Increases in Medicare Spending and Use after Private Equity Acquisition of Retina Practices.

PURPOSE: Private equity (PE) firms increasingly are acquiring physician practices in the United States, particularly within procedural-based specialties such as ophthalmology including retina. To date, the potential impact of ophthalmology practice acquisitions remains unknown. We evaluated the association between PE acquisition and Medicare spending and use for common retina services. DESIGN: Retrospective difference-in-differences analysis using the 20% Medicare fee-for-service claims dataset from January 1, 2015, through December 31, 2019. PARTICIPANTS: Eighty-two practices acquired by PE during the study period and matched control practices. METHODS: We used novel data on PE acquisitions of retina practices linked to the 20% sample Medicare claims data. Retina practices acquired by PE between 2016 and 2019 were matched to up to 3 non-PE (control) practices based on characteristics before acquisition. Private equity-acquired practices were compared with matched control practices through 6 quarters after acquisition using a difference-in-differences event study design. Data analyses were performed between August 2022 and April 2023. MAIN OUTCOME MEASURES: Medicare spending and use of common retina services. RESULTS: Relative to control practices, PE-acquired retina practices increased the use of higher-priced anti-vascular endothelial growth factor (VEGF) agents including aflibercept, which differentially increased by 6.5 injections (95% confidence interval, 0.4-12.5; P = 0.03) per practice-quarter, or 22% from baseline. As a result, Medicare spending on aflibercept differentially increased by $13 028 per practice-quarter, or 21%. No statistically significant differences were found in use or spending for evaluation and management visits or diagnostic imaging. CONCLUSIONS: Private equity acquisition of retina practices are associated with modest increases in the use of higher-priced anti-VEGF drugs like aflibercept, leading to higher Medicare spending. This finding highlights the need to monitor the influence of PE firms' financial incentives over clinician decision-making and the appropriateness of care, which could be swayed by strong economic incentives. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Private equity in ophthalmology: taking the long view.

PURPOSE OF REVIEW: Private equity's momentum in eye care remains controversial, even as investment continues to hasten the consolidation of ophthalmology and optometry practices. In this review, we discuss the growing implications of private equity activity in ophthalmology, drawing on updated empirical findings from the literature. We also examine recent legal and policy efforts to address private equity investment in healthcare, with implications for ophthalmologists considering sales to private equity. RECENT FINDINGS: Concerns about private equity centres around evidence that some investment entities are not just valuable sources of capital or business expertise, but that they take outright ownership and control of acquired practices in order to drive high returns on investment. Although practices may receive considerable benefits from private equity investment, empirical evidence suggests that private equity's most consistent effect on acquired practices is to increase spending and utilization without commensurate benefits on patient health. Although data on workforce effects are limited, an early study on workforce composition changes in private equity-acquired practices demonstrates that physicians were more likely to enter and exit a given practice than their counterparts in nonacquired practices, suggesting some degree of workforce flux. State and federal oversight of private equity's impact on healthcare may be ramping up in response to these demonstrated changes. SUMMARY: Private equity will continue to broaden their footprint in eye care, necessitating ophthalmologists to take the long view of private equity's net effects. For practices considering a private equity sale, recent policy developments highlight the importance of identifying and vetting a well aligned investment partner, with safeguards to preserve clinical decision-making and physician autonomy.

BILATERAL ENTEROCOCCUS FAECALIS ENDOPHTHALMITIS WITH MULTIPLE RECURRENCES.

PURPOSE: To describe the first case report of a bilateral recurrent Enterococcus faecalis endophthalmitis postcataract surgery. METHODS: Case report with a description of the timeline, diagnosis, and management of a patient with bilateral recurrent E. faecalis endophthalmitis. RESULTS: An 89-year-old man presented 6 weeks' postcataract surgery with pain, tearing, and blurred vision in the left eye. B-scan ultrasonography revealed vitritis and cultures postvitrectomy grew E. faecalis. There was gradual improvement in vision postintravitreal vancomycin administration. Four years later, the patient experienced another episode of E. faecalis endophthalmitis in the right eye postcataract extraction, followed by several additional episodes in both eyes posttreatment. CONCLUSION: Enterococcus faecalis is a rare but highly virulent cause of endophthalmitis that may remain sequestered in the capsular bag, despite aggressive treatment. Even after recurrent episodes, early vitrectomy and aggressive antibiotic therapy may prove to be effective in preventing vision loss.

REVERSIBLE RETINAL TOXICITY IN A PATIENT TAKING AXITINIB.

PURPOSE: Axitinib (Inlyta, New York, NY) is a kinase inhibitor indicated for the treatment of advanced renal cell carcinoma after failure of one previous systemic therapy. A case of bilateral retinal hemorrhages and cotton wool spots associated with axitinib is reported. METHODS: A 62-year-old woman with a 4-year history of renal cell carcinoma with metastases was treated with axitinib at a maximum oral daily dose of 8 mg. Soon after beginning higher dose therapy, she developed blurred vision, floaters, and photopsias. RESULTS: Funduscopic examination of both eyes revealed cotton wool spots and retinal hemorrhages that improved with cessation of therapy. CONCLUSION: Axitinib may be associated with microangiopathic retinal toxicity.

Prognostic Utility of Whole-Genome Sequencing and Polymerase Chain Reaction Tests of Ocular Fluids in Postprocedural Endophthalmitis.

PURPOSE: To associate detection of potential pathogen DNA in endophthalmitis with clinical outcomes. DESIGN: Prospective cohort study. METHODS: Patients in whom endophthalmitis was diagnosed following an intraocular procedure were recruited. Clinical outcome data from baseline, week-1, month-1, and month-3 visits were collected. Intraocular biopsy samples were cultured by standard methods. Quantitative polymerase chain reaction (qPCR) was performed for specific pathogens and whole-genome sequencing (WGS). RESULTS: A total of 50 patients (mean age 72 years old; 52% male) were enrolled. Twenty-four cases were culture-positive and 26 were culture-negative. WGS identified the cultured organism in 76% of culture-positive cases and identified potential pathogens in 33% of culture-negative cases. Month-1 and -3 visual acuities did not vary by pathogen-positive versus pathogen-negative cases as detected by either culture or WGS. Visual outcomes of Staphylococcus epidermidis endophthalmitis were no different than those of pathogen-negative cases, whereas the patients infected with other pathogens showed worse outcome. Higher baseline bacterial DNA loads of bacteria other than those of S epidermidis detected by WGS were associated with worse month-1 and -3 visual acuity, whereas the S epidermidis loads did not appear to influence outcomes. Torque teno virus (TTV) and Merkel cell polyomavirus (MCV) were detected by qPCR in 49% and 19% of cases, respectively. Presence of TTV at presentation was associated with a higher rate of secondary pars plana vitrectomy (P = .009) and retinal detachment (P = .022). CONCLUSIONS: The presence and higher load of bacteria other than S epidermidis detected by WGS or DNA from TTV by qPCR in ocular fluids is associated with worse outcomes in post-procedure endophthalmitis.

PPV, Retinectomy, and Silicone Oil Without Scleral Buckle for Recurrent RRD From Proliferative Vitreoretinopathy.

BACKGROUND AND OBJECTIVE: To analyze the anatomic success rate of pars plana vitrectomy (PPV), retinectomy, and silicone oil (SO) tamponade without scleral buckle (SB) for repair of recurrent rhegmatogenous retinal detachment (RRD) associated with proliferative vitreoretinopathy (PVR). PATIENTS AND METHODS: Retrospective, consecutive, single-surgeon case series of 28 eyes of 28 patients with PVR-associated RRD repaired with PPV, retinectomy, and SO tamponade without SB. RESULTS: The single-procedure anatomic success rate was 85.2% at 3 months and 82.1% at 12 months. Final reattachment rate was 100.0%. There were no preoperative factors that predicted single procedure anatomic success. Mean logarithm of the minimal angle of resolution visual acuity (VA) was improved at 3 months (1.61 to 1.51, P = .732) and at 12 months (1.61 to 1.41; P = .271). VA outcome was related to preoperative macula and lens status. CONCLUSION: The single-procedure anatomic success rate of PPV, retinectomy, and SO tamponade without SB for PVR-related recurrent RRD is comparable to prior reports of similar surgery incorporating SB. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e278-e287.].

Intravitreal Anti-Vascular Endothelial Growth Factor Injections for Macular Edema Associated With Central Retinal Vein Occlusion in Patients Age 40 Years or Younger.

BACKGROUND AND OBJECTIVE: To determine the efficacy of anti-vascular endothelial growth factor (VEGF) therapy for macular edema due to central retinal vein occlusion (CRVO) in younger adults. PATIENTS AND METHODS: The outcomes of CRVO patients age 40 years or younger with baseline logarithm of the minimum angle of resolution (logMAR) visual acuity (VA) between 1.30 (20/400 Snellen equivalent) and 0.30 (20/40 Snellen equivalent) and central retinal thickness (CRT) greater than 250 µm were reviewed. VA and CRT were measured at baseline and months 1, 3, 6, and 12. RESULTS: Seventeen eyes of 17 young CRVO patients were included in this study. The logMAR VA improved significantly from 0.64 (20/87 Snellen equivalent) to 0.14 (20/28 Snellen equivalent) 12 months following treatments (P < .001). The CRT decreased from 619 µm ± 238 µm at baseline to 290 µm ± 34 µm at 12 months (P < .001). CONCLUSION: Anti-VEGF injections appear to be effective for macular edema regression and vision improvement in younger adults with CRVO over 12 months of follow-up. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e96-e104.].

Loss to Follow-up After Intravitreal Anti-Vascular Endothelial Growth Factor Injections in Patients with Diabetic Macular Edema.

PURPOSE: To determine the rate of loss to follow-up (LTFU) and associated risk factors in patients with nonproliferative diabetic retinopathy (NPDR) who had diabetic macular edema (DME) and were receiving intravitreal anti-vascular endothelial growth factor (VEGF) injections. DESIGN: Retrospective cohort study. PARTICIPANTS: A total of 2595 NPDR patients with DME who received at least one anti-VEGF injection at a single large retina practice from January 1, 2012, to January 1, 2017. METHODS: A retrospective review based on billing codes was performed. LTFU was defined as no subsequent office visits within 12 months after an intravitreal injection. Patient demographics and clinical features were evaluated, and logistic regression was used to identify independent predictors for LTFU. MAIN OUTCOME MEASURES: LTFU rates and potential risk factors. RESULTS: LTFU was found in 413 (25.3%) of 1632 patients. Examining LTFU by racial groups, 21.3% identified themselves as white, 29.1% as black, 30.6% as Asian, and 35.0% as Hispanic (P < 0.001). A difference in LTFU was also found based on average adjusted gross income (AGI) (P < 0.001) and NPDR stage (P = 0.04). In the multivariate model, factors associated with LTFU included Hispanic (odds ratio [OR] 1.66), American Indian, Pacific Islander, multiple races (OR 2.60), and unknown race (OR 1.59) compared with those who were white. Additional factors included those with an average AGI of $50000 to $75000 (OR 1.37) and <$50000 (OR 1.88) compared with those with an average AGI > $75000. Based on subgroup analysis of patients with available visual acuity data, a significant association was found between decreasing baseline vision and LTFU (P < 0.001). CONCLUSIONS: Approximately 1 in 4 patients with NPDR who had DME had no follow-up visit for at least 1 year after an anti-VEGF injection. Given the importance of ongoing therapy, these real-world findings may help identify at-risk groups for noncompliance with care.

Comparison of a Three-Dimensional Heads-Up Display Surgical Platform with a Standard Operating Microscope for Macular Surgery.

PURPOSE: To assess safety, efficacy, and outcomes of vitreoretinal surgery for macular pathology using a 3-dimensional heads-up display (3D HUD) surgical platform compared with a standard operating microscope (SOM). DESIGN: Prospective, single-center, unmasked, randomized study. PARTICIPANTS: Patients undergoing pars plana vitrectomy (PPV) for epiretinal membrane (ERM) or full-thickness macular hole (MH) at Wills Eye Hospital. METHODS: Patients were randomized 1:1 to undergo surgery with a 3D HUD surgical platform or SOM. Patients who had previous PPV were excluded. Surgical choices, including PPV gauge, were based on surgeon preference. Standard surgical safety parameters, Early Treatment Diabetic Retinopathy Study visual acuity (VA), minimum required endoillumination levels, operative times, and surgeon "ease of use" of the viewing platform were recorded. Patients were followed up to postoperative month 3 (POM3). MAIN OUTCOME MEASURES: The main outcome measures were total operative time, macular peel time, surgeon rating of viewing system ease of use, minimum required endoillumination, intraoperative complication rate, and postoperative VA. RESULTS: Thirty-nine eyes of 39 patients with a mean age of 67.60±8.21 SD years were enrolled. Indications included ERM (n = 26 [3D HUD = 14, SOM = 12]) and MH (n = 13 [3D HUD = 9, SOM = 4]). Minimum required endoillumination was significantly lower with 3D HUD (mean 22.70%±15.10% SD) compared with SOM (mean 39.06%±2.72%; P < 0.001). There was no significant difference in overall operative time, but macular peel time was significantly longer using 3D HUD (mean 14.76±4.79 minutes) than SOM (11.87±8.07 minutes; P = 0.004). Surgeon-reported ease of use was significantly higher (easier) using SOM compared with 3D HUD (P = 0.004). There was no statistically significant difference between the groups in POM3 logarithm of the minimum angle of resolution (logMAR) VA or change in logMAR VA from baseline (all P > 0.681). There were no clinically significant intraoperative complications in either group. CONCLUSIONS: Three-dimensional heads-up display surgical visualization is an evolving technology demonstrating comparable efficacy to the SOM for macular surgery. Although overall surgical times were similar, 3D HUD macular peel times were longer and associated with less ease of use in this study, which may partly be due to a learning curve with new technology.

Loss to Follow-up Among Patients With Neovascular Age-Related Macular Degeneration Who Received Intravitreal Anti-Vascular Endothelial Growth Factor Injections.

Importance: Loss to follow-up (LTFU) after anti-vascular endothelial growth factor (anti-VEGF) injections increases the risk of vision loss among patients with neovascular age-related macular degeneration (nAMD). Objective: To report rates of LTFU among patients with nAMD after anti-VEGF injections and to identify risk factors associated with LTFU in this population. Design, Setting, and Participants: This retrospective cohort study of data from 9007 patients who received anti-VEGF injections for treatment of nAMD was performed at an urban, private retina practice with multiple locations from April 1, 2012, to January 12, 2016. Main Outcomes and Measures: Rates of LTFU after anti-VEGF injections. Loss to follow-up was defined as receipt of 1 or more injections with no subsequent follow-up visit within 12 months. Results: Among the 9007 patients (mean [SD] age, 81.2 [8.8] years; 5917 [65.7%] female; 7905 [87.8%] white), 2003 (22.2%) were LTFU. Odds of LTFU were greater among patients 81 to 85 years of age (odds ratio [OR], 1.58; 95% CI, 1.38-1.82; P < .001), 86 to 90 years of age (OR, 2.29; 95% CI, 2.00-2.62; P < .001), and more than 90 years of age (OR, 3.31; 95% CI, 2.83-3.86; P < .001) compared with patients 80 years of age and younger. Odds of LTFU among African American patients (OR, 1.47; 95% CI, 1.00-2.16; P = .05), Asian patients (OR, 2.63; 95% CI, 1.71-4.03; P < .001), patients of other race (OR, 3.07; 95% CI, 1.38-6.82; P = .006), and patients of unreported race (OR, 2.29; 95% CI, 1.96-2.68; P < .001) were greater than odds of LTFU among white patients. Odds of LTFU were greater among patients with regional adjusted gross income of $50 000 or less (OR, 1.52; 95% CI, 1.30-1.79; P < .001), $51 000 to $75 000 (OR, 1.35; 95% CI, 1.17-1.56; P < .001), and $76 000 to $100 000 (OR, 1.28; 95% CI, 1.08-1.50; P = .004) compared with patients with incomes greater than $100 000. Odds of LTFU for patients living 21 to 30 miles (OR, 1.33; 95% CI, 1.05-1.69; P = .02) and more than 30 miles (OR, 1.55; 95% CI, 1.28-1.88; P < .001) from clinic were greater compared with patients who lived 10 miles or less from the clinic. Odds of LTFU were greater among patients who received unilateral injections (OR, 1.44; 95% CI, 1.28-1.61; P < .001) than among patients who received bilateral injections. Conclusions and Relevance: We found a high rate of LTFU after anti-VEGF injections among patients with nAMD and identified multiple risk factors associated with LTFU among this population. Although our results may not be generalizable, data on LTFU in a clinical practice setting are needed to understand the scope of the problem so that interventions may be designed to improve outcomes.

Cryptococcal choroiditis in advanced AIDS with clinicopathologic correlation.

PURPOSE: To describe a case of disseminated cryptococcal meningitis with multifocal choroiditis and provide optical coherence tomography (OCT) findings correlated with described histopathology in a patient with advanced acquired immunodeficiency syndrome (AIDS). OBSERVATIONS: The patient was a 54-year-old man with AIDS who presented with dyspnea and headache followed by acute vision loss. OCT demonstrated a lesion with a small area of fluid that was limited by a more prominent and irregular external limiting membrane with underlying nodular choroidal thickening, mild RPE disorganization, and hyperreflectivity of the overlying photoreceptor layer. Patient was found to have disseminated cryptococcal infection and passed away despite aggressive therapy. Autopsy was performed including bilateral enucleation and a Cryptococcus lesion was confirmed on histopathology. CONCLUSION AND IMPORTANCE: This case highlights the clinical, imaging, and histopathologic findings of cryptococcal choroiditis and provides a review of the updated treatment recommendations for disseminated infection in a patient with advanced AIDS. Although currently fundoscopy has proven most useful in directing the diagnostic algorithm in choroiditis in the setting of advanced immunosuppression, OCT may provide insight into the spread of Cryptococcus within the eye.

Loss to Follow-Up in Patients with Proliferative Diabetic Retinopathy after Panretinal Photocoagulation or Intravitreal Anti-VEGF Injections.

PURPOSE: Loss to follow-up (LTFU) may contribute to vision loss in patients with active proliferative diabetic retinopathy (PDR). The aim of this study is to determine and compare the rates of LTFU in patients with PDR receiving panretinal photocoagulation (PRP) or intravitreal injections (IVIs) with anti-vascular endothelial growth factor (VEGF) over approximately 4 years. Moreover, this study evaluates various risk factors for LTFU. DESIGN: Retrospective cohort study. PARTICIPANTS: A total of 2302 patients with PDR receiving IVIs with anti-VEGF or PRP between January 1, 2012, and April 20, 2016. METHODS: Intervals between each procedure and the subsequent follow-up visit were measured. Loss to follow-up was defined as at least 1 interval exceeding 12 months duration. MAIN OUTCOME MEASURES: The LTFU rates and associated risk factors. RESULTS: A total of 1718 patients (74.6%) followed up postprocedure and 584 patients (25.4%) were LTFU over approximately 4 years. Of the patients receiving PRP, 28.0% were LTFU compared with 22.1% of patients receiving IVI with anti-VEGF (P = 0.001). The LTFU rates decreased as age increased, with rates of 28.1% for patients aged ≤55 years, 27.0% for patients aged 56 to 65 years, and 20.9% for patients aged >65 years (P = 0.002). Loss to follow-up also differed by race, with rates of 19.4% for whites, 30.2% for African Americans, 19.7% for Asians, 38.0% for Hispanics, Native Americans, and Pacific Islanders, and 34.9% for patients of unreported race (P < 0.001). The LTFU rates also increased as regional average adjusted gross incomes (AGIs) decreased, with rates of 33.9% for patients with regional average AGI of ≤$40 000, 24.0% for patients with regional average AGI from $41 000 to $80 000, and 19.7% for patients with regional average AGI >$80 000 (P < 0.001). Procedure type, age, race, and regional average AGI were all significant (P < 0.05) independent risk factors of LTFU in the multivariate regression. CONCLUSIONS: A large proportion of patients with PDR were LTFU after receiving PRP or an anti-VEGF injection over approximately 4 years. Key risk factors included age, race, and regional average AGI.

Optical Coherence Tomography Angiography of Punctate Inner Choroidopathy.

PURPOSE: To report a case of bilateral choroidal neovascularization (CNV) in punctate inner choroidopathy (PIC) visualized utilizing optical coherence tomography angiography (OCT-A). METHODS: Case report. RESULTS: A 29-year-old woman presented with new visual symptoms in both eyes. Fundoscopic exam revealed bilateral multifocal, small, well-defined lesions consistent with PIC. Optical coherence tomography demonstrated subretinal fluid and retinal pigment epithelium detachments (RPEDs) in both eyes. OCT-A revealed bilateral abnormal increased flow within the RPEDs consistent with CNV. Fluorescein angiography confirmed the presence of bilateral CNV. CONCLUSION: CNV secondary to PIC may be identified using noninvasive optical coherence tomography angiography.

Outcome of Micropulse Laser Transscleral Cyclophotocoagulation on Pediatric Versus Adult Glaucoma Patients.

PURPOSE: To study and compare the outcome of micropulse transscelral cyclophotocoagulation in pediatric glaucoma patients to that in adult glaucoma patients. METHODS: Consecutive pediatric and adult patients who received micropulse transscelral cyclophotocoagulation between July 2015 and December 2016 at University of California, San Francisco were retrospectively analyzed. All cases had at least 12 months of follow-up. RESULTS: Nine eyes from 9 pediatric patients and 27 eyes from 25 adult patients were included. The sample size in pediatric group is small because MP-TCP was not offered to pediatric patients after unsatisfactory results in initial cases. Preoperatively, the mean intraocular pressure (IOP) was 28.41±8.32 mm Hg in adult patients and 34.28±9.92 mm Hg in pediatric patients. Postoperatively, the mean IOP in adult patients significantly decreased at all follow-up points (P<0.001). In pediatric patients, the mean IOP decreased to 20.44±13.41 mm Hg at 1 month (P=0.021), 23.56±10.10 mm Hg at 3 months (P=0.093), 23.00±8.31 mm Hg (P=0.018) at 6 months, and 27.20±15.68 mm Hg (P=0.15) at 12 months. No significant complications were noted in either group. The success rate in adults was 72.22% versus 22.22% in pediatric patients at 12 months (P=0.02). Seven of 9 pediatric patients required reoperation during the 12 months of follow-up. CONCLUSIONS: Micropulse transscelral cyclophotocoagulation is a safe procedure for pediatric as well as adult glaucoma patients. Its effect seems to be short lived in pediatric patients and the rate of reoperation was high.

DNA sequence variants in PPARGC1A, a gene encoding a coactivator of the ω-3 LCPUFA sensing PPAR-RXR transcription complex, are associated with NV AMD and AMD-associated loci in genes of complement and VEGF signaling pathways.

BACKGROUND: Increased intake of ω-3 long-chain polyunsaturated fatty acids (LCPUFAs) and use of peroxisome proliferator activator receptor (PPAR)-activating drugs are associated with attenuation of pathologic retinal angiogenesis. ω-3 LCPUFAs are endogenous agonists of PPARs. We postulated that DNA sequence variation in PPAR gamma (PPARG) co-activator 1 alpha (PPARGC1A), a gene encoding a co-activator of the LCPUFA-sensing PPARG-retinoid X receptor (RXR) transcription complex, may influence neovascularization (NV) in age-related macular degeneration (AMD). METHODS: We applied exact testing methods to examine distributions of DNA sequence variants in PPARGC1A for association with NV AMD and interaction of AMD-associated loci in genes of complement, lipid metabolism, and VEGF signaling systems. Our sample contained 1858 people from 3 elderly cohorts of western European ancestry. We concurrently investigated retinal gene expression profiles in 17-day-old neonatal mice on a 2% LCPUFA feeding paradigm to identify LCPUFA-regulated genes both associated with pathologic retinal angiogenesis and known to interact with PPARs or PPARGC1A. RESULTS: A DNA coding variant (rs3736265) and a 3'UTR-resident regulatory variant (rs3774923) in PPARGC1A were independently associated with NV AMD (exact P = 0.003, both SNPs). SNP-SNP interactions existed for NV AMD (P<0.005) with rs3736265 and a AMD-associated variant in complement factor B (CFB, rs512559). PPARGC1A influences activation of the AMD-associated complement component 3 (C3) promoter fragment and CFB influences activation and proteolysis of C3. We observed interaction (P ≤ 0.003) of rs3736265 with a variant in vascular endothelial growth factor A (VEGFA, rs3025033), a key molecule in retinal angiogenesis. Another PPARGC1A coding variant (rs8192678) showed statistical interaction with a SNP in the VEGFA receptor fms-related tyrosine kinase 1 (FLT1, rs10507386; P ≤ 0.003). C3 expression was down-regulated 2-fold in retinas of ω-3 LCPUFA-fed mice - these animals also showed 70% reduction in retinal NV (P ≤ 0.001). CONCLUSION: Ligands and co-activators of the ω-3 LCPUFA sensing PPAR-RXR axis may influence retinal angiogenesis in NV AMD via the complement and VEGF signaling systems. We have linked the co-activator of a lipid-sensing transcription factor (PPARG co-activator 1 alpha, PPARGC1A) to age-related macular degeneration (AMD) and AMD-associated genes.

Retinal expression of Wnt-pathway mediated genes in low-density lipoprotein receptor-related protein 5 (Lrp5) knockout mice.

Mutations in low-density lipoprotein receptor-related protein 5 (Lrp5) impair retinal angiogenesis in patients with familial exudative vitreoretinopathy (FEVR), a rare type of blinding vascular eye disease. The defective retinal vasculature phenotype in human FEVR patients is recapitulated in Lrp5 knockout (Lrp5(-/-)) mouse with delayed and incomplete development of retinal vessels. In this study we examined gene expression changes in the developing Lrp5(-/-) mouse retina to gain insight into the molecular mechanisms that underlie the pathology of FEVR in humans. Gene expression levels were assessed with an Illumina microarray on total RNA from Lrp5(-/-) and WT retinas isolated on postnatal day (P) 8. Regulated genes were confirmed using RT-qPCR analysis. Consistent with a role in vascular development, we identified expression changes in genes involved in cell-cell adhesion, blood vessel morphogenesis and membrane transport in Lrp5(-/-) retina compared to WT retina. In particular, tight junction protein claudin5 and amino acid transporter slc38a5 are both highly down-regulated in Lrp5(-/-) retina. Similarly, several Wnt ligands including Wnt7b show decreased expression levels. Plasmalemma vesicle associated protein (plvap), an endothelial permeability marker, in contrast, is up-regulated consistent with increased permeability in Lrp5(-/-) retinas. Together these data suggest that Lrp5 regulates multiple groups of genes that influence retinal angiogenesis and may contribute to the pathogenesis of FEVR.

Wnt signaling mediates pathological vascular growth in proliferative retinopathy.

BACKGROUND: Ischemic proliferative retinopathy, characterized by pathological retinal neovascularization, is a major cause of blindness in working-age adults and children. Defining the molecular pathways distinguishing pathological neovascularization from normal vessels is critical to controlling these blinding diseases with targeted therapy. Because mutations in Wnt signaling cause defective retinal vasculature in humans with some characteristics of the pathological vessels in retinopathy, we investigated the potential role of Wnt signaling in pathological retinal vascular growth in proliferative retinopathy. METHODS AND RESULTS: In this study, we show that Wnt receptors (Frizzled4 and low-density lipoprotein receptor-related protein5 [Lrp5]) and activity are significantly increased in pathological neovascularization in a mouse model of oxygen-induced proliferative retinopathy. Loss of Wnt coreceptor Lrp5 and downstream signaling molecule dishevelled2 significantly decreases the formation of pathological retinal neovascularization in retinopathy. Loss of Lrp5 also affects retinal angiogenesis during development and formation of the blood-retinal barrier, which is linked to significant downregulation of tight junction protein claudin5 in Lrp5(-/-) vessels. Blocking claudin5 significantly suppresses Wnt pathway-driven endothelial cell sprouting in vitro and developmental and pathological vascular growth in retinopathy in vivo. CONCLUSIONS: These results demonstrate an important role of Wnt signaling in pathological vascular development in retinopathy and show a novel function of Cln5 in promoting angiogenesis.

5-Lipoxygenase metabolite 4-HDHA is a mediator of the antiangiogenic effect of ω-3 polyunsaturated fatty acids.

Lipid signaling is dysregulated in many diseases with vascular pathology, including cancer, diabetic retinopathy, retinopathy of prematurity, and age-related macular degeneration. We have previously demonstrated that diets enriched in ω-3 polyunsaturated fatty acids (PUFAs) effectively reduce pathological retinal neovascularization in a mouse model of oxygen-induced retinopathy, in part through metabolic products that suppress microglial-derived tumor necrosis factor-α. To better understand the protective effects of ω-3 PUFAs, we examined the relative importance of major lipid metabolic pathways and their products in contributing to this effect. ω-3 PUFA diets were fed to four lines of mice deficient in each key lipid-processing enzyme (cyclooxygenase 1 or 2, or lipoxygenase 5 or 12/15), retinopathy was induced by oxygen exposure; only loss of 5-lipoxygenase (5-LOX) abrogated the protection against retinopathy of dietary ω-3 PUFAs. This protective effect was due to 5-LOX oxidation of the ω-3 PUFA lipid docosahexaenoic acid to 4-hydroxy-docosahexaenoic acid (4-HDHA). 4-HDHA directly inhibited endothelial cell proliferation and sprouting angiogenesis via peroxisome proliferator-activated receptor γ (PPARγ), independent of 4-HDHA's anti-inflammatory effects. Our study suggests that ω-3 PUFAs may be profitably used as an alternative or supplement to current anti-vascular endothelial growth factor (VEGF) treatment for proliferative retinopathy and points to the therapeutic potential of ω-3 PUFAs and metabolites in other diseases of vasoproliferation. It also suggests that cyclooxygenase inhibitors such as aspirin and ibuprofen (but not lipoxygenase inhibitors such as zileuton) might be used without losing the beneficial effect of dietary ω-3 PUFA.