A novel GFAP frameshift variant identified in a family with optico-retinal dysplasia and vision impairment.

Gain-of-function variants in GFAP leads to protein aggregation and is the cause of the severe neurodegenerative disorder Alexander Disease (AxD), while loss of GFAP function has been considered benign. Here, we investigated a six-generation family, where multiple individuals presented with gliosis of the optic nerve head and visual impairment. Whole genome sequencing (WGS) revealed a frameshift variant in GFAP (c.928dup, p.(Met310Asnfs*113)) segregating with disease. Analysis of human embryonic tissues revealed strong expression of GFAP in retinal neural progenitors. A zebrafish model verified that c.928dup does not result in extensive GFAP protein aggregation and zebrafish gfap loss-of-function mutants showed vision impairment and retinal dysplasia, characterized by a significant loss of Müller glia cells and photoreceptor cells. Our findings show how different mutational mechanisms can cause diverging phenotypes and reveal a novel function of GFAP in vertebrate eye development.

Semaglutide versus placebo in patients with heart failure and mildly reduced or preserved ejection fraction: a pooled analysis of the SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM randomised trials.

BACKGROUND: Heart failure with mildly reduced or preserved ejection fraction (hereafter referred to as HFpEF) is the most common type of heart failure and is associated with a high risk of hospitalisation and death, especially in patients with overweight, obesity, or type 2 diabetes. In the STEP-HFpEF and STEP-HFpEF DM trials, semaglutide improved heart failure-related symptoms and physical limitations in participants with HFpEF. Whether semaglutide also reduces clinical heart failure events in this group remains to be established. METHODS: We conducted a post-hoc pooled, participant-level analysis of four randomised, placebo-controlled trials (SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM) to examine the effects of once-weekly subcutaneous semaglutide (2·4 mg in SELECT, STEP-HFpEF, and STEP-HFpEF DM; 1·0 mg in FLOW) on heart failure events. The STEP-HFpEF and STEP-HFpF DM trials enrolled participants with obesity-related HFpEF, the SELECT trial enrolled participants with atherosclerotic cardiovascular disease and overweight or obesity, and the FLOW trial enrolled participants with type 2 diabetes and chronic kidney disease. Hence, for this analysis, we include all participants from the STEP-HFpEF trials and those with an investigator-reported history of HFpEF from SELECT and FLOW. The main outcomes for this analysis were the composite endpoint of time to cardiovascular death or first worsening heart failure event (defined as hospitalisation or urgent visit due to heart failure), time to first worsening heart failure event, and time to cardiovascular death. Efficacy and safety endpoints were analysed with the full analysis set (ie, all participants randomly assigned to treatment, according to the intention-to-treat principle). The SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM trials are registered at ClinicalTrials.gov, NCT03574597, NCT03819153, NCT04788511, and NCT04916470, respectively, and all are complete. FINDINGS: Across the four trials, 3743 (16·8%) of 22 282 participants had a history of HFpEF (1914 assigned to semaglutide and 1829 assigned to placebo). In this group of participants with HFpEF, semaglutide reduced the risk of the combined endpoint of cardiovascular death or heart failure events (103 [5·4%] of 1914 in the semaglutide group had events vs 138 [7·5%] of 1829 in the placebo group; hazard ratio [HR] 0·69 [95% CI 0·53-0·89]; p=0·0045). Semaglutide also reduced the risk of worsening heart failure events (54 [2·8%] vs 86 [4·7%]; HR 0·59 [0·41-0·82]; p=0·0019). No significant effect on cardiovascular death alone was seen (59 [3·1%] vs 67 [3·7%]; HR 0·82 [0·57-1·16]; p=0·25). A lower proportion of patients treated with semaglutide had serious adverse events than did those who were treated with placebo (572 [29·9%] vs 708 [38·7%]). INTERPRETATION: In patients with HFpEF, semaglutide reduced the risk of the combined endpoint of cardiovascular death or worsening heart failure events, and worsening heart failure events alone, whereas its effect on cardiovascular death alone was not significant. These data support the use of semaglutide as an efficacious therapy to reduce the risk of clinical heart failure events in patients with HFpEF, for whom few treatment options are currently available. FUNDING: Novo Nordisk.

Increased steroidogenesis promotes early-onset and severe vision loss in females with OPA1 dominant optic atrophy.

OPA1 mutations are responsible for autosomal dominant optic atrophy (ADOA), a progressive blinding disease characterized by retinal ganglion cell (RGC) degeneration and large phenotypic variations, the underlying mechanisms of which are poorly understood. OPA1 encodes a mitochondrial protein with essential biological functions, its main roles residing in the control of mitochondrial membrane dynamics as a pro-fusion protein and prevention of apoptosis. Considering recent findings showing the importance of the mitochondrial fusion process and the involvement of OPA1 in controlling steroidogenesis, we tested the hypothesis of deregulated steroid production in retina due to a disease-causing OPA1 mutation and its contribution to the visual phenotypic variations. Using the mouse model carrying the human recurrent OPA1 mutation, we disclosed that Opa1 haploinsufficiency leads to very high circulating levels of steroid precursor pregnenolone in females, causing an early-onset vision loss, abolished by ovariectomy. In addition, steroid production in retina is also increased which, in conjunction with high circulating levels, impairs estrogen receptor expression and mitochondrial respiratory complex IV activity, promoting RGC apoptosis in females. We further demonstrate the involvement of Muller glial cells as increased pregnenolone production in female cells is noxious and compromises their role in supporting RGC survival. In parallel, we analyzed ophthalmological data of a multicentre OPA1 patient cohort and found that women undergo more severe visual loss at adolescence and greater progressive thinning of the retinal nerve fibres than males. Thus, we disclosed a gender-dependent effect on ADOA severity, involving for the first time steroids and Müller glial cells, responsible for RGC degeneration.

Atrial Fibrillation and Semaglutide Effects in Obesity-Related Heart Failure With Preserved Ejection Fraction: STEP-HFpEF Program.

BACKGROUND: Obesity is a key factor in the development and progression of both heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF). In the STEP-HFpEF Program (comprising the STEP-HFpEF [Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity] and STEP-HFpEF DM [Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes] trials), once-weekly semaglutide 2.4 mg improved HF-related symptoms, physical limitations, and exercise function and reduced body weight in patients with obesity-related HFpEF. Whether the effects of semaglutide in this patient group differ in participants with and without AF (and across various AF types) has not been fully examined. OBJECTIVES: The goals of this study were: 1) to evaluate baseline characteristics and clinical features of patients with obesity-related HFpEF with and without a history of AF; and 2) to determine if the efficacy of semaglutide across all key trial outcomes are influenced by baseline history of AF (and AF types) in the STEP-HFpEF Program. METHODS: This was a secondary analysis of pooled data from the STEP-HFpEF and STEP-HFpEF DM trials. Patients with heart failure, left ventricular ejection fraction ≥45%, body mass index ≥30 kg/m2, and Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) <90 points were randomized 1:1 to receive once-weekly semaglutide 2.4 mg or matching placebo for 52 weeks. Dual primary endpoints (change in KCCQ-CSS and percent change in body weight), confirmatory secondary endpoints (change in 6-minute walk distance; hierarchical composite endpoint comprising all-cause death, HF events, thresholds of change in KCCQ-CSS, and 6-minute walk distance; and C-reactive protein [CRP]), and exploratory endpoint (change in N-terminal pro-B-type natriuretic peptide [NT-proBNP]) were examined according to investigator-reported history of AF (yes/no). Responder analyses examined the proportions of patients who experienced a ≥5-, ≥10, ≥15, and ≥20-point improvement in KCCQ-CSS per history of AF. RESULTS: Of the 1,145 participants, 518 (45%) had a history of AF (40% paroxysmal, 24% persistent AF, and 35% permanent AF) and 627 (55%) did not. Participants with (vs without) AF were older, more often male, had higher NT-proBNP levels, included a higher proportion of those with NYHA functional class III symptoms, and used more antithrombotic therapies, beta-blockers, and diuretics. Semaglutide led to larger improvements in KCCQ-CSS (11.5 points [95% CI: 8.3-14.8] vs 4.3 points [95% CI: 1.3-7.2]; P interaction = 0.001) and the hierarchal composite endpoint (win ratio of 2.25 [95% CI: 1.79-2.83] vs 1.30 [95% CI: 1.06-1.59]; P interaction < 0.001) in participants with AF vs without AF, respectively. The proportions of patients receiving semaglutide vs those receiving placebo experiencing ≥5-, ≥10-, ≥15-, and ≥20-point improvement in KCCQ-CSS were also higher in those with (vs without) AF (all P interaction values <0.05). Semaglutide consistently reduced CRP, NT-proBNP, and body weight regardless of AF status (all P interaction values not significant). There were fewer serious adverse events and serious cardiac disorders in participants treated with semaglutide vs placebo irrespective of AF history. CONCLUSIONS: In the STEP-HFpEF Program, AF was observed in nearly one-half of patients with obesity-related HFpEF and was associated with several features of more advanced HF. Treatment with semaglutide led to significant improvements in HF-related symptoms, physical limitations, and exercise function, as well as reductions in weight, CRP, and NT-proBNP in people with and without AF and across AF types. The magnitude of semaglutide-mediated improvements in HF-related symptoms and physical limitations was more pronounced in those with AF vs without AF at baseline. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF; NCT04788511]; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP-HFpEF DM; NCT04916470]).

Efficacy of Semaglutide by Sex in Obesity-Related Heart Failure With Preserved Ejection Fraction: STEP-HFpEF Trials.

BACKGROUND: More women than men have heart failure with preserved ejection fraction (HFpEF). OBJECTIVES: The purpose of this study was to assess baseline characteristics and treatment effect of semaglutide by sex across the STEP-HFpEF (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity) program. METHODS: In a prespecified secondary analysis of pooled data from STEP-HFpEF and STEP-HFpEF DM (Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes), patients with heart failure (HF), left ventricular ejection fraction ≥45%, body mass index ≥30 kg/m2, and Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) <90 points were randomized 1:1 to once-weekly semaglutide 2.4 mg or matched placebo for 52 weeks. Dual primary endpoints (KCCQ-CSS change and percentage change in body weight) and confirmatory secondary endpoints (6-minute walking distance [6MWD] change; hierarchical composite endpoint comprising all-cause death, HF events, changes in KCCQ-CSS, and 6MWD; and C-reactive protein) were compared between sexes. RESULTS: Of 1,145 patients, 570 (49.7%) were women. Women had higher body mass index, left ventricular ejection fraction, C-reactive protein, and worse HF symptoms, and were less likely to have atrial fibrillation or coronary artery disease vs men. Semaglutide improved KCCQ-CSS regardless of sex (mean difference in women +7.6 points [95% CI: 4.5-10.7 points]; men +7.5 points [95% CI: 4.3-10.6 points]; P interaction = 0.94) but reduced body weight more in women (mean difference in women -9.6% [95% CI: -10.9% to -8.4%]; men -7.2% [95% CI: -8.4% to -6.0%]; P interaction = 0.006). Semaglutide improved 6MWD (P interaction = 0.21) and the hierarchical composite endpoint (P interaction = 0.66) in both sexes. Fewer serious adverse events were reported with semaglutide vs placebo. CONCLUSIONS: In patients with obesity-related HFpEF, semaglutide 2.4 mg reduced body weight to a greater extent in women, and produced similar improvements in HF-related symptoms, physical limitations, and exercise function, regardless of sex. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF]; NCT04788511; and Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP HFpEF DM]; NCT04916470).

Inflammation in Obesity-Related HFpEF: The STEP-HFpEF Program.

BACKGROUND: Inflammation is thought to be an important mechanism for the development and progression of obesity-related heart failure with preserved ejection fraction (HFpEF). In the STEP-HFpEF Program, once-weekly 2.4 mg semaglutide improved heart failure-related symptoms, physical limitations, and exercise function, reduced the levels of C-reactive protein (CRP), a biomarker of inflammation, and reduced body weight in participants with obesity-related HFpEF. However, neither the prevalence nor the clinical characteristics of patients who have various magnitudes of inflammation in the context of obesity-related HFpEF have been well described. Furthermore, whether the beneficial effects of semaglutide on the various HF efficacy endpoints in the STEP-HFpEF Program are modified by the baseline levels of inflammation has not been fully established. Finally, the relationship between weight reduction and changes in CRP across the STEP-HFpEF Program have not been fully defined. OBJECTIVES: This study sought to: 1) evaluate baseline characteristics and clinical features of patients with obesity-related HFpEF that have various levels of inflammation in the STEP-HFpEF Program; 2) determine if the effects of weekly semaglutide 2.4 mg vs placebo across all key outcomes are influenced by baseline levels of inflammation assessed by CRP levels; and 3) determine the relationship between change in CRP and weight loss in the STEP-HFpEF Program. METHODS: This was a secondary analysis of pooled data from 2 international, double-blind, placebo-controlled, randomized trials (STEP-HFpEF and STEP-HFpEF DM). The outcomes were change in the dual primary endpoints (health status [measured by the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS)] and body weight) from baseline to 52 weeks according to baseline CRP levels. Additional efficacy endpoints included change in 6-minute walk distance (6MWD), a hierarchical composite endpoint that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6MWD, and levels of CRP in semaglutide- vs placebo-treated patients. Patients were stratified into 3 categories based on baseline CRP levels (<2, ≥2 to <10, and ≥10 mg/L). RESULTS: In total, 1,145 patients were randomized, of which 71% of patients had evidence of inflammation (CRP ≥2 mg/L). At baseline, those with higher levels of inflammation were younger, were more likely to be female, and had higher body mass index, worse health status (KCCQ-CSS), and shorter 6MWD. Semaglutide vs placebo led to reductions in HF-related symptoms and physical limitations as well as body weight, and to improvements in 6MWD and the hierarchical composite endpoint that were consistent across baseline CRP categories (all P interaction nonsignificant). Semaglutide also reduced CRP to a greater extent than placebo regardless of baseline CRP levels (P interaction = 0.32). Change in CRP from baseline to 52 weeks was similar regardless of the magnitude of weight loss (P interaction = 0.91). CONCLUSIONS: Inflammation is highly prevalent in obesity-related HFpEF. Semaglutide consistently improved HF-related symptoms, physical limitations, and exercise function, and reduced body weight across the categories of baseline CRP. Semaglutide also reduced inflammation, regardless of either baseline CRP or magnitude of weight loss during the trials. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF; NCT04788511]; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP HFpEF DM; NCT04916470]).

Imaging of the macula indicates early completion of structural deficit in autosomal-dominant optic atrophy.

PURPOSE: Optical coherence tomography (OCT) enables 3-dimensional imaging of the retina, including the layer of ganglion cells that supplies the optic nerve with its axons. We tested OCT as means of diagnosing and phenotyping autosomal-dominant optic atrophy (ADOA). DESIGN: Cross-sectional study. PARTICIPANTS: The study included 49 patients with OPA1 exon 28 (2826delT) ADOA (age, 8.6-71.5 years; best-corrected visual acuity [BCVA], 20/700-20/20) and 51 mutation-free first-degree relatives as healthy controls (BCVA 20/25-20/10). METHODS: Participants underwent routine examination, including automated perimetry, and OCT with segmentation of the perifoveal retinal ganglion cell-inner plexiform layer (GC-IPL) and the peripapillary retinal nerve fiber layer (RNFL). MAIN OUTCOME MEASURES: Perifoveal GC-IPL thickness. RESULTS: All subjects with ADOA had a thinner GC-IPL in the inferonasal macula than the thinnest healthy control. The GC-IPL thickness was also subnormal in the superotemporal macula (P<0.0001), where it varied with visual acuity (P ≤ 0.03). Attenuation of the peripapillary nerve fiber layer was prominent on the temporal side of the optic disc in ADOA (P <0.0001), but there was considerable overlap with healthy controls. In ADOA, there was no detectable variation with age in BCVA, autoperimetry mean deviation, GC-IPL thickness, or RNFL thickness, except that the thickness of the superior RNFL quadrant decreased with age. CONCLUSIONS: Optical coherence tomography enabled a highly sensitive diagnosis of ADOA and identification of a structural correlate with the variation in visual acuity. The defect associated with the OPA1 exon 28 (2826delT) seems to be fully developed from early childhood or the perinatal period.

The Importance and Control of Low-Grade Inflammation Due to Damage of Cellular Barrier Systems That May Lead to Systemic Inflammation.

Systemic low-grade inflammation can be initiated in vivo after traumatic injury or in chronic diseases such as neurodegenerative, metabolic, and autoimmune diseases. Inducers of inflammation trigger production of inflammatory mediators, which alter the functionality of tissues and organs and leads to harmful induction of different barrier systems in the body, where the blood-brain barrier, the blood-retinal barrier, blood-nerve barrier, blood-lymph barrier and the blood-cerebrospinal fluid barrier play major roles. The different barriers are unique but structured in a similar way. They are equipped with sophisticated junctional complexes where different connexins, protein subunits of gap junction channels and hemichannels, constitute important partners. The cells involved in the various barriers are coupled in networks, are excitable but do not express action potentials and may be targets for inflammation leading to changes in several biochemical cellular parameters. During any type of inflammation barrier break-down is observed where any form of injury can start with low-grade inflammation and may lead to systemic inflammation.

Thickness mapping of individual retinal layers and sectors by Spectralis SD-OCT in Autosomal Dominant Optic Atrophy.

PURPOSE: To assess layer- and location-specific retinal thickness deficits in autosomal dominant optic atrophy (ADOA) using Spectralis SD-OCT. METHODS: This cross-sectional study included 41 ADOA patients with OPA1 exon 28 (2826delT) mutation [age, 8.6-83.5 years; best-corrected visual acuity (BCVA), 8-89 Early Treatment Diabetic Retinopathy Study (ETDRS) letters] and 55 mutation-free first-degree relatives as healthy controls (age, 8.9-68.7; BCVA, 80-99). Participants underwent routine examination and optical coherence tomography (OCT) with segmentation of the whole retina, inner retinal layers (IRL) and outer retinal layers (ORL). Individual segmentation was performed of the perifoveal retinal nerve fibre layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), retinal pigment epithelium (RPE) and the peripapillary RNFL. Combinations of layers and sectors were tested for their diagnostic significance. Only right eye data are presented. Statistical analysis was adjusted for age, gender, spherical equivalent, axial length and family clustering in a mixed model analysis. RESULTS: The perifoveal RNFL, GCL, IPL and the peripapillary RNFL were all significantly thinner in ADOA patients than in healthy controls (p < 0.0001). No statistical difference was found for other layers. The most prominent and diagnostically most valuable deficit was found in the GCL (-49.9%) in the 'nasal inner macula' (NIM) sector (-63%). Attenuation of the peripapillary RNFL was most significant in the temporal sector (-58.4%). CONCLUSION: In ADOA, retinal ganglion cells are most prominently reduced in the nasal perifoveal area of the GCL, which together with the temporal peripapillary RNFL area serves as the strongest diagnostic OCT marker.

Genotype-phenotype heterogeneity of ganglion cell and inner plexiform layer deficit in autosomal-dominant optic atrophy.

PURPOSE: To describe the thickness of the combined ganglion cell and inner plexiform layers (GC-IPL) and the peripapillary retinal nerve fibre layer (RNFL) in patients with OPA1 c.983A>G or c.2708_2711delTTAG autosomal-dominant optic atrophy (ADOA). METHODS: The study included 20 individuals with c.983A>G and nine individuals with c.2708_2711delTTAG. Data for comparison were drawn from 49, previously published, individuals with OPA1 c.2826_2836delinsGGATGCTCCA and 51 individuals with no OPA1 mutation. Subjects underwent refraction, best-corrected visual acuity assessment, axial length measurement and high-definition optical coherence tomography. RESULTS: There was overlap in GC-IPL thickness in subjects younger than 20-30 years between the two new groups of ADOA patients and controls. Numerical decreases in GC-IPL thickness with age did not reach statistical significance in individuals with c.983A>G (p = 0.18) or in healthy controls (p = 0.22), but it did in individuals with c.2708_2711delTTAG (p = 0.02). Visual acuity decreased with decreasing GC-IPL thickness (p = 0.0006 in c.983A>G and p = 0.0084 in c.2708_2711delTTAG). Unlike c.2826_2836delinsGGATGCTCCA, individuals with c.983A>G or c.2708_2711delTTAG did not show a pattern of maximum GC-IPL deficit inferonasal of the fovea. CONCLUSION: Genotype-phenotype heterogeneity in OPA1 ADOA is evident when inner retinal atrophy is examined as a function of age. Thus, a pronounced decline with age in GC-IPL thickness is observed in c.2708_2711delTTAG ADOA, an intermediate decline with age is observed in c.983A>G ADOA, whereas little or no change with age is observed in c.2826_2836delinsGGATGCTCCA ADOA. This genotype-phenotype heterogeneity may explain why some patients have progressive visual loss while others have a relatively stable prognosis.

Dissociation of Pupillary Post-Illumination Responses from Visual Function in Confirmed OPA1 c.983A > G and c.2708_2711delTTAG Autosomal Dominant Optic Atrophy.

PURPOSE: To test whether the melanopsin-containing, intrinsically photosensitive retinal ganglion cells (ipRGCs), as evaluated by examination of the pupillary light reflex (PLR), are preserved in genetically confirmed autosomal dominant optic atrophy (ADOA). METHOD: Twenty-nine patients with either the c.983A > G (n = 14) or the c.2708_ 2711delTTAG mutation (n = 15) were examined with monochromatic pupillometry, using isoluminant (300 cd/m(2)), red (660 nm) or blue (470 nm) light, optical coherence tomography, automated visual field analysis, and with determination of best corrected visual acuity (BCVA). Since we examined two different mutations, initially we compared all outcome variables between the two, and finding no statistically significant difference, pooled them. RESULTS: Despite a poor BCVA (56 letters, ETDRS) in the ADOA patients, their post-illuminatory pupil responses did not differ significantly from those of healthy controls (blue, p = 0.45, red, p = 0.49, t-test), and no statistically significant effect was noted of peripapillary retinal nerve fiber layer thickness, ganglion cell-inner plexiform layer thickness, or age. CONCLUSION: The PLR to blue light of high luminance (300 cd/m(2)) was preserved in both c.983A > G and c.2708_2711delTTAG ADOA despite severe visual loss and optic nerve atrophy. The study confirms, in a large sample of two genetically homogenous groups, that the ipRGCs are spared in ADOA.

Macular sensitivity and fixation patterns in patients with autosomal dominant optic atrophy.

INTRODUCTION: The objective of this study was to test macular sensitivity, fixation stability and fixation location using microperimetry in patients with autosomal dominant optic atrophy (ADOA) and mutation-free relatives. MATERIAL AND METHODS: This was a cross-sectional study of 43 patients with exon 28 (2826 delT) mutation in OPA1 (age 11.7-71.5 years, best-corrected visual acuity (BCVA) 20/24-20/13). The patients and 49 mutation-free first-degree relatives (BCVA 20/25-20/10) underwent ophthalmic examination including macular microperimetry out to 12° eccentricity with registration of fixation stability and fixation location. RESULTS: The average (± standard deviation) sensitivity was significantly reduced in ADOA patients compared with controls, 14.9 (± 4.4) dB versus 19.7 (± 0.4) dB (p < 0.0001). In a retinotopic projection, the largest relative sensitivity deficits in ADOA were seen in the nasal macula (13.6 (± 5.7) dB versus 19.7 (± 0.7) dB) and in the central macula (14.2 (± 5.1) dB versus 19.9 (± 0.3) dB). The average sensitivity decreased with decreasing BCVA in ADOA (p < 0.0001). Stable fixation was found in 58% of ADOA patients versus 86% of controls, and relatively unstable fixation was observed in 35% of ADOA patients versus 14% of controls. Unstable fixation was found only in ADOA, where its prevalence was 7%. CONCLUSION: ADOA was associated with unstable fixation and subnormal microperimetric sensitivity, especially in the central and nasal macula where the ganglion cell deficit is most pronounced. FUNDING: The study was supported by Øjenfonden, Øjenforeningen, and Synoptikfonden. TRIAL REGISTRATION: NCT01522638.

Retinal vessel diameters decrease with macular ganglion cell layer thickness in autosomal dominant optic atrophy and in healthy subjects.

PURPOSE: To investigate retinal trunk vessel diameters in subjects with autosomal dominant optic atrophy (ADOA) and mutation-free healthy relatives. METHODS: This cross-sectional study included 52 ADOA patients with the optic atrophy 1 (OPA1) exon 28 (c.2826_2836delinsGGATGCTCCA) mutation (age 8.6-83.5 years) (best-corrected visual acuity (BCVA) 8-94 Early Treatment Diabetic Retinopathy Study (ETDRS) letters) and 55 mutation-free first-degree healthy relatives (age 8.9-68.7 years, BCVA 80-99). Analysis of fundus photographs provided integrated magnification-corrected measures of retinal vessel diameters (central retinal artery equivalent, CRAE, and central retinal vein equivalent, CRVE). Statistical analysis was corrected for age, gender, spherical equivalent refraction, axial length and mean arterial blood pressure (MABP) in a mixed model analysis. RESULTS: Retinal arteries and veins were thinner in ADOA than in healthy controls (CRAE (mean ± 2 standard deviations (SD)) 153.9 ± 41.0 µm and CRVE 236.1 ± 42.0 µm in ADOA, CRAE 172.5 ± 25.0 µm (p = 0.0004) and CRVE 254.2 ± 37.6 µm (p = 0.0019) in healthy controls). MABP was comparable in the two groups (p = 0.18), and in both groups, CRAE decreased with increasing MABP (p = 0.01 and p < 0.0001, respectively). In ADOA, CRAE and CRVE decreased with age (p = 0.011 and p = 0.020, respectively) and CRAE decreased with decreasing BCVA (p = 0.011). In patients with ADOA and in healthy controls, CRAE decreased with decreasing average macular ganglion cell-inner plexiform layer (GC-IPL) thickness (p = 0.0017 and p = 0.0057, respectively). CONCLUSION: Narrow retinal arteries and veins were associated not only with the severity of ADOA but with ganglion cell volume in patients with ADOA and in healthy subjects. This suggests that narrow vessels are a consequence rather than the cause of inner retinal hypoplasia or atrophy, although longitudinal studies are needed to confirm this hypothesis.