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Warburg Effect as a Novel Mechanism for Homocysteine-Induced Features of Age-Related Macular Degeneration
Yara A. Samra, Yusra Zaidi, Pragya Rajpurohit, Raju Raghavan, Lun Cai, Ismail Kaddour-Djebbar and Amany Tawfik
Abstract: Age-related macular degeneration (AMD) is a major cause of blindness. Recent studies have reported impaired glycolysis in AMD patients with a high lactate/pyruvate ratio. Elevated homocysteine (Hcy) (Hyperhomocysteinemia, HHcy) was observed in several clinical studies, reporting an association between HHcy and AMD.We established the effect of HHcy on barrier function, retinal pigment epithelium (RPE) structure, and induced choroidal neovascularization (CNV) in mice. We hypothesize that HHcy contributes to AMD by inducing a metabolic switch in the mitochondria, in which cells predominantly produce energy by the high rate of glycolysis, or “Warburg”, effect. Increased glycolysis results in an increased production of lactate, cellular acidity, activation of angiogenesis, RPE barrier dysfunction, and CNV. Evaluation of cellular energy production under HHcy was assessed by seahorse analysis, immunofluorescence, and western blot experiments. The seahorse analysis evaluated the extracellular acidification rate (ECAR) as indicative of glycolysis. HHcy showed a significant increase in ECAR both in vivo using (Cystathionine β-synthase) cbs+/- and cbs-/- mice retinas and in vitro (Hcy-treated ARPE-19) compared to wild-type mice and RPE cells. Moreover, HHcy up-regulated glycolytic enzyme (Glucose transporter-1 (GlUT-1), lactate dehydrogenase (LDH), and hexokinase 1 (HK1)) in Hcy-treated ARPE-19 and primary RPE cells isolated from cbs+/+, cbs+/-, and cbs-/- mice retinas. Inhibition of GLUT-1 or blocking of N-methyl-D-aspartate receptors (NMDAR) reduced glycolysis in Hcy-treated RPE and improved albumin leakage and CNV induction in Hcy-injected mice eyes. The current study suggests that HHcy causes a metabolic switch in the RPE cells from mitochondrial respiration to glycolysis during AMD and confirms the involvement of NMDAR in this process. Therefore, targeting Glycolysis or NMDAR could be a novel therapeutic target for AMD.
Retinal venous pressure is decreased after anti-VEGF therapy in patients with retinal vein occlusion–related macular edema
Teruyo Kida & Josef Flammer & Katarzyna Konieczka & Tsunehiko Ikeda
Abstract
Purpose: The pathomechanism leading to retinal vein occlusion (RVO) is unclear. Mechanical compression, thrombosis, and functional contractions of veins are discussed as the reasons for the increased resistance of venous outflow. We evaluated changes in the retinal venous pressure (RVP) following intravitreal injection of anti-vascular endothelial growth factor (VEGF) agent to determine the effect on RVO-related macular edema.
Methods: Twenty-six patients with RVO-related macular edema (16 branch RVOs [BRVOs] and 10 central RVOs [CRVOs], age 72.5 ± 8.8 years) who visited our hospital were included in this prospective study. Visual acuity (VA), intraocular pressure (IOP), central retinal thickness (CRT) determined by macular optical coherence tomography, and RVP measured using an ophthalmodynamometer were obtained before intravitreal injection of ranibizumab (IVR) and 1 month later.
Results: Comparison of the BRVOs and CRVOs showed thatVAwas significantly improved by a single injection in BRVOs (P < 0.0001; P = 0.1087 for CRVOs), but CRT and RVP were significantly decreased without significant difference in IOP after the treatment in both groups (P < 0.0001).
Conclusion: The anti-VEGF treatment resulted in a significant decrease in the RVP, but the RVP remained significantly higher than the IOP. An increased RVP plays a decisive role in the formation of macula edema, and reducing it is desirable.
Outcomes in patients with retinal vein occlusion with good baseline visual acuity
Jessica C. Liu, Thanvi Vatti, Kanika Seth, Carolina C. S. Valentim, Aleksandra V. Rachitskaya and Rishi P. Singh
Background: Intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) are first-line therapy for macular oedema in retinal vein occlusion (RVO). Appropriate management for RVO with good visual acuity at diagnosis has not been evaluated. The purpose of this study is to analyse the visual and anatomic outcomes from anti-VEGF treatment among RVO patients with good vision at baseline.
Methods: This retrospective cohort study evaluated patients diagnosed with macular oedema secondary to RVO from January 2012 to February 2021 at a tertiary ophthalmic centre. Patients had a Snellen acuity of 20/32 or better at diagnosis. Three cohorts were compared: patients with no anti-VEGF treatment, delayed anti-VEGF treatment (initial injection >30 days post-diagnosis) and immediate anti-VEGF treatment (initial injection ≤30 days post-diagnosis). Central subfield thickness (CST) and best visual acuity (BVA) were collected at diagnosis and 6-, 12- and 24-month follow-up appointments.
Results: Among 131 eyes, mean BVA values among treatment groups did not differ at 6-, 12- or 24-month follow up visits (P = 0.521, 0.426, 0.356, respectively). The percentage of eyes with at least a 5-letter BVA decrease at 24 months was 24.1%, 65.0% and 30.8% in the no treatment, delayed and immediate treatment groups respectively (P = 0.010). There was no significant difference in the percentage of eyes with at least a 10% decrease in CST at 24 months among groups (P = 0.095).
Conclusions: Close observation with initiation of treatment in patients with good visual acuity with macular oedema secondary to RVO as indicated has similar outcomes in the setting of routine clinical practice.
Prevalence, incidence and healthcare needs
Jeany Q. Li, Thomas Welchowski, Mathias Schmid, Julia Letow, A. Caroline Wolpers, Frank G. Holz, Robert P. Finger
The majority of blindness and severe vision loss in Europe is due to age-related retinal diseases. Considering current demographic trends, both an increase in prevalence and incidence of, as well as an increase in the lifetime lived with age-related retinal disease is expected. This will put enormous pressure on European health care systems.
In order to allow for both tailored health service planning as well as focussed research to address these future challenges, we provide a comprehensive situation analysis and future prediction for retinal diseases in Europe.
We performed a systematic review and meta-analysis of the European literature on prevalence and incidence as well as health care services for age-related macular degeneration (AMD), diabetic eye disease (DED) and retinal vein occlusions (RVO).
We estimated that AMD currently affects around 34 million people in the European Union (EU) and 22 million people in the five most populous European countries alone: Germany, France, the United Kingdom (UK), Italy and Spain. The number of patients affected by AMD in the EU is expected to rise by almost 25% based on population growth and ageing until 2050. For diabetic eye disease, the current and future situation is similar. More than 25% of diabetic patients are affected by any DED, amounting to nearly 4 million individuals in the EU. Nearly one million individuals are estimated to require treatment due to proliferative DED or clinically significant macular oedema. As the prevalence of diabetes is increasing considerably due to both demographic trends and lifestyle changes, DED in turn will increase too. European countries have introduced very heterogeneous approaches to screen for DED with some countries using national registers and/or programmes. Reported uptake of screening for DED was highest in the UK (83%) which has a national screening programme, and lowest for Italy (11%) with no systematic screening programme. National screening programmes incur high health care expenditures, but there is evidence for a significant reduction in blindness due to diabetic retinopathy in England after the implementation of the National Diabetic Eye Screening Programme.
With the introduction of intravitreal (IVT) therapy, both AMD and DED have much improved visual outcomes but available health care service data demonstrate that IVT treatment provision puts a con-siderable strain on healthcare systems and alternative approaches to service provision including delegation to auxiliary cadres have been implemented in for example the UK.
Data on RVO were fewer, but sufficient to perform a meta-analysis. More than one million Europeans aged 55 years and older are affected by RVO and also require IVT as well as laser and other treatment which puts additional strain on ophthalmic healthcare systems.
Retinal diseases are the main causes of blindness and severe visual loss in Europe already today and will continue to increase. Both health service provision and future research should focus on this in order to address these challenges and preserve sight for the ageing European populations.
https://miloftalmica.it/wp-content/uploads/2021/07/Euretina-Retinal-Diseases.pdf
Prevalence, incidence and future projection of diabetic eye disease in Europe: a systematic review and meta-analysis
Jeany Q Li, Thomas Welchowski, Matthias Schmid, Julia Letow, Caroline Wolpers, Isabel Pascual-Camps, Frank G Holz, Robert P Finger
To examine the prevalence and incidence of diabetic eye disease (DED) among individuals with diabetes in Europe, a systematic review to identify all published European prevalence and incidence studies of DED in individuals with diabetes managed in primary health care was performed according to the MOOSE and PRISMA guidelines. The databases Medline, Embase and Web of Science were searched to 2 September 2017. Meta-analyses and meta-regressions were performed. The pooled prevalence estimates were applied to diabetes prevalence rates provided by the International Diabetes Foundation atlas and Eurostat population data, and extrapolated to the year 2050. Data of 35 prevalence and four incidence studies were meta-analyzed. Any diabetic retinopathy (DR) and diabetic macular edema (DME) were prevalent in 25.7% (95% CI 22.8-28.8%) and 3.7% (95% CI 2.2-6.2%), respectively. In meta-regression, the prevalence of DR in persons with type 1 diabetes was significantly higher compared to persons with type 2 diabetes (54.4% vs. 25.0%). The pooled mean annual incidence of any DR and DME in in persons with type 2 diabetes was 4.6% (95% CI 2.3-8.8%) and 0.4% (95% CI 0.5-1.4%), respectively. We estimated that persons with diabetes affected by any DED in Europe will increase from 6.4 million today to 8.6 million in 2050, of whom 30% require close monitoring and/or treatment. DED is estimated to be present in more than a quarter of persons with type 2 diabetes and half of persons with type 1 diabetes underlining the importance of regular monitoring. Future health services need to be planned accordingly.
Dietary Nutrient Intake and Progression to Late Age-Related Macular Degeneration in the Age-Related Eye Disease Studies 1 and 2
Elvira Agrón, Julie Mares, Traci E Clemons, Anand Swaroop, Emily Y Chew, Tiarnan D L Keenan; AREDS and AREDS2 Research Groups
Purpose: To analyze associations between the dietary intake of multiple nutrients and risk of progression to late age-related macular degeneration (AMD), its subtypes, and large drusen.
Design: Post hoc analysis of 2 controlled clinical trial cohorts: Age-Related Eye Disease Study (AREDS) and AREDS2.
Participants: Eyes with no late AMD at baseline among AREDS participants (n = 4504) and AREDS2 participants (n = 3738) totaled 14 135 eyes. Mean age was 71.0 years (standard deviation, 6.7 years), and 56.5% of patients were women.
Methods: Fundus photographs were collected at annual study visits and graded centrally for late AMD. Dietary intake of multiple nutrients was calculated from food frequency questionnaires.
Main outcome measures: Progression to late AMD, geographic atrophy (GA), neovascular AMD, and (separate analyses) large drusen.
Results: Over median follow-up of 10.2 years, of the 14 135 eyes, 32.7% progressed to late AMD. For 9 nutrients, intake quintiles 4 or 5 (vs. 1) were associated significantly (P ≤ 0.0005) with decreased risk of late AMD: vitamin A, vitamin B6, vitamin C, folate, β-carotene, lutein and zeaxanthin, magnesium, copper, and alcohol. For 3 nutrients, quintiles 4 or 5 were associated significantly with increased risk: saturated fatty acid, monounsaturated fatty acid, and oleic acid. Similar results were observed for GA. Regarding neovascular AMD, 9 nutrients were associated nominally with decreased risk-vitamin A, vitamin B6, β-carotene, lutein and zeaxanthin, magnesium, copper, docosahexaenoic acid, omega-3 fatty acid, and alcohol-and 3 nutrients were associated with increased risk-saturated fatty acid, monounsaturated fatty acid, and oleic acid. In separate analyses (n = 5399 eyes of 3164 AREDS participants), 12 nutrients were associated nominally with decreased risk of large drusen.
Conclusions: Higher dietary intake of multiple nutrients, including minerals, vitamins, and carotenoids, is associated with decreased risk of progression to late AMD. These associations are stronger for GA than for neovascular AMD. The same nutrients also tend to show protective associations against large drusen development. Strong genetic interactions exist for some nutrient-genotype combinations, particularly omega-3 fatty acids and CFH. These data may justify further research into underlying mechanisms and randomized trials of supplementation.
Folic acid, pyridoxine, and cyanocobalamin combination treatment and age-related macular degeneration in women: the Women's Antioxidant and Folic Acid Cardiovascular Study
William G Christen, Robert J Glynn, Emily Y Chew, Christine M Albert, Joann E Manson
Background: Observational epidemiologic studies indicate a direct association between homocysteine concentration in the blood and the risk of age-related macular degeneration (AMD), but randomized trial data to examine the effect of therapy to lower homocysteine levels in AMD are lacking. Our objective was to examine the incidence of AMD in a trial of combined folic acid, pyridoxine hydrochloride (vitamin B(6)), and cyanocobalamin (vitamin B(12)) therapy.
Methods: We conducted a randomized, double-blind, placebo-controlled trial including 5442 female health care professionals 40 years or older with preexisting cardiovascular disease or 3 or more cardiovascular disease risk factors. A total of 5205 of these women did not have a diagnosis of AMD at baseline and were included in this analysis. Participants were randomly assigned to receive a combination of folic acid (2.5 mg/d), pyridoxine hydrochloride (50 mg/d), and cyanocobalamin (1 mg/d) or placebo. Our main outcome measures included total AMD, defined as a self-report documented by medical record evidence of an initial diagnosis after randomization, and visually significant AMD, defined as confirmed incident AMD with visual acuity of 20/30 or worse attributable to this condition.
Results: After an average of 7.3 years of treatment and follow-up, there were 55 cases of AMD in the combination treatment group and 82 in the placebo group (relative risk, 0.66; 95% confidence interval, 0.47-0.93 [P = .02]). For visually significant AMD, there were 26 cases in the combination treatment group and 44 in the placebo group (relative risk, 0.59; 95% confidence interval, 0.36-0.95 [P = .03]).
Conclusions: These randomized trial data from a large cohort of women at high risk of cardiovascular disease indicate that daily supplementation with folic acid, pyridoxine, and cyanocobalamin may reduce the risk of AMD.
B Vitamins and Incidence of Advanced Age-Related Macular Degeneration: The Alienor Study
Bénédicte M. J. Merle, Stéphanie Barthes, Catherine Féart, Audrey Cougnard-Grégoire, Jean-François Korobelnik, Marie-Bénédicte Rougier, Marie-Noëlle Delyfer and Cécile Delcourt
B vitamins may protect against age-related macular degeneration (AMD). We evaluated the associations of dietary intake and serum vitamins with the incidence of advanced AMD in the Alienor study. The Alienor study is a prospective population-based cohort of 963 residents of Bordeaux, France, who were 73 years or older at baseline (2006–2008). Examinations were performed every two years over an eight-year period. The incidence of AMD is based on retinal fundus photographs and spectral-domain optical coherence tomography examinations. Among the 861 included participants, 93 developed incident AMD during a median follow-up time of 9.8 years. Participants with normal serum folate (≥10 nmol/L) significantly had a 51% reduced risk for AMD in the fully adjusted Cox model (HR, 0.49 [95% CI, 0.25–0.95], p = 0.036). Participants with a higher dietary intake of B5 and B6 vitamins had a lower risk for developing AMD of up to 28% (HR, 0.72 for 1-SD increase [0.53–0.99], p = 0.049; HR, 0.90 [0.81–0.99], p = 0.049, respectively). This cohort study of older adults suggests a strong association between a normal serum folate status, a high dietary intake of B5 and B6 and a lower risk for developing advanced AMD. Adopting a healthy diet rich in B vitamins may help to reduce vision loss due to AMD.
Nutritional and medical food therapies for diabetic retinopathy
Ce Shi, Peng Wang, Shriya Airen, Craig Brown, Zhiping Liu, Justin H Townsend, Jianhua Wang, Hong Jiang
Diabetic retinopathy (DR) is a form of microangiopathy. Reducing oxidative stress in the mitochondria and cell membranes decreases ischemic injury and end-organ damage to the retina. New approaches are needed, which reduce the risk and improve the outcomes of DR while complementing current therapeutic approaches. Homocysteine (Hcy) elevation and oxidative stress are potential therapeutic targets in DR. Common genetic polymorphisms such as those of methylenetetrahydrofolate reductase (MTHFR), increase Hcy and DR risk and severity. Patients with DR have high incidences of deficiencies of crucial vitamins, minerals, and related compounds, which also lead to elevation of Hcy and oxidative stress. Addressing the effects of the MTHFR polymorphism and addressing comorbid deficiencies and insufficiencies reduce the impact and severity of the disease. This approach provides safe and simple strategies that support conventional care and improve outcomes. Suboptimal vitamin co-factor availability also impairs the release of neurotrophic and neuroprotective growth factors. Collectively, this accounts for variability in presentation and response of DR to conventional therapy. Fortunately, there are straightforward recommendations for addressing these issues and supporting traditional treatment plans. We have reviewed the literature for nutritional interventions that support conventional therapies to reduce disease risk and severity. Optimal combinations of vitamins B1, B2, B6, L-methylfolate, methylcobalamin (B12), C, D, natural vitamin E complex, lutein, zeaxanthin, alpha-lipoic acid, and n-acetylcysteine are identified for protecting the retina and choroid. Certain medical foods have been successfully used as therapy for retinopathy. Recommendations based on this review and our clinical experience are developed for clinicians to use to support conventional therapy for DR. DR from both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) have similar retinal findings and responses to nutritional therapies.