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PURPOSE: Rhegmatogenous retinal detachment is a severe vision-threatening complication that can result into proliferative vitreoretinopathy (PVR) and re-detachment of the retina if recovery from surgery fails. Inflammation and changes in retinal pigment epithelial (RPE) cells are important contributors to the disease. Here, we studied the effects of simvastatin and amfenac on ARPE-19 cells under inflammatory conditions. METHODS: ARPE-19 cells were pre-treated with simvastatin and/or amfenac for 24 h after which interleukin (IL)-1α or IL-1ß was added for another 24 h. After treatments, lactate dehydrogenase release, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) processing, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activity, prostaglandin E2 (PGE2) level, and extracellular levels of IL-6, IL-8, monocytic chemoattractant protein (MCP-1), vascular endothelial growth factor (VEGF), and pigment epithelium-derived factor, as well as the production of reactive oxygen species (ROS) were determined. RESULTS: Pre-treatment of human ARPE-19 cells with simvastatin reduced the production of IL-6, IL-8, and MCP-1 cytokines, PGE2 levels, as well as NF-κB activity upon inflammation, whereas amfenac reduced IL-8 and MCP-1 release but increased ROS production. Together, simvastatin and amfenac reduced the release of IL-6, IL-8, and MCP-1 cytokines as well as NF-κB activity but increased the VEGF release upon inflammation in ARPE-19 cells. CONCLUSION: Our present study supports the anti-inflammatory capacity of simvastatin as pre-treatment against inflammation in human RPE cells, and the addition of amfenac complements the effect. The early modulation of local conditions in the retina can prevent inflammation induced PVR formation and subsequent retinal re-detachment.
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Fenilacetatos , Desprendimiento de Retina , Vitreorretinopatía Proliferativa , Humanos , Vitreorretinopatía Proliferativa/metabolismo , Desprendimiento de Retina/cirugía , FN-kappa B/metabolismo , FN-kappa B/farmacología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Epitelio Pigmentado de la Retina , Simvastatina/metabolismo , Simvastatina/farmacología , Especies Reactivas de Oxígeno/metabolismo , Dinoprostona/metabolismo , Dinoprostona/farmacología , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Citocinas/metabolismo , Antiinflamatorios , Inflamación/metabolismoRESUMEN
Proliferative diabetic retinopathy (PDR) is a major diabetic microvascular complication characterized by pathological angiogenesis. Several retinopathy animal models have been developed to study the disease mechanisms and putative targets. However, knowledge on the human proliferative disease remains incomplete, relying on steady-state results from thin histological neovascular tissue sections and vitreous samples. New translational models are thus required to comprehensively understand the disease pathophysiology and develop improved therapeutic interventions. We describe here a clinically relevant model, whereby the native multicellular PDR landscape and neo(fibro)vascular processes can be analysed ex vivo and related to clinical data. As characterized by three-dimensional whole-mount immunofluorescence and electron microscopy, heterogeneity in patient-derived PDR neovascular tissues included discontinuous capillaries coupled with aberrantly differentiated, lymphatic-like and tortuous endothelia. Spatially confined apoptosis and proliferation coexisted with inflammatory cell infiltration and unique vascular islet formation. Ex vivo-cultured explants retained multicellularity, islet patterning and capillary or fibrotic outgrowth in response to vitreoretinal factors. Strikingly, PDR neovascular tissues, whose matched vitreous samples enhanced lymphatic endothelial cell sprouting, contained lymphatic-like capillaries in vivo and developed Prox1+ capillaries and sprouts with lymphatic endothelial ultrastructures ex vivo. Among multiple vitreal components, vascular endothelial growth factor C was one factor found at lymphatic endothelium-activating concentrations. These results indicate that the ischaemia-induced and inflammation-induced human PDR microenvironment supports pathological neolymphovascularization, providing a new concept regarding PDR mechanisms and targeting options. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Microambiente Celular , Retinopatía Diabética/patología , Células Endoteliales/patología , Linfangiogénesis , Vasos Linfáticos/patología , Neovascularización Patológica , Vasos Retinianos/patología , Adulto , Apoptosis , Diferenciación Celular , Proliferación Celular , Células Cultivadas , Retinopatía Diabética/metabolismo , Células Endoteliales/metabolismo , Femenino , Fibrosis , Humanos , Vasos Linfáticos/metabolismo , Masculino , Persona de Mediana Edad , Comunicación Paracrina , Estudios Prospectivos , Vasos Retinianos/metabolismo , Transducción de Señal , Técnicas de Cultivo de Tejidos , Cuerpo Vítreo/metabolismo , Adulto JovenRESUMEN
Diabetic retinopathy (DR) is the most common diabetic microvascular complication and major cause of blindness in working-age adults. According to the level of microvascular degeneration and ischemic damage, DR is classified into non-proliferative DR (NPDR), and end-stage, proliferative DR (PDR). Despite advances in the disease etiology and pathogenesis, molecular understanding of end-stage PDR, characterized by ischemia- and inflammation-associated neovascularization and fibrosis, remains incomplete due to the limited availability of ideal clinical samples and experimental research models. Since a great portion of patients do not benefit from current treatments, improved therapies are essential. DR is known to be a complex and multifactorial disease featuring the interplay of microvascular, neurodegenerative, metabolic, genetic/epigenetic, immunological, and inflammation-related factors. Particularly, deeper knowledge on the mechanisms and pathophysiology of most advanced PDR is critical. Lymphatic-like vessel formation coupled with abnormal endothelial differentiation and progenitor cell involvement in the neovascularization associated with PDR are novel recent findings which hold potential for improved DR treatment. Understanding the underlying mechanisms of PDR pathogenesis is therefore crucial. To this goal, multidisciplinary approaches and new ex vivo models have been developed for a more comprehensive molecular, cellular and tissue-level understanding of the disease. This is the first step to gain the needed information on how PDR can be better evaluated, stratified, and treated.
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Retinopatía Diabética/patología , Neovascularización Patológica/patología , Diferenciación Celular , Retinopatía Diabética/genética , Retinopatía Diabética/metabolismo , Células Progenitoras Endoteliales/citología , Células Progenitoras Endoteliales/metabolismo , Epigénesis Genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Redes y Vías Metabólicas , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismoRESUMEN
Initial triggers for diabetic retinopathy (DR) are hyperglycemia-induced oxidative stress and advanced glycation end-products. The most pathological structural changes occur in retinal microvasculature, but the overall development of DR is multifactorial, with a complex interplay of microvascular, neurodegenerative, genetic/epigenetic, immunological, and secondary inflammation-related factors. Although several individual factors and pathways have been associated with retinopathy, a systems level understanding of the disease is lacking. To address this, we performed mass spectrometry based label-free quantitative proteomics analysis of 138 vitreous humor samples from patients with nonproliferative DR or the more severe proliferative form of the disease. Additionally, we analyzed samples from anti-VEGF (vascular endothelial growth factor) (bevacizumab)-treated patients from both groups. In our study, we identified 2482 and quantified the abundancy of 1351 vitreous proteins. Of these, the abundancy of 230 proteins was significantly higher in proliferative retinopathy compared with nonproliferative retinopathy. This specific subset of proteins was linked to inflammation, complement, and coagulation cascade proteins, protease inhibitors, apolipoproteins, immunoglobulins, and cellular adhesion molecules, reflecting the multifactorial nature of the disease. The identification of the key molecules of the disease is critical for the development of new therapeutic molecules and for the new use of existing drugs.
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Retinopatía Diabética/metabolismo , Proteoma/análisis , Cuerpo Vítreo/metabolismo , Bevacizumab/uso terapéutico , Cromatografía Liquida , Retinopatía Diabética/tratamiento farmacológico , Humanos , Espectrometría de Masas/métodos , Proteómica/métodos , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/metabolismo , Cuerpo Vítreo/patologíaRESUMEN
PURPOSE: In rhegmatogenous retinal detachment (RRD), intravitreal growth factors and cytokines may compromise post-vitrectomy outcomes. Here, we analysed perioperative intravitreal protein levels of potent vasoactive, pro-inflammatory, and extracellular matrix-remodelling factors in RRD eyes of patients treated with statins and evaluated post-vitrectomy outcome in the same study eyes. METHODS: Institutional, retrospective, observational study of 14 patients operated on for RRD while on statins compared to patients without statin medication (n = 82). Vitreous samples were subjected to protein measurements of angiopoietin (ANGPT)-1 and -2, transforming growth factor-ß1, and vascular endothelial growth factor (VEGF) by ELISA, and of matrix metalloproteinase (MMP)-2 and -9 by gelatin zymography. A 1-month best-corrected visual acuity (BCVA) gain was modelled by Student's T-test and multivariate linear regression with concomitant perioperative medication. Cumulative 12-month revitrectomy frequency was modelled by Kaplan-Meier log-rank test. RESULTS: Intravitreal levels of ANGPT-2 (49.2 ± 33.1 vs. 112.8 ± 134.1 pg/ml, mean ± SD, p < 0.001), VEGF (2.3 ± 2.4 vs. 17.7 ± 57.8 pg/ml, p = 0.021), and MMP-2 (1107.1 ± 884.6 vs 1976.4 ± 970.1 AU/ml, p = 0.005) in RRD eyes of patients treated with statins were lower than in non-statin-treated controls. Patients on statins had better 1-month BCVA improvement than did those not on statins (p = 0.022), with no difference in 1-year re-vitrectomy rates. CONCLUSIONS: Intravitreal levels of ANGPT-2, VEGF, factors involved in vascular permeability and inflammation, and activity of MMP-2, the factor connected with breakdown of basement membrane and fibroproliferation, were lower in RRD eyes of patients with statin treatment. At 1-month, postoperative BCVA gain was improved in statin-treated RRD eyes, suggesting that statin administration may be effective in preventing inflammation-related PVR formation.
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Angiopoyetina 2/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Metaloproteinasa 2 de la Matriz/metabolismo , Desprendimiento de Retina/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular/metabolismo , Agudeza Visual/fisiología , Vitrectomía , Anciano , Atorvastatina/uso terapéutico , Biomarcadores/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Desprendimiento de Retina/metabolismo , Estudios Retrospectivos , Rosuvastatina Cálcica/uso terapéutico , Simvastatina/uso terapéutico , Cuerpo Vítreo/metabolismoRESUMEN
PURPOSE: To explore factors related to pathogenesis of rhegmatogenous retinal detachment (RRD) and development of proliferative vitreoretinopathy (PVR), vitreous levels of angiopoietin-1 and -2 (Ang-1 and -2), previously undefined in RRD, transforming growth factor-(TGF) ß1, vascular endothelial growth factor (VEGF), erythropoietin (EPO) and proteolytic mediators of extracellular matrix remodelling (MMP-2 and -9) were compared in eyes with RRD and eyes with idiopathic macular hole or pucker. METHODS: Vitreous samples were collected from 117 eyes with RRD (study group) and 40 eyes with macular hole or pucker (control group). Growth factors were measured by ELISA and matrix metalloproteinases (MMPs) by gelatin zymography. RESULTS: The mean vitreous concentrations of Ang-2, MMP-2, and MMP-9 were higher (all p < 0.01), whereas concentration of VEGF was lower (p = 0.01) in eyes with RRD relative to controls. Logistic regression analysis identified Ang-2 concentration as a novel marker of RRD (p = 0.0001, OR 48.7). Ang-1, EPO, and total TGF-ß1 levels were not significantly different between the groups. However, TGF-ß1 and MMP-2 were increased in eyes with total RRD compared to those with local RRD (p ≤ 0.05). In eyes with PVR, no differences were observed in any studied marker as compared with non-PVR eyes. CONCLUSIONS: Current results reveal Ang-2 as a key factor upregulated in RRD. It may co-operate with fibrosis-associated factors and contribute to vascular complications such as breakdown of blood-eye barrier and PVR development.
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Angiopoyetina 2/metabolismo , Biomarcadores/metabolismo , Desprendimiento de Retina/metabolismo , Cuerpo Vítreo/metabolismo , Anciano , Angiopoyetina 1/metabolismo , Ensayo de Inmunoadsorción Enzimática , Eritropoyetina/metabolismo , Femenino , Humanos , Masculino , Metaloproteinasas de la Matriz/metabolismo , Persona de Mediana Edad , Estudios Prospectivos , Desprendimiento de Retina/diagnóstico , Factor de Crecimiento Transformador beta1/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
AIMS: To investigate the rate and risk factors of undergoing glaucoma filtration surgery (GFS) in patients with newly diagnosed open-angle glaucoma (OAG). METHODS: This is a population-based historic cohort study, consisting of 9420 patients older than 45 years diagnosed with OAG during 1997-2010. Follow-up spanned from 1997 to 2017. We obtained data for trabeculectomy (TRE), deep sclerectomy (DS), and glaucoma drainage implant (GDI) surgeries from national administrative healthcare registers by hospital billing data. We plotted the cumulative incidence of GFS and carried out a multivariate Poisson regression analysis adjusted for age, sex, hospital district, systemic comorbidities, and the number of IOP-lowering drugs. We reported incidence rate ratios (IRR) with 95% confidence intervals (CI) for GFS after the onset of OAG. RESULTS: The cumulative incidence of GFS at 5 years from OAG onset was 3.1% and at 10 years 5.4%. Age over 80 years at baseline was associated with lower GFS incidence (IRR 0.51, CI 0.31-0.84). The number of IOP-lowering drugs in the first 2 years of treatment correlated with the risk of GFS increasing from (IRR 3.23, CI 2.32-4.50) for two drugs, (IRR 7.44, CI 5.28-10.47) for three and to (IRR 14.95, CI 10.38-21.52) for four drugs. CONCLUSION: This study characterized the treatment path of OAG from diagnosis to surgical intervention refining the role of GFS among glaucoma therapies.
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Cirugía Filtrante , Glaucoma de Ángulo Abierto , Glaucoma , Humanos , Anciano de 80 o más Años , Glaucoma de Ángulo Abierto/epidemiología , Glaucoma de Ángulo Abierto/cirugía , Glaucoma de Ángulo Abierto/tratamiento farmacológico , Incidencia , Estudios de Cohortes , Glaucoma/cirugía , Cirugía Filtrante/efectos adversos , Presión IntraocularRESUMEN
Proliferative vitreoretinopathy (PVR) develops after an unsuccessful or complicated recovery from rhegmatogenous retinal detachment (RRD) surgery. Intraocular scar formation with the contribution of epithelial-mesenchymal transition (EMT) in RPE cells is prominent in the pathology of PVR. In the present study, the EMT process was experimentally induced in human retinal pigment epithelium (RPE; ARPE-19) cells, and the effect of atorvastatin on the process was studied. The mRNA and protein levels of mesenchymal markers actin alpha 2 (ACTA2) / alpha-smooth muscle actin (α-SMA) and fibronectin (FN), and epithelial markers occludin (OCLN) and zonula occludens-1 (ZO-1) were measured using quantitative real-time PCR (qRT-PCR) and western blot methods, respectively. In addition, α-SMA and FN were visualized using immunofluorescence staining. Cells were photographed under a phase contrast light microscope. Changes in the functionality of cells following the EMT process were studied using the IncuCyte scratch wound cell migration assay and the collagen cell invasion assay with confocal microscopy. The induction of EMT in ARPE-19 cells increased the expression of mesenchymal markers ACTA2/α-SMA and fibronectin and reduced the expression of epithelial marker OCLN both at mRNA and protein levels. The mRNA levels of ZO-1 were lower after EMT, as well. Increased levels of α-SMA and FN were confirmed by immunofluorescence staining. Atorvastatin further increased the mRNA levels of mesenchymal markers ACTA2 and FN as well as the protein levels of α-SMA and reduced the mRNA levels of epithelial markers OCLN and ZO-1 under the EMT process. EMT promoted wound closure and cell invasion into the 3D collagen matrix when compared to untreated control cells. These data present cellular changes upon the induction of the EMT process in ARPE-19 cells and the propensity of atorvastatin to complement the effect. More studies are needed to confirm the exact influence of the EMT process and atorvastatin treatment on the PVR development after RRD surgery.
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Actinas , Atorvastatina , Movimiento Celular , Transición Epitelial-Mesenquimal , Fibronectinas , Epitelio Pigmentado de la Retina , Proteína de la Zonula Occludens-1 , Transición Epitelial-Mesenquimal/efectos de los fármacos , Humanos , Atorvastatina/farmacología , Epitelio Pigmentado de la Retina/citología , Epitelio Pigmentado de la Retina/efectos de los fármacos , Epitelio Pigmentado de la Retina/metabolismo , Actinas/metabolismo , Actinas/genética , Línea Celular , Fibronectinas/metabolismo , Fibronectinas/genética , Movimiento Celular/efectos de los fármacos , Proteína de la Zonula Occludens-1/metabolismo , Proteína de la Zonula Occludens-1/genética , Ocludina/metabolismo , Ocludina/genéticaRESUMEN
PURPOSE: The aim of this study was to investigate the association of diabetes mellitus (DM) and risk of open-angle glaucoma (OAG). METHODS: This population-based historic cohort consisted of individuals at age ≥ 40 years with DM treatment initiated 2001-2010 and a reference population matched by age, gender and hospital district. Incidence of OAG was compared between individuals with DM and their matched non-diabetic reference pairs. New glaucoma cases were identified from medication reimbursement certificates and hospital billing records. Incidence rate ratios (IRR) were analysed with Poisson regression models adjusted for age, sex, hospital district, socioeconomic status, systemic medications and chronic diseases. We analysed the sensitivity of the results with adapted input variables and performed a competing events analysis. RESULTS: Of the 244 100 study subjects meeting inclusion criteria, 2721 (1.1%) developed OAG. Follow-up spanned from 2001 to 2017. DM was associated with a modestly reduced incidence of OAG when adjusted for confounding factors (IRR 0.92, CI 0.85-0.99). CONCLUSIONS: In our longitudinal population-based study, we found a modest decrease in the risk of OAG for individuals with DM.
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Diabetes Mellitus , Glaucoma de Ángulo Abierto , Humanos , Adulto , Estudios de Seguimiento , Factores de Riesgo , IncidenciaRESUMEN
PURPOSE: To identify associations between systemic drugs and the incidence of diabetic macular oedema (DME). Of interest was to find beneficial and/or deleterious associations of used drugs. METHODS: A historic cohort design based on administrative data. Study population consisted of 150 353 individuals with diabetes. Endpoint event was the development of DME (ICD-10 H36.01), censoring events were death or study end December 2017. The follow-up started between 1997 and 2010. The systemic medication consisted of 95 substances. We constructed a nested case-control study design comparing 2630 cases with DME to 13 144 age- and sex-matched controls without DME. Results are reported as odds ratios (ORs) with 95% confidence intervals (CIs) based on conditional logistic regression models. RESULTS: Incidence rate for DME was 1.80 per 1000 person-years (95% CI 1.73-1.87). In all, we observed a lower incidence rate of DME in females (IRR 0.57; 95% CI 0.52-0.62) compared to males. Exposure to hormone replacement therapy estradiol (OR 0.42; 0.25-0.68), temazepam (0.23; 0.08-0.62) and allopurinol (0.61; 0.43-0.86) were associated with lower risk of DME, while use of insulin or insulin analogue (3.30; 2.99-3.64), sulfonylureas (1.21; 1.05-1.40), diuretic furosemide (1.90; 1.61-2.24), calcium channel blocker amlodipine (1.53; 1.34-1.75), ACE inhibitors ramipril (1.66; 1.46-1.89) and enalapril (1.38; 1.16-1.64) were associated with an increased risk of DME. CONCLUSIONS: Large-scale studies examining the incidence of DME are lacking. Our findings suggest that associations of systemic medications with the incidence of DME may shed light on the pathogenesis of complex DME, encouraging further studies.
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Purpose: To examine the association between the use of topical non-steroidal anti-inflammatory (NSAID) medication, systemic statin therapy, and the incidence rate of two of the most common postsurgical procedures in adult patients undergoing cataract surgery in Finland between January 1, 2010 and December 31, 2016. Methods: This retrospective, nationwide cohort study considered 176,052 cataract operations coded with the International Classification of Disease coding: early adult (H25.0), normal (H25.1), other senile (H25.8), pre-senile (H26.02), or other (related to trauma, other eye disease, or medication). Operations were linked to purchased and reimbursed medications using Anatomical Therapeutic Chemical codes. The incidence rate of intravitreal anti-vascular endothelial growth factor (VEGF) injections, and neodymium-doped yttrium aluminum (Nd:YAG) laser treatments of posterior capsular opacification were evaluated using the Poisson regression model. Results: In our registry cohort, patients with a prescription of topical NSAID (ketorolac) at the time of cataract surgery were less likely treated with intravitreal anti-VEGF injections after surgery (adjusted Poisson regression model IRR 0.3; 95% CI: 0.15-0.60, P = 0.0007), and also had reduced incidence of Nd:YAG laser (0.59, CI: 0.43-0.81, P = 0.0011) treatments. Unlike topical NSAID, the use of systemic statin therapy was not associated with these two most common surgical procedures (RR 1.04, 95% CI: 0.96-1.12, P = 0.33). Conclusion: The use of topical NSAIDs is associated with reduced rates of intravitreal anti-VEGF injections and Nd:YAG laser treatments after cataract surgery. More observational and experimental studies are warranted to confirm possible benefits of topical NSAID administration after cataract surgery.
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PURPOSE: To examine whether systemic medications are associated with the subsequent development of wet age-related macular degeneration (AMD). METHODS: A retrospective study of 259 562 individuals based on registry data, from January 1, 2001, to December 31, 2017. End-point event was the International Classification of Diseases (ICD)-10 diagnosis for wet AMD. Association between use of systemic medication covering 85 generic drugs categorized according to Anatomical Therapeutic Chemical (ATC) codes and the incidence of wet AMD was evaluated using multivariate Poisson regression model (adjusted for age, sex, diabetes, cancer and socioeconomic group) and nested case-control design. RESULTS: The mean length of follow-up was 9.84 years. The number of cases with wet AMD was 2947 and incidence rate was 1.15 per 1000 person-years. After adjustment, we observed an increased risk for the development of wet AMD for patients exposed to amlodipine (IRR 1.33, 95% CI 1.16-1.53), or felodipine (1.24, 95% CI 1.02-1.50). Similarly, an increased risk of wet AMD was associated with the use of bicalutamide (2.14, 95% CI 1.14-4.02), estradiol (1.20, 95% CI 1.03-1.40) and atorvastatin (1.22, 95% CI 1.05-1.43). Of note, digoxin (0.72, 95% CI 0.57-0.91), and ramipril (0.80, 95% CI 0.65-0.99) users had a lower incidence of wet AMD. CONCLUSIONS: Our findings suggest that the use of second-generation calcium channel blockers could be associated with an increased risk for wet AMD development. Of note, the incidence of wet AMD seemed to be lower in patients using ramipril and digoxin. More studies are needed to elucidate the associations further.
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Ramipril , Degeneración Macular Húmeda , Digoxina , Humanos , Incidencia , Estudios Retrospectivos , Factores de Riesgo , Degeneración Macular Húmeda/diagnóstico , Degeneración Macular Húmeda/tratamiento farmacológico , Degeneración Macular Húmeda/epidemiologíaRESUMEN
PURPOSE: To examine the association of systemic statin therapy and reoperation rate after glaucoma filtration surgery (GFS). METHODS: This is a population-based, historic cohort study of 2705 eyes undergoing GFS in Finland between July 2009 and December 2016. GFSs were identified from national administrative healthcare registers. Baseline sociodemographic and health characteristics were documented. Reoperation rates of GFS subgroups were analysed, with statin users compared to non-users. The outcomes were modelled using a Poisson regression model adjusted for age, sex, education, statin use, chronic comorbidities, and cataract surgery with incident rate ratios (IRR) as the main outcome measure. RESULTS: The cohort contained 2263 subjects with open-angle glaucoma (OAG), 823 men and 1440 women. Surgery was performed on 2705 eyes. First documented procedures: deep sclerectomy (DS) (n = 1601), trabeculectomy (TRE) (799) and glaucoma drainage device (GDD) implantation (305) respectively. In total, 438 secondary operations were performed during the 7.5-year (median 2.25 years) follow-up period. The reoperation rates were 19% after DS, 12% after TRE, and 13% after GDD. Of the surgical procedures, 32% were performed on eyes of patients receiving statin therapy. Statin users showed no difference in reoperation rates (IRR 1.06, CI 0.82-1.37). In subgroups, no difference was observed in the reoperation rates adjusted with statin use after filtration surgery (DS, TRE) (IRR 1.06, CI 0.8-1.40) or GDD implantation (0.57, CI 0.20-1.63). CONCLUSION: Systemic statin therapy among surgically treated OAG patients had no impact on secondary surgery rates following DS, TRE or GDD implantation.
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Cirugía Filtrante/métodos , Glaucoma de Ángulo Abierto/cirugía , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Presión Intraocular/fisiología , Vigilancia de la Población/métodos , Complicaciones Posoperatorias/prevención & control , Reoperación/estadística & datos numéricos , Anciano , Femenino , Finlandia/epidemiología , Estudios de Seguimiento , Implantes de Drenaje de Glaucoma , Glaucoma de Ángulo Abierto/tratamiento farmacológico , Glaucoma de Ángulo Abierto/fisiopatología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/epidemiología , Sistema de Registros , Estudios Retrospectivos , Factores de TiempoRESUMEN
PURPOSE: To investigate the association between different types of vitrectomy and risk of different types of glaucoma and to determine the effect of systemic medication and diabetes status on this risk. METHODS: A population-based nested case-control study included individuals of age ≥ 18 years who had undergone single vitrectomy, vitrectomy with retinal procedure, or combined phaco-vitrectomy between 2001 and 2010. End of follow-up was 2017. Odds ratio (OR) for the development of glaucoma after different types of vitrectomy and 95% confidence interval (CI) were based on conditional logistic regression models. For every glaucoma case, five controls were matched by age, sex, start of follow-up year, and hospital district. RESULTS: The cohort (n = 37 687), of which 52.8% was female, consisted of 6552 individuals diagnosed with glaucoma and 31 135 controls matched by age, sex, and hospital district. Vitrectomy was performed on 103 eyes in the glaucoma group and 158 eyes in the control group. As regards the risk of any glaucoma, the risk was lowest in eyes that underwent combined phaco-vitrectomy (OR: 2.7, 95% CI: 1.8-4.1), followed by single vitrectomy (OR: 3.15, 95% CI: 2.1-4.8), and highest in eyes that underwent vitrectomy with retinal procedure (OR: 4.5, 95% CI: 2.7-7.4). Diabetes had no effect (OR: 0.96, 95% CI: 0.92-1.01), but 5-year systemic statin use slightly decreased glaucoma risk (OR: 0.86, 95% CI: 0.77-0.97). CONCLUSIONS: Vitreoretinal surgery was associated with an increased glaucoma risk; the risk being related to the complexity of vitrectomy. Long-term systemic statin therapy may decrease glaucoma risk, while diabetes had no association.
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Glaucoma , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Cirugía Vitreorretiniana , Adolescente , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Glaucoma/epidemiología , Glaucoma/etiología , Glaucoma/cirugía , Humanos , Presión Intraocular , Estudios Retrospectivos , Agudeza Visual , Vitrectomía/efectos adversos , Vitrectomía/métodos , Cirugía Vitreorretiniana/efectos adversosAsunto(s)
Adenosina Difosfato/metabolismo , Retinopatía Diabética/tratamiento farmacológico , Retina/metabolismo , Simvastatina/uso terapéutico , Animales , Biomarcadores/metabolismo , Células Cultivadas , Retinopatía Diabética/metabolismo , Retinopatía Diabética/patología , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Retina/patologíaRESUMEN
PURPOSE: To examine whether real-world clinical patients with macular oedema (MO) receiving intravitreal antivascular endothelial growth factor (VEGF) therapy have a higher mortality compared with a matched reference population. METHODS: A population-based, retrospective cohort study of 26 386 patients from Finland, from January 1, 2001, to December 31, 2017. Index patients were identified through the Caring Epidemiology Project database, receiving at least one intravitreal anti-VEGF injection for wet age-related macular degeneration (AMD, n = 2243, 48.61%), diabetic MO (n = 744, 16.12%), MO due to retinal vascular occlusion (n = 589, 12.77%), or other MO (n = 1038, 22.5%). For each individual treated with intravitreal injection (n = 4614), five age- , sex- , calendar year- and hospital district- matched control individuals (n = 21 772) were chosen. Baseline data of chronic conditions were available. All-cause and cause-specific mortality was analysed using Cox´s proportional hazards model. RESULTS: In general, the anti-VEGF treated patients had a higher prevalence of systemic conditions, including diabetes (60.1% vs. 46.8%, p < 0.001), chronic hypertension (38.4% vs. 34.6%, p < 0.001), in hospital-treated ischaemic heart disease (23.1% vs. 21.5%, p = 0.014), and glaucoma (11.1% vs. 6.3%, p < 0.001) than controls. There was no difference in all-cause mortality between the anti-VEGF treated patients and matched controls (p = 0.62). In unadjusted Kaplan-Meier analysis of wet AMD subgroup, all-cause mortality was lower in anti-VEGF treated patients than matched controls (p = 0.015), but adjusted Cox´s proportional hazards model showed no difference in the risk of all-cause mortality (HR 0.85, 95% CI 0.66-1.09). CONCLUSIONS: Intravitreal anti-VEGF therapy was not associated with an increase in the risk of mortality in patients with MO compared with age- and sex-matched controls.
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Inhibidores de la Angiogénesis/administración & dosificación , Predicción , Edema Macular/tratamiento farmacológico , Vigilancia de la Población , Vasos Retinianos/diagnóstico por imagen , Medición de Riesgo/métodos , Enfermedades Vasculares/complicaciones , Anciano , Causas de Muerte/tendencias , Femenino , Finlandia/epidemiología , Estudios de Seguimiento , Humanos , Edema Macular/etiología , Edema Macular/mortalidad , Masculino , Segmento Posterior del Ojo , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia/tendencias , Enfermedades Vasculares/diagnóstico , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
Proliferative diabetic retinopathy (PDR) is a sight-threatening diabetic complication in urgent need of new therapies. In this study we identify potential molecular mechanisms and target candidates in the pathogenesis of PDR fibrovascular tissue formation. We performed mRNA sequencing of RNA isolated from eleven excised fibrovascular membranes of type 1 diabetic PDR patients and two non-diabetic patients with rhegmatogenous retinal detachment with proliferative vitreoretinopathy. We determined differentially expressed genes between these groups and performed pathway and gene ontology term enrichment analyses to identify potential underlying mechanisms, pathways, and regulators. Multiple pro-angiogenic processes, including VEGFA-dependent and -independent pathways, as well as processes related to lymphatic development, epithelial to mesenchymal transition (EMT), wound healing, inflammation, fibrosis, and extracellular matrix (ECM) composition, were overrepresented in PDR. Overrepresentation of different angiogenic processes may help to explain the transient nature of the benefits that many patients receive from current intravitreal anti-angiogenic therapies, highlighting the importance of combinatorial treatments. Enrichment of genes and pathways related to lymphatic development indicates that targeting lymphatic involvement in PDR progression could have therapeutic relevance. Together with overrepresentation of EMT and fibrosis as well as differential ECM composition, these findings demonstrate the complexity of PDR fibrovascular tissue formation and provide avenues for the development of novel treatments.
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Retinopatía Diabética/metabolismo , Neovascularización Patológica/metabolismo , Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/inmunología , Retinopatía Diabética/patología , Transición Epitelial-Mesenquimal , Enfermedades Hereditarias del Ojo/metabolismo , Fibrosis , Perfilación de la Expresión Génica , Humanos , Inflamación/metabolismo , Redes y Vías Metabólicas , ARN Mensajero/genética , Desprendimiento de Retina/metabolismo , Epitelio Pigmentado de la Retina/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
PURPOSE: To examine whether serum cholesterol in early middle age is associated with age-related macular degeneration (AMD) later in life. METHODS: A group of Helsinki Businessmen Study (HBS) participants (n = 209) were recruited for the study. Total cholesterol (TC), triglyceride and body mass index (BMI) were measured at the HBS baseline visit in 1964-1973. Lipid subfractions, BMI, smoking status and statin use were recorded in 2011 and fundus photographs graded for AMD in 2005-2012. The subjects were genotyped for the main AMD risk single nucleotide polymorphisms (SNPs). RESULTS: TC measured at baseline 1964-1973 was significantly higher in subjects later developing intermediate or late AMD (6.67 mmol/l versus 6.20 mmol/l, p = 0.024) or with drusen size of ≥125 µm (6.68 mmol/l versus 6.21 mmol/l, p = 0.030) compared with the rest of the study population. TC, LDL and TG values at follow-up 2011 were lower in subjects with AMD compared to those without, whereas HDL levels showed no difference. In multivariate analysis, baseline TC associated with intermediate or late AMD (OR 1.59, p = 0.004) and drusen size ≥ 125 µm (OR 1.57, p = 0.006) when corrected for age, BMI, AMD risk SNPs and smoking. Lipid values measured 2011 had no associations after correction. CONCLUSIONS: High systemic total cholesterol in early middle age may have a role in the initial development of AMD, especially in patients later developing large drusen.
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Colesterol/sangre , Degeneración Macular/sangre , Polimorfismo de Nucleótido Simple , Medición de Riesgo/métodos , Adulto , Distribución por Edad , Factores de Edad , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Finlandia/epidemiología , Estudios de Seguimiento , Humanos , Incidencia , Degeneración Macular/epidemiología , Degeneración Macular/genética , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Factores de TiempoRESUMEN
Rhegmatogenous retinal detachment (RRD) is an ophthalmic emergency, which usually requires prompt surgery to prevent further detachment and restore sensory function. Although several individual factors have been suggested, a systems level understanding of molecular pathomechanisms underlying this severe eye disorder is lacking. To address this gap in knowledge we performed the molecular level systems pathology analysis of the vitreous from 127 patients with RRD using state-of-the art quantitative mass spectrometry to identify the individual key proteins, as well as the biochemical pathways contributing to the development of the disease. RRD patients have specific vitreous proteome profiles compared to other diseases such as macular hole, pucker, or proliferative diabetic retinopathy eyes. Our data indicate that various mechanisms, including glycolysis, photoreceptor death, and Wnt and MAPK signaling, are activated during or after the RRD to promote retinal cell survival. In addition, platelet-mediated wound healing processes, cell adhesion molecules reorganization and apoptotic processes were detected during RRD progression or proliferative vitreoretinopathy formation. These findings improve the understanding of RRD pathogenesis, identify novel targets for treatment of this ophthalmic disease, and possibly affect the prognosis of eyes treated or operated upon due to RRD.
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Retina/patología , Desprendimiento de Retina/patología , Apoptosis/fisiología , Plaquetas/metabolismo , Plaquetas/patología , Adhesión Celular/fisiología , Proliferación Celular/fisiología , Supervivencia Celular/fisiología , Retinopatía Diabética/metabolismo , Retinopatía Diabética/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteoma/metabolismo , Retina/metabolismo , Desprendimiento de Retina/metabolismo , Perforaciones de la Retina/metabolismo , Perforaciones de la Retina/patología , Transducción de Señal/fisiología , Vitreorretinopatía Proliferativa/metabolismo , Vitreorretinopatía Proliferativa/patología , Cuerpo Vítreo/metabolismo , Cuerpo Vítreo/patología , Cicatrización de Heridas/fisiologíaRESUMEN
Proliferative vitreoretinopathy (PVR) with rhegmatogenous retinal detachment (RRD) is a complex inflammatory ocular disease. Statins are widely used cholesterol-lowering drugs with putative anti-inflammatory properties. In this study, we have explored their efficacy in controlling post-surgical PVR formation. Simvastatin (SIM), atorvastatin (ATV), or rosuvastatin (RSV) were added to cultures of human retinal pigment epithelial cells (ARPE-19) prior to exposure with the bacterial lipopolysaccharide (LPS), and the production of pro-inflammatory cytokines (IL-6, IL-8, MCP-1) was examined using an enzyme-linked immunosorbent assay. In addition, the concentrations of simvastatin, atorvastatin, rosuvastatin, and their metabolites were measured from the vitreal samples of 20 patients undergoing vitrectomy (16 of them receiving oral statin therapy) using an ultra-performance liquid chromatography-tandem mass spectrometer technique. All statins alleviated LPS-induced inflammation at 5 µM concentration in the ARPE-19 cell cultures. Statin levels in the vitreous samples ranged from 6 to 316 pg/mL (ca. 0.1-7 M-10). Vitreal statin concentrations were similar to the typical steady-state unbound statin concentrations in plasma, indicating that only the unbound drug distributes from the blood circulation into the vitreous. Pharmacokinetic simulations of the intravitreal delivery of statins indicate that the measured clinical statin concentrations could be maintained with existing drug delivery technologies for months. Our results suggest that intravitreal statin therapy may have the potential in alleviating the risk of post-surgical PVR.