic and functional properties of the retinal circulation in pulmonary hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a disease characterized by progressive loss and remodeling of the pulmonary arteries resulting in right heart failure and death. The majority of research has focused on endothelial dysfunction in the pulmonary circulation without much attention to whether similar pathology may be found in the rest of the circulatory system. However, there is growing evidence that PAH patients also exhibit systemic endothelial dysfunction as evidenced by impaired brachial artery flow-mediated dilation, abnormal cerebral blood flow and intrinsic kidney disease. Besides abnormalities in vascular function and metabolic processes, patients with systemic sclerosis and PAH have been reported to exhibit distinctive morphological changes in kidney, skin, nailfold capillaries and sublingual vessels. 1 The eye is a highly vascularized organ that is sensitive to systemic changes in oxygen and blood flow. Interestingly, abnormally dilated episcleral vessels were found not only in PAH patients but also in unaffected carriers before the development of the disease. A more recent study by Chyou and colleagues using the Multi-Ethnic Study of Atherosclerosis database demonstrated that a higher right ventricular mass and volume by MRI correlated with a wider diameter in retinal vessels in women compared to men independent of body size, diabetes mellitus, cholesterol, age and alcohol use. 2 While this study did not involve PAH * Both authors contributed equally.

Hypoxia-induced inflammation: Profiling the first 24-hour posthypoxic plasma and central nervous system changes

“…In our study, we found evidence of a robust inflammatory response in the post-hypoxic period after only 1 week in hypoxia. However, evidence of retinal angiogenesis such as increased retinal vessel area and branching was only found after 2 to 3 weeks of hypoxia, as described by previous studies from our group and others [ 36 , 37 ]. Hypoxia-induced angiogenesis is a hallmark of ocular diseases such as diabetic retinopathy and vascular occlusion, although vessel hemorrhaging, which is common in these diseases, is not observed in whole-body hypoxia, suggesting different disease mechanisms [ 37 ].…”

“…Previous studies in systemic hypoxia in humans and animals, including from our laboratory, have shown that hypoxia is associated with retinal and optic nerve structural changes consistent with edema and inflammation and that retinal and optic nerve glial changes predominate after 48h hypoxia [ 30 ], while retinal vascular changes are common after 3-week hypoxia [ 36 ]. In this study, we examined the retinal, optic nerve, and plasma changes after 1-week hypoxia–a clinically relevant time point–and found that by 18h of posthypoxic recovery, serial OCT revealed significant new thickening of the peripapillary retina consistent with posthypoxic retinal edema.…”

“…As posthypoxic inflammation develops, this thinning of retina evolved to swelling, and future study to more finely delineate the hour-by-hour time course of retinal OCT changes and histologic correlation is needed. Ocular imaging studies have been done in hypoxia associated with pulmonary or cardiac disease, but they have mostly described retinal vascular changes [ 36 ] and oxygen levels [ 82 ], but not assessed retinal edema. OCT is a non-invasive technique that does not require pupil dilation, has high resolution and fast image acquisition [ 83 , 84 ].…”

“…Our study supports natural history plasma and OCT studies in individuals at risk of systemic hypoxia. Given the importance of vascular changes in systemic hypoxia, which we have shown in patients with chronic pulmonary hypertension [ 36 ], future hypoxia studies should include OCT angiography (OCTA), which can be performed rapidly at the same time as OCT typically without pupillary dilatation. OCTA imaging can provide high-resolution vascular imaging to analyze capillary changes at different retinal layers in vivo.…”

“…Hypoxia effects in the CNS tissue are exacerbated by the release of pro-inflammatory mediators by glial cells [32,33], and systemic inflammation in the setting of hypobaric hypoxia leads to cerebral edema facilitated by the interaction between astrocytes and microglia through toll-like receptors, upregulation of Aquaporin-4 (AQP4) and water permeability [34,35]. In the mouse retina, we have shown that 3-week systemic hypoxia leads to retinal angiogenesis [36], which develops between 2 and 3 weeks in hypoxia [37] and is consistent with increased vascular density in brain striatum, hippocampus, cerebellum and medulla oblongata after 2 weeks of hypoxia [38].…”