Arteriolar Tortuosity Research Articles

Assessment of retinal arteriolar tortuosity in patients with COL4A1 or COL4A2 mutations.

Qualitative and quantitative analyzes of retinal arteriolar tortuosity (RAT) in patients with COL4A1 and COL4A2 mutations to identify a tortuosity index (TI) threshold for detecting increased RAT. Fifty-two eyes of 28 patients were included. Group 1 included eyes with a normal arteriolar pattern (n=19, 37%), group 2 included eyes with moderately increased arteriolar tortuosity (n=13, 25%), and group 3 included eyes with typical abnormal arteriolar tortuosity (n=20, 38%). The TI was measured by calculating the arc-to-chord ratio of arterioles and venules in the posterior pole. The mean arteriolar TI was significantly higher in all groups with a COL4A1/A2 mutation compared to controls: 1.19 ± 0.03, 1.24 ±0.05, and 1.57 ± 0.23 in groups 1, 2 and 3, respectively, vs. 1.12 ± 0.01 (all p <0.0001). The TI threshold was 1.13, with a sensitivity of 98.1% and a specificity of 100%. The area under the curve was 0.995. Measuring the arteriolar TI allowed diagnosing increased RAT in all eyes with a COL4A1/A2 mutation, whereas the subjective assessment suspected or detected it in only 62% of eyes. In adult patients with cerebral microangiopathy, detecting increased RAT, even when mild, directs the diagnosis towards COL4A1/A2-related cerebroretinal angiopathy.

Repeated treatment with VEGF receptor inhibitors induces phenotypic changes in endothelial cells and pericytes in the rat retina

Abnormal ocular angiogenesis is a major cause of visual impairment and vision loss in neovascularization-related diseases. Currently, anti-vascular endothelial growth factor (VEGF) drugs are used to treat ocular neovascularization, but repeated injections are needed to maintain their therapeutic effects. However, repeated injection of anti-VEGF drugs may affect the retinal blood vessel phenotype and diminish therapeutic effects. In this study, we aimed to investigate the phenotypic changes in endothelial cells and pericytes caused by the repeated interruption of the VEGF receptor signaling pathway in neonatal rats. KRN633 (10 mg/kg), a VEGF receptor tyrosine kinase inhibitor, was subcutaneously administered on postnatal day (P)-7 and P8 (first round), P14 and P15 (second round), and P21 and P22 (third round). The rat eyes were collected on P7, P9, P14, P16, P21, P23, P28, and P35. Using retinal flat-mount specimens stained with specific markers for vascular endothelial cells, basement membranes, and pericytes, the arteriolar tortuosity, capillary area density, and distribution of pericytes were evaluated. Significant loss of capillaries was observed the day after the first round of KRN633 treatment, after which aggressive angiogenesis occurred, leading to the formation of tortuous arterioles. Rats that completed second and third rounds of KRN633 treatment showed more severe abnormalities in the retinal vasculature than those that only completed first round treatment. Repeated treatment with KRN633 decreased the anti-angiogenic effects but increased the immunoreactivity of α-smooth muscle actin in the pericytes on veins and capillaries. α-Smooth muscle actin expression was inversely correlated to anti-angiogenic effects. Overall, these results revealed that repeated interruption of VEGF receptor signaling pathway altered the phenotypes of endothelial cells and pericytes and induced anti-VEGF drug resistance. Therefore, careful follow-up is necessary when using anti-VEGF drugs to treat abnormal angiogenesis-associated ocular diseases.

The role of Perifoveal Arteriolar Tortuosity in Optical Coherence Tomography Angiography (OCTA) images as an early indicator of hypertensive retinopathy.

To assess the value of increased perifoveal retinal vascular tortuosity in optical coherence tomography angiography (OCTA) images as a biomarker of early hypertensive retinopathy and compare its clinical sensitivity and accuracy with traditional morphological changes used for Scheie classification. OCTA images of 81 eyes (40 eyes from 20 hypertensive subjects and 41 eyes from 21 control subjects) were obtained retrospectively. Hypertensive retinopathy changes in randomized eyes were graded according to the Scheie classification, and perifoveal vessels were traced in a masked fashion. Tortuosity values of the perifoveal vessels were then calculated along with interobserver agreement in determining the morphometric values. There were no differences in perifoveal venular tortuosity between the hypertensive and control groups (Mean = 1.13 ± 0.04 vs. 1.13 ± 0.03), but significant differences existed for arterioles (Mean = 1.14 ± 0.05 vs. 1.11 ± 0.04). Tortuosity measurements demonstrated a significant interobserver agreement (p < 0.001), while Scheie ratings had a poor interobserver agreement (p = 0.735). There was a significant difference in Scheie classification between the hypertensive and control groups (Mean = 1.06 ± 0.54 vs. 0.50 ± 0.43, p = 0.005). OCTA-based perifoveal retinal arteriolar tortuosity may be a potential reliable biomarker with certain advantages for detecting early hypertensive retinopathy than morphological changes used for the Scheie classification. This may have broad applications and establish important parameters in utilizing OCTA for screening protocols, considering the importance of early detection of systemic hypertension.

Aging drives cerebrovascular network remodeling and functional changes in the mouse brain

Aging is frequently associated with compromised cerebrovasculature and pericytes. However, we do not know how normal aging differentially impacts vascular structure and function in different brain areas. Here we utilize mesoscale microscopy methods and in vivo imaging to determine detailed changes in aged murine cerebrovascular networks. Whole-brain vascular tracing shows an overall ~10% decrease in vascular length and branching density with ~7% increase in vascular radii in aged brains. Light sheet imaging with 3D immunolabeling reveals increased arteriole tortuosity of aged brains. Notably, vasculature and pericyte densities show selective and significant reductions in the deep cortical layers, hippocampal network, and basal forebrain areas. We find increased blood extravasation, implying compromised blood-brain barrier function in aged brains. Moreover, in vivo imaging in awake mice demonstrates reduced baseline and on-demand blood oxygenation despite relatively intact neurovascular coupling. Collectively, we uncover regional vulnerabilities of cerebrovascular network and physiological changes that can mediate cognitive decline in normal aging.

Association of retinal microvascular curve tortuosity and multiple sclerosis: A cross-section analysis from the UK Biobank

BackgroundThere is growing evidence supporting that vascular abnormalities contribute to multiple sclerosis (MS), and retinal microvasculature functions as a visible window to observe vessels. We hypothesized that retinal vascular curve tortuosity is associated with MS, which this study aims to address. MethodsParticipants from the UK Biobank with complete clinical records and gradable fundus photos were included in the study. Arteriolar and venular curve tortuosity and vessel area density are quantified automatically using a deep learning system. Individuals with MS were matched to healthy controls using propensity score matching (PSM). Conditional logistic regression was used to investigate the association between retinal vascular characteristics and MS. We also used a receiver operating characteristic (ROC) curve to assess the diagnostic performance of MS. ResultsVenular curve tortuosity (VCT) was found to be significantly associated with MS. And patients with multiple sclerosis were probable to have lower VCT than the non-MS group (OR = 0.22 [95 % CI, 0.05 to 0.92], P < 0.05). ConclusionsOur study reveals a significant association between vessel curve tortuosity and MS. The lower curve tortuosity of the retinal venular network may indicate a higher risk of incident multiple sclerosis.

Longitudinal associations of retinal vessel morphology with intraocular pressure and blood pressure at follow-up visit-Findings from a Danish eye and vision cohort, Project FOREVER.

To characterise the retinal vasculometry of a Danish eye and vision cohort and examine associations with systolic blood pressure (BP), diastolic BP, mean arterial BP, and intraocular pressure (IOP). Longitudinal study. The retinal vasculature of fundus images from the FOREVER (Finding Ophthalmic Risks and Evaluating the Value of Eye exams and their predictive Reliability) cohort was analysed using a fully automated image analysis program. Longitudinal associations of retinal vessel morphology at follow-up visit with IOP (baseline and follow-up) and BP (follow-up) were examined using multilevel linear regression models adjusting for age, sex and retinal vasculometry at baseline as fixed effects and person as random effect. Width measurements were additionally adjusted for the spherical equivalent. A total of 2089 subjects (62% female) with a mean age of 61 (standard deviation 8) years and a mean follow-up period of 4.1 years (SD 0.6 years) were included. The mean arteriolar diameter was approximately 20% thinner than the mean venular diameter, and venules were about 21%-23% less tortuous than arterioles. BP at follow-up was associated with decreased arteriolar diameter from baseline to follow-up. After adjusting for baseline IOP, IOP at follow-up was associated with increased arteriolar tortuosity above baseline (0.59%, 95% CI 0.08-1.10, p-value 0.024). In a Danish eye and vision cohort, variations in BP and alterations in IOP over time were associated with changes in the width and tortuosity of retinal vessels. Our findings contribute novel insights into retinal vascular alterations over time.

Occult retinal neovascularization following intravitreal bevacizumab and laser treatment for retinopathy of prematurity

BackgroundWe present a patient with retinopathy of prematurity (ROP) who developed worsening plus disease after complete regression of stage 3 ROP. The use of fundus fluorescein angiography (FFA) aided the visualization of occult neovascularization that caused the disease progression.Case presentationThe patient was at high risk for ROP due to low birth weight of 690 g and gestational age of 25 weeks. After the diagnosis of stage 3 ROP in zone I without plus disease, she was treated initially with bilateral intravitreal bevacizumab (IVB) and followed by laser photocoagulation 5 weeks later. Despite the resolution of ROP stage, the plus disease worsened. Neither systemic risk factors nor skip laser areas were observed. Hence, FFA was performed and subsequently identified occult neovascularization with active leakage. Additional IVB and laser treatment in the capillary dropout area inside vascularized retina were added. The plus disease improved but mild arteriolar tortuosity persisted.ConclusionsWorsening of plus disease after completion of laser ablation and IVB with complete regression of stage 3 ROP is rare. Systemic risk factors such as continuous oxygen therapy and cardiovascular disease should be ruled out. FFA aided in identifying occult neovascularization and prompted further treatment.

Early and late chorioretinal complications of preeclampsia

Preeclampsia remains a serious problem of obstetric practice, the growth of severe forms of this complication of pregnancy is predicted in the future, which determines the scientific interest of specialists in the search for new markers of preeclampsia to prevent the progression of preeclampsia and maternal mortality. The ocular fundus is an area where vessels can be observed in real time, in addition, the structure of the retina predisposes to the development of edema, up to retinal detachment in severe preeclampsia. In the last decade, new diagnostic equipment has become available to study chorioretinal changes at the stage of preclinical manifestations. In order to study early and late complications of pre-eclampsia from the retina and vasculature, we analyzed domestic and foreign scientific sources published in the last five years. According to a number of authors, changes in the visual organ of varying degrees of severity in preeclampsia occur in 100% of cases. It is established that the key role in the pathogenesis of vascular disorders in preeclampsia belongs to endothelial dysfunction. Preeclampsia may be accompanied by hemorrhagic and ischemic retinal infarcts, retinal pigment epithelium detachment, corkscrew-shaped tortuosity of arterioles in the periphery of the retina, retinal detachment, optic disc edema, less frequently vitreous hemorrhages, lesions of the optic nerve, conjunctiva and cerebral cortex in the area of visual centers, which may resolve against the background of therapy when the patient's general condition improves. However, in some women endothelial dysfunction may persist for many years, the most frequent late complications of preeclampsia are retinal detachment and diabetic retinopathy. Along with traditional methods of ophthalmoscopy of the eye fundus for diagnostics of chorioretinal complications OCT for determination of serous retinal detachment, subretinal deposits and other pathologies of the vasculature, USDG of the central retinal artery, posterior short ciliary arteries, ocular artery for diagnostics of ophthalmologic complications of preeclampsia can be used. As a result of the analysis of scientific data, conclusions are drawn about the association of preeclampsia with the development of certain early and distant chorioretinal complications. The search for new, earlier changes on the ocular fundus may serve for early diagnosis of preeclampsia, prevention of severe complications of pregnancy.

Retinal microvasculature and risk of incident dementia over a 10‐year period: results from the 3C‐Alienor population‐based study

AbstractBackgroundThe retina and the brain microvasculatures share many anatomical and physiological similarities; thus, retinal microvasculature could represent a potential screening tool for cerebrovascular and neurodegenerative diseases. Changes in retinal microvasculature have been associated with dementia in previous studies. However, all the previous studies analyzing retinal vascular network features in relation to dementia or Alzheimer Disease (AD) were cross‐sectional. This study aimed to explore the longitudinal relationship between retinal microvascular features and dementia incidence over a 10‐year follow‐up period.MethodWe included 617 participants from the Three‐City (3C) population‐based cohort and its ancillary ophthalmological study, the Alienor study. Quantitative retinal vascular features (caliber, tortuosity, fractal dimension) were assessed at baseline in the Alienor study using the semi‐automated Singapore I Vessel Assessment (SIVA) software; dementia was actively screened and diagnosed over a 10‐year period. Cox proportional‐hazards models were used to estimate the risk of incident dementia and its main etiologies (i.e., probable or possible AD and mixed or vascular dementia) associated with retinal vascular features.ResultThe mean age of the participants was 79.5 years (SD 4.4) and 66.6% were women. During the follow‐up (median of 7.2 years), 134 participants developed dementia (87 probable or possible AD and 38 mixed or vascular dementia). In multivariate models adjusted for the main potential confounders (socio‐demographic factors, vascular co‐morbidities and Apolipoprotein ε4 allele), increased arteriolar tortuosity was associated with increased risk of dementia (HR per SD increase = 1.26, 95%CI: 1.07; 1.50). Despite some trends, retinal calibers were not significantly associated with dementia all‐cause. When considering the different etiologies of dementia, wider retinal venular calibers were associated with mixed or vascular dementia, but not with Alzheimer’s disease. Fractal dimensions were not associated with dementia.ConclusionChanges in retinal microvasculature were associated with risk of incident dementia. More works are needed to replicate and determine which features could help identifying persons at risk of future dementia at an early stage, and to examine the specific processes that might be involved according to dementia etiology.

Role of mammalian target of rapamycin in the formation and progression of retinopathy of prematurity-like vascular abnormalities in neonatal rats

Retinopathy of prematurity (ROP), a retinal disease that can occur in premature infants, can lead to severe visual impairment. In this study, we examined the preventive and therapeutic effects of mammalian target of rapamycin complex 1 (mTORC1) inhibition on abnormal retinal blood vessels in a rat model of ROP. To induce ROP-like vascular abnormalities, rats were subcutaneously treated with KRN633, an inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinase, on postnatal day 7 (P7) and P8. KRN633-treated (ROP) rats were treated subcutaneously with the mTORC1 inhibitor rapamycin according to preventive and therapeutic protocols, i.e., from P11 to P13 (P11–P13) and from P14 to P20 (P14–P20), respectively. To compare with the effects of VEGF inhibition, KRN633 was administered according to similar protocols. Changes in retinal vasculature, phosphorylated ribosomal protein S6 (pS6), a downstream indicator of mTORC1 activity, and the proliferative status of vascular cells were evaluated at P14 and P21 using immunohistochemistry. Rapamycin treatment from P11 to P13 prevented increases in arteriolar tortuosity, capillary density, and the number of proliferating vascular cells, and eliminated pS6 immunoreactivity in ROP rats. KRN633 treatment at P11 and P12 (P11/P12) also prevented the appearance of ROP-like retinal blood vessels. Rapamycin treatment from P14 to P20 failed to attenuate arteriolar tortuosity but prevented increases in capillary density and proliferating vascular cell number at the vascular front, but not at the central zone. KRN633 treatment from P14 to P20 significantly reduced abnormalities in the retinal vasculature; however, the effects were inferior to those of KRN633 treatment on P11/P12. These results suggest that activation of the mTORC1 pathway in proliferating endothelial cells contributes to the appearance and progression of ROP-like retinal blood vessels. Therefore, inhibition of mTORC1 may be a promising approach for selectively targeting abnormal retinal blood vessels in ROP.

Abstract 12907: Aging Drives Cerebrovascular Network Remodeling and Functional Changes in the Mouse Brain

Introduction: Cerebrovascular dysfunction has been implicated in age-related cognitive decline and dementia, but the underlying vascular mechanisms are not well understood. An improved understanding of the nature of normal cerebrovascular aging is needed to help to establish the role that vascular dysfunction might play in cognitive decline and dementia. Methods: Here, we asked how normal aging differentially impacts the vascular structure and function in different brain areas in mice. We investigated structural changes in aged cerebrovascular networks and pericytes utilizing serial two-photon tomography (STPT). To further investigate potential remodeling of different vascular compartments and pericyte subtypes, we utilized tissue clearing, 3D immunolabeling, and light sheet fluorescence microscopy (LSFM) imaging. We also assessed how healthy aging impacts brain hemodynamics in response to voluntary locomotion and whisker stimulation in awake, head-fixed mice using wide field optical signal imaging and two-photon imaging. We tested mice of both sexes at 2-month, 18-month (early aging), and 24-month (late aging) of age. Results: Whole-brain vascular tracing using STPT showed an overall ~10% decrease in vascular length and branching density, and LSFM imaging with 3D immunolabeling further revealed increased arteriole tortuosity in aged brains. We also uncovered a selective vascular and pericyte loss in deep cortical layers, basal forebrain regions, and the hippocampal network. This may contribute to their regional vulnerabilities in neurodegenerative disorders. Moreover, our in vivo imaging in awake, head-fixed mice identified delayed neurovascular coupling response and inefficient oxygen delivery in aged brains. Conclusions: Our study reveals aging-related brain-wide changes in vascular and mural cell types that can explain vulnerability and resilience of different brain areas in normal aging. Moreover, we identified an age-related decrease in brain oxygenation and delayed neurovascular coupling responses which can be linked with cognitive impairment in aged brains. These aging-related changes will serve as a common factor to understand many neurodegenerative disorders and cognition decline in the elderly population.

Retinal microvasculature and incident dementia over 10 years: The Three-City-Alienor cohort.

We explored the longitudinal relationship between retinal vascular features and dementia incidence over 10 years. Among 584 participants from the Three-City-Alienor (3C-Alienor) population-based cohort, quantitative retinal vascular features (caliber, tortuosity, fractal dimension) were measured using semi-automated software. Dementia was actively diagnosed over the follow-up period. One hundred twenty-eight participants (21.9%) developed dementia over a median of 7.1 years. In Cox proportional hazards models adjusted for sociodemographic characteristics, apolipoprotein E (APOE) ε4, and vascular factors, increased retinal arteriolar tortuosity was associated with all-cause dementia (hazard ratio per standard deviation increase, 1.21; 95% confidence interval: 1.02-1.44). Wider retinal calibers and a higher venular tortuosity were associated with mixed/vascular dementia, but not Alzheimer's disease. Fractal dimensions were not associated with dementia. Changes in the retinal microvasculature were associated with dementia risk. More studies are needed to replicate these findings and determine which features might help identify persons at risk at an early stage. The retinal microvasculature might reflect the brain microvasculatureWe explored the association between retinal vascular features and incident dementia584 participants from the Three-City-Alienor cohort were followed-up over 10 yearsIncreased arteriolar tortuosity and venular calibers were associated with dementia riskRetinal imaging might help identify persons at risk of future dementia.

Ocular features in Williams-Beuren syndrome: a review of the literature.

The current review will discuss the pathophysiology, work-up and clinical relevance of the ocular phenotype in Williams-Beuren syndrome in detail. Few case reports, case series and retrospective studies reported the ophthalmic features in Williams-Beuren syndrome, focusing on specific aspects of the ocular involvement. Recently, novel retinal findings have been described in association with the disease. Numerous ocular features have been described in Williams-Beuren syndrome. Some of them, such as the stellate pattern of the iris or the retinal arteriolar tortuosity may be helpful for the diagnosis but have no significant clinical implications; others, such as strabismus and refractive errors require early treatment to reduce the risk of irreversible visual impairment. Finally, some features, such as a broad foveal pit and thinner retina still have unknown significance and require further longitudinal and multimodal studies.

Retinal vessel caliber and tortuosity and prediction of 5-year incidence of hypertension.

With arterial hypertension as a global risk factor for cerebrovascular and cardiovascular diseases, we examined whether retinal blood vessel caliber and tortuosity assessed by a vessel-constraint network model can predict the incidence of hypertension. The community-based prospective study included 9230 individuals who were followed for 5 years. Ocular fundus photographs taken at baseline were analyzed by a vessel-constraint network model. Within the 5-year follow-up, 1279 (18.8%) and 474 (7.0%) participants out of 6813 individuals free of hypertension at baseline developed hypertension and severe hypertension, respectively. In multivariable analysis, a higher incidence of hypertension was related to a narrower retinal arteriolar diameter ( P < 0.001), wider venular diameter ( P = 0.005), and a smaller arteriole-to-venule diameter ratio ( P < 0.001) at baseline. Individuals with the 5% narrowest arteriole or the 5% widest venule diameter had a 17.1-fold [95% confidence interval (CI):7.9, 37.2] or 2.3-fold (95% CI: 1.4, 3.7) increased risk for developing hypertension, as compared with those with the 5% widest arteriole or the 5% narrowest venule. The area under the receiver operator characteristic curve for predicting the 5-year incidence of hypertension and severe hypertension was 0.791 (95% CI: 0.778, 0.804) and 0.839 (95% CI: 0.821, 0.856), respectively. Although the venular tortuosity was positively associated with the presence of hypertension at baseline ( P = 0.01), neither arteriolar tortuosity nor venular tortuosity was associated with incident hypertension (both P ≥ 0.10). Narrower retinal arterioles and wider venules indicate an increased risk for incident hypertension within 5 years, while tortuous retinal venules are associated with the presence rather than the incidence of hypertension. The automatic assessment of retinal vessel features performed well in identifying individuals at risk of developing hypertension.

GWAS on retinal vasculometry phenotypes.

The eye is the window through which light is transmitted and visual sensory signalling originates. It is also a window through which elements of the cardiovascular and nervous systems can be directly inspected, using ophthalmoscopy or retinal imaging. Measurements of ocular parameters may therefore offer important information on the physiology and homeostasis of these two important systems. Here we report the results of a genetic characterisation of retinal vasculature. Four genome-wide association studies performed on different aspects of retinal vasculometry phenotypes, such as arteriolar and venular tortuosity and width, found significant similarities between retinal vascular characteristics and cardiometabolic health. Our analyses identified 119 different regions of association with traits of retinal vasculature, including 89 loci associated arteriolar tortuosity, the strongest of which was rs35131825 (p = 2.00×10-108), 2 loci with arteriolar width (rs12969347, p = 3.30×10-09 and rs5442, p = 1.9E-15), 17 other loci associated with venular tortuosity and 11 novel associations with venular width. Our causal inference analyses also found that factors linked to arteriolar tortuosity cause elevated diastolic blood pressure and not vice versa.

Retinal vessel diameters and microvascular abnormalities in patients with carotid stenosis before and 6months after carotid endarterectomy: A prospective study.

To assess retinal findings in patients with severe carotid stenosis (CS) before and after carotid endarterectomy (CEA) compared to those in controls. This study is based on 70 patients (male 81%, mean age 69) scheduled for CEA in Helsinki University Hospital and 41 healthy nonmedicated controls (male 76%, mean age 68). Our examinations included fundus photographs. Semi-automated software (Vesselmap, Imedos) served for evaluation of central retinal arterial equivalent (CRAE) and venular equivalent (CRVE), and arterio-venous ratio (AVR) in both eyes. We assessed fundus photographs to subjectively grade microvascular abnormalities in the ipsilateral eyes including focal arteriolar narrowing and irregularities, arteriolar wall reflex, arterio-venous crossing signs and arteriolar and venular tortuosity in the macula. CRAE was similar in the ipsi-and contralateral eyes of our patients, and similar to that of the controls both pre- and postoperatively. Preoperatively, we observed higher CRVE in the patients' ipsilateral than in their contralateral eyes (222 vs. 217 μm, p=0.009), and likewise higher than in controls' eyes (222 vs. 214 μm, p=0.024). CRVE decreased postoperatively in the patients' ipsilateral eyes (222 vs. 217 μm, p=0.037). Among the microvascular abnormalities, arteriolar and venular tortuosity in the macula showed higher grades in the patients than in the controls preoperatively (p=0.035 and p=0.043), but not postoperatively (p=0.15 and p=0.10). CRVE decreased after CEA, showing that venules constrict after the mechanical hindrance of blood flow is removed. Higher grades in arteriolar and venular tortuosity in the macula, a potential ocular biomarker of CS, subsided after CEA.

Structural and functional analysis of retinal vasculature in HANAC syndrome with a novel intronic COL4A1 mutation.

Mutations of the COL4A1 gene, a major structural protein of vessels, may cause hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC) syndrome. The vascular structure and function of patients with HANAC is poorly known. Here, we report a family with HANAC syndrome associated to a previously unreported mutation in COL4A1. The structure and function of retinal vessels were detailed by adaptive optics ophthalmoscopy (AOO) and optical coherence tomography (OCT) angiography. Clinical data from six affected individuals (43 to 72years old) from a single family comprising two generations were collected. Imaging charts including conventional fundus imaging, OCT-angiography and AOO in static and dynamic (flicker) mode were reviewed. DNA sequencing was done in the proband. DNA sequencing of the proband revealed a heterozygous deletion of COL4A1 (NM_001845) at position 1120 in the intron 20 resulting in the loss of splicing donor site for exon 20 (c.1120+2_1120+8del heterozygote). Four patients had arterial hypertension, and three had kidney dysfunction, one of which under dialysis. By fundus examination, five had typical retinal arteriolar tortuosity with arteriolar loops. Wall-to-lumen ratio of arteries was within normal limits, that is, lower than expected for hypertensive patients. Several foci of arteriolar irregularities were noted in the two oldest patients. In three affected subjects, evaluation of the neurovascular coupling showed a higher flicker-induced vasodilation than a control population (6% to 11%; n<5%). Structural and dynamic analysis of retinal vessels in a HANAC family bearing a previously unreported intronic COL4 mutation was done. In addition to arteriolar tortuosity, we found reduced wall-to-lumen ratio, arteriolar irregularity and increased vasodilatory response to flicker light. These abnormalities were more marked in the oldest subjects. This abnormal flicker response affected also non-tortuous arteries, suggesting that microvascular dysfunction extends beyond tortuosity. Such explorations may help to better vascular dysfunction related to HANAC and hence better understand the mechanisms of end-organ damage.

Retinal Vascular Geometry in Hypertension: cSLO-Based Method.

We aim to introduce a method using confocal scanning laser ophthalmoscopy (cSLO) images for measuring retinal vascular geometry, including vessel branch angle (BA), vessel diameter, vessel tortuosity, and fractal dimension (Df), and to elucidate the relationship between hypertension and these metrics. A total of 119 participants (119 eyes) were enrolled, among which 72 were normotensive and 47 were hypertensive. Infrared cSLO images were extracted from the circular scan around the optics disc using a commercial cSLO + optical coherence tomography instrument. Preprocessed cSLO images were further analyzed using the appropriate tool/macro/plugin of ImageJ. Intraclass correlation coefficients of selected methods used for conducting the cSLO-based geometric analyses were all higher than 0.80. Arterial/arteriolar BA, arteriolar vessel diameter, and total Df in normotensive subjects were 85.80 ± 7.79°, 116.80 ± 12.58μm, and 1.430 ± 0.037, respectively, significantly higher than those of hypertensive subjects (82.13 ± 10.83°, 108.2 ± 11.12μm, and 1.361 ± 0.044, all P < 0.05). The aforementioned metrics remained negatively correlated with hypertension even after adjusting for age alone or age and gender (P < 0.05). However, the difference between arteriolar tortuosity and all studied venous/venular geometric parameters in both subjects was insignificant (all P > 0.05). Proposed cSLO-based methods for assessing various vascular geometric parameters were highly repeatable and reproducible. Arterial/arteriolar BA, arteriolar vessel diameter, and total Df were retinal vascular parameters significantly correlated with hypertension in a negative manner.

Structural and functional exploration of the retinal vasculature in HANAC syndrome associated with a novel intronic COL4A1 mutation

AbstractPurpose: Mutations of the COL4A1 gene may cause hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC) syndrome. The vascular structure and function of patients with HANAC is poorly known. Here, we report a family with HANAC syndrome associated to a previously unreported mutation in COL4A1. The structure and function of retinal vessels were detailed by adaptive optics ophthalmoscopy (AOO) and optical coherence tomography (OCT) angiography.Methods: Clinical data from six affected individuals from a single family over two generations were collected. Imaging charts including conventional fundus imaging, OCT‐angiography and AOO in static and dynamic (flicker) mode were reviewed. DNA sequencing was done in the proband.Results: DNA sequencing of the proband revealed a heterozygous deletion of COL4A1 (NM_001845) at position 1120 in the intron 20 resulting in the loss of splicing donor site for exon 20 (c.1120 + 2_1120 + 8del heterozygote). Four had arterial hypertension, and three had kidney dysfunction, one of which under dialysis. Examination of retinal vessels showed that all patients had retinal arteriolar tortuosity which peaked in precapillary arterioles but spared capillaries and veins. Wall‐to‐lumen ratio of arteries was within normal limits, that is, lower than expected for hypertensive patients. Several foci of arteriolar irregularities were noted I the oldest patients. In three affected subjects, evaluation of the neurovascular coupling showed a high flicker‐induced vasodilation (from 6% to 10.8%; n &lt; 5%).Conclusions: Structural and dynamic analysis of retinal vessels in a HANAC family bearing a novel intronic COL4 mutation showed reduced parietal thickness, arteriolar irregularity and increased dilatory response to flicker light. This affected as well non tortuous arteries, suggesting that HANAC causes diffuse microvascular dysfunction. Our findings may help to better understand end‐organ damage related to HANAC.

Retinal arteriole tortuosity changes over time in a veteran population with diabetes

PurposeArteriole tortuosity is an important sign of retinal disease which is associated with diabetic retinopathy, but it is unclear how arteriole tortuosity changes over time in populations with diabetes. It has been suggested that retinal vasculature geometry changes precede diabetic retinopathy. Here, we evaluate whether arteriole tortuosity changes precede diabetic retinopathy by examining arteriole tortuosity and retinopathy at two points in time four years apart. MethodsA population of 126 subjects had retinal photographs at baseline and approximately four years later (48 ± 9 months) in a telehealth screening program. The photographs from both eyes at baseline and follow up were graded for tortuosity (straight, wavy, or tortuous) and retinopathy using clinical ETDRS guidelines. Consensus grades (across graders) were used, but when consensus was not reached or the image quality was too poor to grade, the subject was removed from analysis. Other health markers, such as duration of diabetes, hemoglobin A1c (HbA1c), neuropathy status, and insulin usage, were also recorded. Differences in time points were assessed with paired t-tests. ResultsOf the 109 subjects (218 eyes) included in final analysis, 24 eyes had retinopathy at baseline and 26 eyes had retinopathy at follow up, which was almost all mild (93%). Tortuosity was largely unchanged at follow up (76%) and on average was straight or wavy. Nine eyes had decreased tortuosity (4.3%). The final 19.7% had arteriole tortuosity which increased a level from baseline. The subjects with increased tortuosity had a shorter duration of diabetes at baseline (5.8 years vs 7.4 years, p<0.04). There was no relationship between retinopathy development and arteriole tortuosity increasing or between HbA1c and change in tortuosity. ConclusionsIt appears that retinal arteriole tortuosity may increase most over early years of diabetes development and then stabilize. Therefore, it may be more valuable to monitor retinal arteriole tortuosity in early years of diagnosis in both clinical and telemedicine settings. More research is needed following changes in tortuosity over time in patients with diabetes.