Emerging therapeutic strategies for unmet need in neovascular age-related macular degeneration.

Neovascular age-related macular degeneration (nAMD) is a major cause of visual impairment and blindness. Anti-vascular endothelial growth factor (VEGF) agents, such as ranibizumab, bevacizumab, aflibercept, brolucizumab and faricimab have revolutionized the clinical management of nAMD. However, there remains an unmet clinical need for new and improved therapies for nAMD, since many patients do not respond optimally, may lose response over time or exhibit sub-optimal durability, impacting on real world effectiveness. Evidence is emerging that targeting VEGF-A alone, as most agents have done until recently, may be insufficient and agents that target multiple pathways (e.g., aflibercept, faricimab and others in development) may be more efficacious. This article reviews issues and limitations that have arisen from the use of existing anti-VEGF agents, and argues that the future may lie in multi-targeted therapies including alternative agents and modalities that target both the VEGF ligand/receptor system as well as other pathways.

Retinal abnormalities, although relatively common in sleep clinic patients referred for polysomnography, are largely unrelated to sleep-disordered breathing.

STUDY OBJECTIVES: There has been long-standing interest in potential links between obstructive sleep apnea (OSA) and eye disease. This study used retinal photography to identify undiagnosed retinal abnormalities in a cohort of sleep clinic patients referred for polysomnography (PSG) and then determined associations with PSG-quantified sleep-disordered breathing (SDB) severity. METHODS: Retinal photographs (n = 396 patients) were taken of each eye prior to polysomnography and graded according to validated, standardized, grading scales. SDB was quantified via in-laboratory polysomnography (PSG; n = 385) using standard metrics. A questionnaire (n = 259) documented patient-identified pre-existing eye disease. Within-group prevalence rates were calculated on a per patient basis. Data were analyzed using multivariate logistic regression models to determine independent predictors for retinal abnormalities. P < 0.05 was considered significant. RESULTS: Main findings were (1) 76% of patients reported no pre-existing "eye problems"; (2) however, 93% of patients had at least one undiagnosed retinal photograph-identified abnormality; (3) most common abnormalities were drusen (72%) and peripapillary atrophy (PPA; 47%); (4) age was the most common risk factor; (5) diabetes history was an expected risk factor for retinopathy; (6) patients with very severe levels of SDB (apnea hypopnea index ≥ 50 events/h) were nearly three times more likely to have PPA. CONCLUSION: Retinal photography in sleep clinic settings will likely detect a range of undiagnosed retinal abnormalities, most related to patient demographics and comorbidities and, except for PPA, not associated with SDB. PPA may be indicative of glaucoma, and any association with severe SDB should be confirmed in larger prospective studies.

Retinal Vasculature Fractal and Stroke Mortality.

BACKGROUND AND PURPOSE: Fractal analysis is a method of quantifying the branching complexity and density of the retinal vessels. We hypothesized that reduced fractal dimension, signifying a sparser vascular network, is associated with long-term stroke mortality. METHODS: We examined the relationship of fractal dimension and stroke mortality in a prospective, population-based cohort of 3143 participants aged 49 years or older. Fractal dimension was measured from digitized fundus photographs using a computer-automated method. Stroke mortality was documented from Australian National Death Index records. We defined reduced fractal dimension as values in the lowest quartile. RESULTS: Over 12 years, there were 132 (4.2%) stroke-related deaths. Stroke-related mortality was higher in participants with reduced fractal dimension (lowest quartile) compared with the highest quartile (7.7% versus 1.3%, P<0.01). After controlling for age, gender, smoking, blood pressure, history of stroke, and other factors, participants with reduced fractal dimension had higher stroke mortality (hazard ratio, 2.42 [95% CI, 1.15-5.07], lowest versus highest quartile). When modeled as a continuous variable, reduced fractal dimension was associated with increased stroke mortality (multivariable-adjusted hazard ratio, 1.26 [95% CI, 1.06-1.51], per SD decrease). CONCLUSIONS: Reduced retinal vascular fractal dimension is independently associated with 12-year stroke mortality. Reduced fractal dimension may indicate cerebral tissue hypoxia and increased risk of stroke.

Baseline extended zone retinal vascular calibres associate with sensory nerve abnormalities in adolescents with type 1 diabetes: A prospective longitudinal study.

OBJECTIVE: The relationship between retinal vascular calibres (RVCs) and diabetic neuropathy is unclear. We investigated associations between RVCs and sensory nerve abnormality in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS: In a prospective longitudinal study of 889 adolescents with type 1 diabetes with baseline mean (±SD) age 14.1 ± 1.5 years and HbA1c IFCC 69.4 ± 14.1 mmol/mol (8.6 ± 1.3%), RVCs were assessed from baseline retinal photographs: 'central zone' calibres, summarized as central retinal arteriolar (CRAE) and venular equivalents (CRVE) and 'extended zone' calibres: mean width of arterioles (MWa) and venules (MWv). Sensory nerve abnormality was defined as at least one abnormal sensory quantitative testing from two thermal and two vibration threshold tests measured at foot every 1-2 years. Associations between baseline RVC and sensory nerve function were examined using generalized estimating equations and cumulative risk by Cox regression analyses. RESULTS: During a median study follow-up of 6.2 [IQR 3.7-10.4] years, sensory nerve abnormality was found in 27% of adolescents. Narrower extended zone calibre quartiles but not CRAE or CRVE quartiles were independently associated with sensory nerve abnormality: MWa (Q1 vs. Q2-4: OR 1.35 (95% CI 1.02, 1.61) and MWv (Q1 vs. Q2-4: 1.31 (1.03, 1.7)), after adjusting for HbA1c , duration and blood pressure. Similarly, in Cox regression, the narrowest quartiles were associated with sensory nerve abnormality: MWa hazard ratio (HR) 1.5 (1.3, 1.8) and MWv 1.6 (1.4, 1.9). CONCLUSIONS: Narrower extended zone retinal calibres were associated with sensory nerve abnormality in adolescents with type 1 diabetes and may present useful biomarkers to understand the pathophysiology of neuropathy.

Sight-threatening retinopathy in nine adolescents with early onset type 1 diabetes.

In adults, there has been a decline in the incidence of diabetic retinopathy (DR) associated with improvements in diabetes management. Data on incident severe DR in adolescents are sparse. In our established diabetes complications assessment service, we recorded nine cases of sight-threatening retinopathy in youth aged 15-17.9 years from 2017 to 2021. Proliferative retinopathy and clinically significant macular oedema were identified. The subjects were diagnosed with type 1 diabetes before the age of 10 years and had a history of poor glycaemic control (HbA1c 86-130 mmol/mol, 10%-15%). Five cases of retinopathy developed rapidly within 2.5 years of a previously normal retinal examination on seven-field stereoscopic retinal photography. Three adolescents required laser photocoagulation therapy. Two adolescents were diagnosed with retinopathy following improvement in diabetes control after being lost to medical follow-up and their retinopathy improved with improved glycaemic control. Thus, we support repeated retinal screening in adolescents with diabetes duration >10 years with suboptimal glycaemic control, even when initial retinal examination is normal, as retinopathy can progress rapidly during adolescence.

Dietary flavonoids are associated with longitudinal treatment outcomes in neovascular age-related macular degeneration.

PURPOSE: To assess whether dietary intake of flavonoids are associated with longitudinal treatment outcomes of patients with neovascular age-related macular degeneration (nAMD). METHODS: 547 participants with nAMD were recruited at baseline, 494 were followed-up after receiving 12 months of anti-vascular endothelial growth factor (anti-VEGF) therapy. Baseline dietary intake of flavonoids was determined using a validated food frequency questionnaire. At follow-up, presence of intra-retinal and sub-retinal fluid (IRF and SRF), retinal pigment epithelium detachment and measurements of central macular thickness (CMT) were recorded from optical coherence tomography scans. Visual acuity (VA) was documented using LogMAR charts. RESULTS: Participants in the first tertile of intake of the flavonol quercetin, and the flavan-3-ols epigallocatechin-3-gallate and epigallocatechin had significantly worse vision than participants in the third tertile-multivariable-adjusted least square (LS) mean VA: 14.68 vs. 19.53 (p = 0.04); 14.06 vs. 18.89 (p = 0.04); 13.86 vs. 18.86 (p = 0.03), respectively. Participants in the first compared to the third tertile of flavan-3-ol, epigallocatechin-3-gallate and epigallocatechin intake all had a twofold higher risk of IRF, multivariable-adjusted p trend of: 0.03, 0.01 and 0.02, respectively. The first vs. the third tertile of tea intake had significantly worse vision (LS mean VA: 13.49 vs. 19.04, p = 0.02), increased risk of IRF (OR 2.13, 95% CI 1.18-3.85) and greater mean CMT (279.59 µm vs. 256.52 µm, p = 0.04). CONCLUSIONS: Higher intakes of dietary flavonoids, specifically flavonols and flavan-3-ols, could be associated with better long-term treatment outcomes in nAMD patients receiving anti-VEGF therapy. Confirmation of these associations in interventional studies could result in promising new therapeutic approaches to the treatment of nAMD.

Perspectives of people with late age-related macular degeneration on mental health and mental wellbeing programmes: a qualitative study.

PURPOSE: People with age-related macular degeneration (AMD) experience high rates of depression, but rarely engage in or have access to tailored mental wellbeing programmes. This qualitative study investigated the perspectives of those primarily with late AMD on mental health and mental wellbeing programmes. METHODS: Twenty-eight people with late AMD in at least one eye, and one person with early AMD in both eyes, aged 56-87 years (mean age 78 years) attending a private eye clinic between December 2019 and January 2020 in Sydney, New South Wales, Australia, participated. Individual semi-structured interviews were conducted and analysed deductively using content analysis, following the individual level factors for health promotion interventions in the behaviour change wheel: Capability (Physical & Psychological), Opportunity (Physical & Social), and Motivation (Reflective & Automatic). RESULTS: Six major themes were identified: Capability: (1) Impact of vision loss on mobility and leisure pursuits; (2) Adjustment to living with vision loss; Opportunity: (3) Program considerations for those with AMD; (4) Stigma and self-perception of vision loss and mental health; Motivation: (5) Accumulation of vision-related issues as a barrier to participation; (6) Examples of others living with vision loss. General personal factors relevant to delivery of a programme in this age group were also identified: Comorbidities; Limitations using technology; Isolation; Financial concerns and Beliefs that undesired effects of aging are inevitable. CONCLUSIONS: Complex individual, environmental and social factors influence the perspectives of people with late AMD on mental health, and potential participation in mental wellbeing programmes. These factors should be considered when developing and implementing mental wellbeing programmes to improve the emotional and functional rehabilitation outcomes for people with AMD.

Genome-wide meta-analysis identifies novel loci associated with age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among the elderly population. To accelerate the understanding of the genetics of AMD, we conducted a meta-analysis of genome-wide association studies (GWAS) combining data from the International AMD Genomics Consortium AMD-2016 GWAS (16,144 advanced AMD cases and 17,832 controls), AMD-2013 GWAS (17,181 cases and 60,074 controls), and new data on 4017 AMD cases and 14,984 controls from Genetic Epidemiology Research on Aging study. We identified 12 novel AMD loci near or within C4BPA-CD55, ZNF385B, ZBTB38, NFKB1, LINC00461, ADAM19, CPN1, ACSL5, CSK, RLBP1, CLUL1, and LBP. We then replicated the associations of the novel loci in independent cohorts, UK Biobank (5860 cases and 126,726 controls) and FinnGen (1266 cases and 47,560 control). In general, the concordance in effect sizes was very high (correlation in effect size estimates 0.89), 11 of 12 novel loci were in the expected direction, 5 were associated with AMD at a nominal significance level, and rs3825991 (near gene RLBP1) after Bonferroni correction. We identified an additional 21 novel genes using a gene-based test. Most of the novel genes are expressed in retinal tissue and could be involved in the pathogenesis of AMD (i.e., complement, inflammation, and lipid pathways). These findings enhance our understanding of the genetic architecture of AMD and shed light on the biological process underlying AMD pathogenesis.

The role of reactive oxygen species in the pathogenesis and treatment of retinal diseases.

Reactive oxygen species (ROS) normally play an important physiological role in health regulating cellular processes and signal transduction. The amount of ROS is usually kept in fine balance with the generation of ROS largely being offset by the body's antioxidants. A tipping of this balance has increasingly been recognised as a contributor to human disease. The retina, as a result of its cellular anatomy and physical location, is a potent generator of ROS that has been linked to several major retinal diseases. This review will provide a summary of the role of oxidative stress in the pathogenesis of diabetic retinopathy, age-related macular degeneration, myopia, retinal vein occlusion, retinitis pigmentosa and retinopathy of prematurity. Therapies aimed at controlling oxidative stress in these diseases are also examined.

Association of dietary nitrate intake with retinal microvascular structure in older adults.

PURPOSE: Existing research suggests that changes to retinal vascular caliber reflect nitric oxide (NO)-dependent endothelial dysfunction. Dietary nitrate is an important source of NO; however, studies on the link between dietary nitrate intake and retinal microvasculature are lacking. We aimed to assess the cross-sectional association between intake of dietary nitrate (from vegetable and non-vegetable sources) and retinal arteriolar and venular caliber among older adults. METHODS: Participants from the Blue Mountains Eye Study aged 49+ years with complete data at baseline on diet and retinal vessel measures were analyzed (n = 2813). Dietary intake was assessed using a validated semi-quantitative food-frequency questionnaire. Nitrate intake from vegetable and non-vegetable sources was estimated using a validated comprehensive database and other published data where necessary. Fundus photographs were taken and retinal vascular caliber measured using validated computer-assisted techniques and summarized. RESULTS: Participants in the lowest versus highest tertile of vegetable nitrate intake had significantly narrower retinal arterioles: 186.2 ± 0.48 versus 187.6 ± 0.48 µm (multivariable-adjusted p = 0.04). After multivariable adjustment, each 10-unit higher intake of total nitrate and vegetable nitrate was associated with 0.089 ± 0.004 and 0.090 ± 0.004 µm wider retinal arteriolar caliber, respectively, both p = 0.03. Each 10-unit higher vegetable nitrate intake was associated with 0.092 ± 0.005 µm narrower retinal venules (p = 0.05). CONCLUSION: Intake of dietary nitrate, particularly from vegetable sources, was associated with beneficial variations in both retinal arteriolar and venular caliber among older adults. Further research into associations between dietary nitrate and the retinal microvasculature could allow for greater understanding and possible prevention of clinical cardiovascular events.

Associations between dietary flavonoids and retinal microvasculature in older adults.

PURPOSE: In this study, we assessed whether there are independent associations between dietary total flavonoid intake and major flavonoid classes with retinal arteriolar and venular calibre. METHODS: Blue Mountains Eye Study participants aged 49+ years who had complete data on diet and retinal vessel measures were analysed (n = 2821). Dietary intake was assessed using a semi-quantitative Food-Frequency Questionnaire (FFQ). Flavonoid content of foods in the FFQ was estimated using the US Department of Agriculture Flavonoid, Isoflavone and Proanthocyanidin databases. Fundus photographs were taken and retinal vascular calibre was measured using validated computer-assisted techniques. The associations of intake of dietary flavonoids with retinal vessel calibre were examined in linear regression models and general linear model. RESULTS: The highest quartile of intake was compared with the lowest quartile using multivariable-adjustment models. Participants with the highest proanthocyanidin intake had narrower retinal venules (223.9 ± 0.62 versus 226.5 ± 0.63, respectively; Ptrend = 0.01); and the highest isoflavone intake was associated with wider retinal arterioles (188.1 ± 0.55 versus 186.3 ± 0.56, respectively; Ptrend = 0.01). The highest apple/pear consumption (a dietary source of catechin) was associated with narrower retinal venules (223.8 ± 0.57 versus 226.1 ± 0.52; Ptrend = 0.01) and wider retinal arterioles (187.9 ± 0.51 versus 186.2 ± 0.51; Ptrend = 0.02). Further, participants who were in the highest versus lowest quartile of chocolate consumption had ~ 2.1 µm narrower retinal venules (multivariable-adjusted P = 0.03). CONCLUSIONS: This study shows that higher intakes of specific flavonoid subclasses are associated with a favourable retinal microvascular profile. Greater consumption of flavonoid-rich apples/pears and chocolate was also associated with beneficial variations in retinal vascular calibre.

Dietary zinc intake is associated with macular fluid in neovascular age-related macular degeneration.

IMPORTANCE: Numerous dietary factors have been shown to reduce progression from early to late age-related macular degeneration (AMD), however, little is known on their impact in patients diagnosed with late-stage disease. BACKGROUND: To determine whether a dietary intake high in antioxidants and zinc, fruits, vegetables and fish is associated with favourable clinical outcomes in patients with neovascular AMD (nAMD) undergoing anti-vascular endothelial growth factor therapy. DESIGN: Cross-sectional study carried out at a private ophthalmology clinic. PARTICIPANTS: Five hundred forty-seven participants with nAMD. METHODS: Diet was determined using a validated food frequency questionnaire. Presence of intra-retinal and sub-retinal fluid (IRF, SRF), pigment epithelial detachment and central macular thickness (CMT) were recorded from ocular coherence tomography images. MAIN OUTCOME MEASURES: Fluid presence, mean CMT and visual acuity. RESULTS: Participants with daily zinc intake below (n = 91) vs above (n = 333) 8.1 mg had greater odds of SRF being present, multivariable-adjusted odds ratio (OR) of 0.56 (95% CI 0.36-0.96). This association was stronger in persons with at least 6 months of treatment, OR of 0.32 (95% CI 0.14-0.75). In the entire cohort, participants in the lowest or first quartile compared to those in the upper three quartiles of zinc intake combined had significantly greater mean CMT (254.81 µm vs 232.15 µm, respectively, multivariable-adjusted P = .03). CONCLUSIONS AND RELEVANCE: Low dietary zinc intake was associated with a greater likelihood of SRF presence, particularly in those treated for at least 6 months, and increased macular thickness in treated eyes with nAMD.

Age-related macular degeneration.

Age-related macular degeneration is a leading cause of visual impairment and severe vision loss. Clinically, it is classified as early-stage (medium-sized drusen and retinal pigmentary changes) to late-stage (neovascular and atrophic). Age-related macular degeneration is a multifactorial disorder, with dysregulation in the complement, lipid, angiogenic, inflammatory, and extracellular matrix pathways implicated in its pathogenesis. More than 50 genetic susceptibility loci have been identified, of which the most important are in the CFH and ARMS2 genes. The major non-genetic risk factors are smoking and low dietary intake of antioxidants (zinc and carotenoids). Progression from early-stage to late-stage disease can be slowed with high-dose zinc and antioxidant vitamin supplements. Intravitreal anti-vascular endothelial growth factor therapy (eg, ranibizumab, aflibercept, or bevacizumab) is highly effective at treating neovascular age-related macular degeneration, and has markedly decreased the prevalence of visual impairment in populations worldwide. Currently, no proven therapies for atrophic disease are available, but several agents are being investigated in clinical trials. Future progress is likely to be from improved efforts in prevention and risk-factor modification, personalised medicine targeting specific pathways, newer anti-vascular endothelial growth factor agents or other agents, and regenerative therapies.

Retinal microvascular changes in microvascular angina: Findings from the Australian Heart Eye Study.

OBJECTIVE: Microvascular changes in microvascular angina are poorly understood due to difficulties in imaging the coronary microcirculation in vivo. The retinal microvasculature may reflect changes in coronary microcirculation. We assessed microvascular changes in the retina in patients with microvascular angina and compared them with patients with angiographically proven coronary artery disease. METHODS: We performed retinal photography and coronary angiography on 915 patients. Retinal vessel calibers were measured using a validated computer-assisted method; coronary artery disease was graded from coronary angiograms. Microvascular angina was defined as angina with <25% stenosis in all coronary epicardial arteries. RESULTS: A total of 139 patients (15.2%) had microvascular angina, while 776 (84.8%) had coronary artery disease. Participants with microvascular angina and coronary artery disease had similar retinal arteriolar and venular calibers. After adjustment for age, ethnicity, mean arterial pressure, diabetes, current smoking, body mass index, and fellow vessel caliber, women with smaller venules were threefold more likely to have microvascular angina than women with larger venules (multivariable-adjusted odds ratio 3.54, 95% confidence interval 1.35 to 9.24, P < 0.01). This difference was not observed in men. CONCLUSIONS: Microvascular angina in women was associated with microvascular changes distinct from those in coronary artery disease.

Carbohydrate nutrition variables and risk of disability in instrumental activities of daily living.

PURPOSE: We aimed to examine the prospective association between dietary glycemic index (GI) and glycemic load (GL) of foods consumed, intakes of carbohydrates and fiber, and the ability to perform activities of daily living (ADL) in older adults. METHODS: A total of 844 participants from the Blue Mountains Eye Study aged 60 years or older were examined from 2002-2004 to 2007-2009. Dietary information was collected using a validated, semi-quantitative food-frequency questionnaire. The Older Americans Resources and Services activities of daily living scale were administered to assess the functional status of participants. Multivariable logistic regression analysis was performed. RESULTS: After multivariable adjustment, participants who were in the second and third quartiles of energy-adjusted total fiber intake compared to those in the first quartile of intake (reference group) at baseline had reduced risk of incident impaired instrumental activities of daily living (IADL) 5 years later: OR, 0.39 (95% CI 0.22-0.70) and OR 0.54 (95% CI 0.30-0.95), respectively. Analyses that involved dichotomized total fiber intake showed that participants in the upper three quartiles of total fiber intake (> 19 g/day), compared to those in the lowest quartile of intake (≤ 19 g/day) or reference group, had reduced IADL disability risk 5 years later: OR 0.49 (95% CI 0.31-0.79). Non-significant associations were observed with total carbohydrates, GI, and GL and with risk of impaired total and basic ADL at 5-year follow-up. CONCLUSIONS: Habitual fiber consumption might be beneficial in leading to improved health status subserving performance of instrumental daily activities, needed to function in the community.

Retinal Vascular Geometry and the Prevalence of Atrial Fibrillation and Heart Failure in a Clinic-Based Sample.

BACKGROUND: We aimed to examine the cross-sectional association between a range of retinal vascular geometric variables and the prevalence of atrial fibrillation (AF) and heart failure. METHODS: The Australian Heart Eye Study (AHES) surveyed 1,680 participants presenting to a tertiary referral hospital for the evaluation of potential coronary artery disease by coronary angiography. Retinal vascular geometric variables (tortuosity, branching, and fractal dimension) were measured from retinal photographs using a computer-assisted program (Singapore I Vessel Assessment). Atrial fibrillation was determined based on a combination of: self-reported history of AF; self-reported use of rate-control and anti-arrhythmic medications; and/or screening electrocardiogram. Self-reported echocardiography-confirmed heart failure was also documented. RESULTS: A total of 1,169 participants had complete information on retinal vascular geometric variables and AF and of these 104 (8.9%) had AF. Participants in the second tertile of fractal dimension (Df) compared to those in the highest tertile (reference group), had 92% increased likelihood of having AF after multivariable adjustment. A threshold effect for Df was identified, and participants below versus those above a Df threshold value of 1.472, had greater odds of having AF: multivariable-adjusted OR 1.85 (95% CI 1.03-3.31). Measures of retinal tortuosity and branching were not associated with AF. Retinal vascular geometric variables were also not associated with prevalence of heart failure. CONCLUSIONS: A sparser retinal microvascular network (lower Df) was independently associated with greater likelihood of AF. Further studies are needed to investigate whether temporal changes to the retinal vascular geometry are predictive of AF in the longer term.

Early atherosclerosis is associated with retinal microvascular changes in adolescents with type 1 diabetes.

BACKGROUND/OBJECTIVE: Adolescents with type 1 diabetes have early macrovascular changes (increased intima-media thickness [IMT]) and early retinal changes that predict clinical disease in adulthood. We hypothesized that early changes in the macrovascular and retinal microvascular beds develop in parallel before retinopathy develops. We therefore aimed to investigate the relationship between changes in atherosclerosis (carotid and aortic IMT) and retinal vascular geometry cross-sectionally and longitudinally in adolescents with type 1 diabetes. METHODS: Ninety adolescents with type 1 diabetes (41 boys, aged 13.6 ± 3.5 years) who were enrolled in a randomized controlled trial had evaluations at baseline; 41 randomized to placebo were also investigated at 12 months for carotid and aortic IMT using ultrasound and retinal vascular geometry was measured from retinal photographs. RESULTS: There were significant associations between thicker mean/maximum carotid IMT and wider retinal arteriolar and venular calibers; for every 0.1 mm increase in mean carotid IMT, retinal arteriolar caliber increased by 7.90 µm (95% confidence interval [CI] 4.50, 11.30, P < 0.0001) and venular caliber by 9.61 µm (95% CI 4.16, 15.06, P = 0.0008). Increased mean aortic IMT was associated with increased arteriolar tortuosity (2.61, 95% CI 0.50, 4.71, P = 0.02). CONCLUSIONS: The early changes of atherosclerosis are associated with retinal microvascular changes in adolescents with type 1 diabetes. This supports parallel adverse changes in the macro and microvascular circulations from early adolescence in type 1 diabetes, and highlights the importance of early intervention.

The eye in CHD.

In recent years, there has been a rise in the number patients with CHD surviving into adulthood. Many have complications related to their CHD or its treatments, outside the heart, including ocular abnormalities. The objective of this review is to highlight the ocular abnormalities that occur in adults with CHD, either from their condition or related to the common drugs prescribed to manage it. In particular, we reviewed the effects of cyanosis, coarctation of the aorta, endocarditis, and the side effects of Sildenafil and Amiodarone. A change in the retinal vasculature is a common observation with cyanosis or coarctation of the aorta. Occlusion of the retinal vessels may also be observed in cyanotic patients, as well as those with infectious endocarditis. Sildenafil has established ocular side effects; here they are explored in the context of therapy for pulmonary hypertension. Similarly, Amiodarone has established ocular risks, which are summarised. The high prevalence of ocular consequences in adult CHD patients reinforces the need for knowledge of the risks involved and for frequent ophthalmological screening where appropriate.

Innovative technology shows impact of glycaemic control on peripheral retinal vessels in adolescents with type 1 diabetes.

AIMS/HYPOTHESIS: Retinal imaging enables non-invasive microvasculature assessment; however, only central retinal vessels have been studied in type 1 diabetes. Peripheral smaller vessels have a major haemodynamic role and may differ from central vessels in their response to the diabetic milieu. We hypothesise that diabetes has a greater impact on peripheral retinal vessels vs central vessels. METHODS: Retinal photographs from adolescents (n = 736; age 12-20 years) with type 1 diabetes were graded (Singapore I Vessel Assessment) with vessel calibres measured in the 'central zone' as central retinal arteriolar and venular equivalents (CRAE and CRVE, respectively) and the 'extended zone' as mean width of arterioles and venules (MWa and MWv, respectively). Multivariable linear regression was used to explore associations between vessel calibres and HbA1c, diabetes duration, sex and BP. RESULTS: Mean ± SD age was 14.1 ± 1.5 years, HbA1c was 8.5 ± 1.3% (69.4 ± 14.1 mmol/mol) and median diabetes duration was 4.9 years (interquartile range 3.1-7.6 years). Wider MWa was associated with HbA1c (ß 0.01 [95% CI 0.004, 0.03]), longer diabetes duration (0.07 [0.02, 0.13]) and higher systolic BP (0.04 [0.02, 0.05]). MWv was associated with HbA1c (0.02 [0.009, 0.03]) and higher systolic BP (0.04 [0.03, 0.06]). CRAE was associated with longer diabetes duration (0.93 [0.58, 1.28]) and higher systolic BP (-0.28 [-0.37, -0.19]). CRVE was associated with longer diabetes duration (0.91 [0.42, 1.41]) and higher systolic BP (-0.20 [-0.33, -0.07]). Girls had wider vessels (for all four calibre measurements). CONCLUSIONS/INTERPRETATION: In adolescents with type 1 diabetes, higher HbA1c is associated with adverse changes to peripheral smaller retinal vessels but not central vessels. The predictive value of retinal vascular imaging should be evaluated using longitudinal data.