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F Semeraro,1 F Morescalchi,1 S Duse,1 F Parmeggiani,2 E Gambicorti,1 C Costagliola31Department of Medical and Surgical Specialties, Radiological Specialties and Public Health, Ophthalmology Clinic, University of Brescia, Brescia, Italy; 2Department of Ophthalmology, University of Ferrara, Ferrara, Italy; 3Department of Health Science, Ophthalmology Clinic, University of Molise, Campobasso, ItalyBackground: Vascular endothelial growth factor (VEGF) is a naturally occurring glycoprotein in the body that acts as a growth factor for endothelial cells. It regulates angiogenesis, enhances vascular permeability, and plays a major role in wet age-related macular degeneration. The consistent association between choroidal neovascularization and increased VEGF expression provides a strong reason for exploring the therapeutic potential of anti-VEGF agents in the treatment of this disorder. Blockade of VEGF activity is currently the most effective strategy for arresting choroidal angiogenesis and reducing vascular permeability, which is frequently the main cause of visual acuity deterioration. In recent years, a number of other molecules have been developed to increase the efficacy and to prolong the durability of the anti-VEGF effect. Aflibercept (EYLEA®; Regeneron Pharmaceutical Inc and Bayer), also named VEGF Trap-eye, is the most recent member of the anti-VEGF armamentarium that was approved by the US Food and Drug Administration in November 2011. Because of its high binding affinity and long duration of action, this drug is considered to be a promising clinically proven anti-VEGF agent for the treatment of wet maculopathy.Objective: This article reviews the current literature and clinical trial data regarding the efficacy and the pharmacological properties of VEGF-Trap eye and describes the possible advantages of its use over the currently used "older" anti-VEGF drugs.Methods: For this review, a search of PubMed from January 1989 to May 2013 was performed using the following terms (or combination of terms): vascular endothelial growth factors, VEGF, age-related macular degeneration, VEGF-Trap eye in wet AMD, VEGF-Trap eye in diabetic retinopathy, VEGF-Trap eye in retinal vein occlusions, aflibercept. Studies were limited to those published in English.Results and conclusion: Two Phase III clinical trials, VEGF Trap-eye Investigation of Efficacy and Safety in Wet AMD (VIEW) 1 and 2, comparing VEGF Trap-eye to ranibizumab demonstrated the noninferiority of this novel compound. The clinical equivalence of this compound against ranibizumab is maintained even when the injections are administered at 8-week intervals, which indicates the potential to reduce the risk of monthly intravitreal injections and the burden of monthly monitoring.Keywords: aflibercept, AMD, neovascularization, VEGF, VEGF inhibition, VEGF-Trap eye

Introduction : Intravitreal anti-VEGF is the most effective therapy for wet AMD, although systemic effects on the endothelium cannot be excluded. Areas covered : The purpose of this review was to evaluate risk of thromboembolic events associated with intravitreal anti-VEGF. Expert opinion : Current data are insufficient to confirm the safety of these compounds, due to the paucity of specific studies. Thus, pharmacovigilance for all anti-VEGF should be improved to verify the true role of anti-VEGF in the occurrence of systemic adverse events.

Background: The evaluation of the morphological characteristics of small resistance arteries in humans is challenging. The gold standard method is generally considered to be the measurement by wire or pressure micromyography of the media-to-lumen ratio of subcutaneous small vessels obtained by local biopsies. However, noninvasive techniques for the evaluation of retinal arterioles were recently proposed; in particular, two approaches, scanning laser Doppler flowmetry (SLDF) and adaptive optics, seem to provide useful information; both of them provide an estimation of the wall-to-lumen ratio (WLR) of retinal arterioles. Moreover, a noninvasive measurement of basal and total capillary density may be obtained by videomicroscopy/capillaroscopy. No direct comparison of these three noninvasive techniques in the same population was previously performed; in particular, adaptive optics was never validated against micromyography., Methods: In the current study, we enrolled 41 controls and patients: 12 normotensive lean controls, 12 essential hypertensive lean patients, nine normotensive obese patients and eight hypertensive obese patients undergoing elective surgery. All patients underwent a biopsy of subcutaneous fat during surgery. Subcutaneous small resistance artery structure was assessed by wire micromyography and the media-to-lumen ratio was calculated. WLR of retinal arterioles was obtained by SLDF and adaptive optics. Functional (basal) and structural (total) microvascular density was evaluated by capillaroscopy before and after venous congestion., Results and Conclusion: Our data suggest that adaptive optics has a substantial advantage over SLDF in terms of evaluation of microvascular morphology, as WLR measured with adaptive optics is more closely correlated with the M/L of subcutaneous small arteries (r = 0.84, P < 0.001 vs. r = 0.52, P < 0.05, slopes of the relations: P < 0.01 adaptive optics vs. SLDF). In addition, the reproducibility of the evaluation of the WLR with adaptive optics is far better, as compared with SLDF, as intraobserver and interobserver variation coefficients are clearly smaller. This may be important in terms of clinical evaluation of microvascular morphology in a clinical setting, as micromyography has substantial limitations in its clinical application due to the local invasiveness of the procedure.

Backgroud and Purpose: Wall-to-lumen ratio of retinal arterioles (W/L ratio) might serve as an in-vivo parameter of microvascular damage. No study has investigated the relationship between carotid stiffness and W/L ratio of retinal arteries. Therefore, the aim of the current study was to assess the correlation between local carotid stiffness, as assessed by echotracking technique, and W/L ratio of retinal arterioles, as assessed by noninvasive flowmetry in normotensive patients and in patients with primary hypertension., Methods: Two hundred and twenty-seven patients underwent renal arteries W/L ratio and local carotid-pulse wave velocity (carotid PWV) measurement. One hundred and fifteen patients had a diagnosis of primary hypertension, whereas 112 were normotensive patients., Results: W/L ratio and carotid PWV were both related with clinic SBP (r = 0.17, P < 0.05; r = 0.50, P < 0.001), clinic pulse pressure (r = 0.22, P < 0.001; r = 0.55, P < 0.001), carotid SBP (r = 0.18, P < 0.05; r = 0.51, P < 0.001) and carotid pulse pressure (r = 0.24, P < 0.001; r = 0.56, P < 0.001). W/L ratio was correlated with carotid PWV (r = 0.18, P < 0.005). At multivariate analysis, carotid PWV remained independently associated with W/L ratio., Conclusion: In hypertensive and normotensive patients, carotid stiffness is significantly correlated with W/L ratio of retinal arteries, independently of possible confounders.

Dihydropyridine calcium channel blockers may possess antioxidant properties, and might improve micro and macrovascular structure and function. Combination treatment with an ACE inhibitor may have additional advantages, compared with a thiazide diuretic. The aim of the present study is to investigate the effects of a short-term treatment with lercanidipine, and to compare two combination treatments: lercanidipine + enalapril vs. lercanidipine + hydrochlorothiazide on structural alterations in retinal arterioles, on skin capillary density and on large artery distensibility. Thirty essential hypertension patients are included in the study, and treated for 4 weeks with lercanidipine 20 mg per day orally. Then, they were treated for 6 months with lercanidipine + enalapril (n = 15) or lercanidipine + hydrochlorothiazide (n = 15) combinations. Investigations were performed on basal condition, after appropriate wash out of previous treatments, after 4 weeks of lercanidipine monotherapy treatment, and at the end of the combination treatment. Non-invasive measurements of wall-to-lumen ratio (WLR) and other morphological parameters of retinal arterioles were performed using either scanning laser Doppler flowmetry or adaptive optics. Capillary density was evaluated by capillaroscopy, while pulse wave velocity was measured, and central blood pressures were assessed by pressure waveform analysis. A significant improvement of WLR and other indices of retinal artery structure is observed with both technical approaches after treatment with lercanidipine alone, with a further improvement after treatment with lercanidipine + enalapril, while after treatment with lercanidipine + hydrochlorothiazide, the improvement is partially blunted. Central systolic and diastolic blood pressures are similarly reduced by both therapeutic strategies. Capillary density is increased only after treatment with lercanidipine + enalapril. In conclusion, lercanidipine both in monotherapy and in combination with enalapril but not with hydrochlorothiazide is able to improve microvascular structure; on the other hand, a decrease in central blood pressure is observed with both therapeutic combinations.

Background and Objective: Different components of the immune system, including innate and adaptive immunity (T effector lymphocytes and T regulatory lymphocytes - TREGs) may be involved in the development of hypertension, vascular injury and inflammation. However, no data are presently available in humans about possible relationships between T-lymphocyte subtypes and microvascular oxidative stress. Our objective was to investigate possible relationships between T-lymphocyte subtypes and systemic and microvascular oxidative stress in a population of normotensive subjects and hypertensive patients., Patients and Methods: In the present study we enrolled 24 normotensive subjects and 12 hypertensive patients undergoing an elective surgical intervention. No sign of local or systemic inflammation was present. All patients underwent a biopsy of subcutaneous fat during surgery. A peripheral blood sample was obtained before surgery for assessment of T lymphocyte subpopulations by flow cytometry and circulating indices of oxidative stress., Results: A significant direct correlation was observed between Th1 lymphocytes and reactive oxygen species (ROS) production (mainly in microvessels). Additionally, significant inverse correlations were observed between ROS and total TREGs, or TREGs subtypes. Significant correlations were detected between circulating indices of oxidative stress/inflammation and indices of microvascular morphology/Th1 and Th17 lymphocytes. In addition, a significant inverse correlation was detected between TREGs in subcutaneous small vessels and C reactive protein., Conclusions: Our data suggest that TREG lymphocytes may be protective against microvascular damage, probably because of their anti-oxidant properties, while Th1-Th17 lymphocytes seem to exert an opposite effect, confirming an involvement of adaptive immune system in microvascular damage.

Purpose: To compare visual and anatomical outcomes between half-dose photodynamic therapy (hd-PDT) and 689 nm laser therapy (689-LT) in chronic central serous chorioretinopathy (CSC)., Methods: Forty eyes of 40 patients with symptomatic chronic CSC were randomized in a 1:1 ratio to receive either hd-PDT or 689-LT delivering 95 J/cm 2 via an intensity application of 805 mW/cm 2 over 118 s. Best-corrected visual acuity (BCVA) and spectral-domain optical coherence tomography findings were compared between the two treatment groups., Results: Mean CSC duration was 17.1 ± 6.66 weeks and 18.7 ± 7.46 weeks in the hd-PDT and 689-LT groups respectively. Both groups showed significant BCVA improvements, as well as reductions in central retinal and subfoveal choroidal thickness. Although hd-PDT led to a faster reduction in central retinal thickness, no significant differences were recorded between groups for any other measured parameter at any time point. Complete photoreceptor recovery was observed in eight and seven eyes in the hd-PDT and 689-LT groups respectively., Conclusions: Both hd-PDT and 689-LT were effective at treating chronic CSC. Further studies are warranted to evaluate long-term safety and efficacy.

Background: Different components of the immune system, including innate and adaptive immunity (T-effector lymphocytes and T-regulatory lymphocytes-TREGs) may be involved in the development of hypertension. In addition, it was demonstrated in animal models that TREGs may prevent angiotensin II-induced hypertension and vascular injury/inflammation. However, no data are presently available in humans about possible relationships between T-lymphocyte subtypes and microvascular structural alterations., Methods: For this purpose, in the present study, we enrolled 24 normotensive subjects and 12 hypertensive patients undergoing an elective surgical intervention. No sign of local or systemic inflammation was present. All patients underwent a biopsy of subcutaneous fat during surgery. Subcutaneous small resistance arteries were dissected and mounted on a wire myograph and the media to lumen ratio (M/L) was calculated. In addition, retinal arteriolar structure was evaluated noninvasively by scanning laser Doppler flowmetry. Capillary density in the nailfold, dorsum of the finger, and forearm were evaluated by videomicroscopy. A peripheral blood sample was obtained before surgery for assessment of T-lymphocyte subpopulations by flow cytometry., Results: Significant negative correlations were observed between indices of microvascular structure (M/L of subcutaneous small arteries and wall to lumen ratio of retinal arterioles) and circulating TREG lymphocytes. A direct correlation was observed between M/L of subcutaneous small arteries and circulating Th17 lymphocytes. In addition, total capillary density was correlated with a TREG effector memory subpopulation., Conclusion: Our data suggest that some lymphocyte subpopulations may be related to microvascular remodeling, confirming previous animal data, and opening therapeutic possibilities., (© American Journal of Hypertension, Ltd 2016. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Surgical management of an idiopathic macular hole consists of vitrectomy to release vitreofoveal traction and intraocular tamponade to flatten and reappose the hole's edges. The intentional atraumatic removal of the internal limiting membrane has been proposed as cost-effective option in macular hole surgery. The internal limiting membrane contributes to tangential traction at the edges of the hole and acts as a platform on which glial cells proliferate. Removal of the internal limiting membrane increases the elasticity of the denuded macula and improves the anatomical success rate; however, the visual consequences of this surgical maneuver are still not fully known. We discuss the beneficial and adverse effects associated with internal limiting membrane peeling in macular hole surgery, highlighting the internal limiting membrane's role in macular hole etiology and pathogenesis and the anatomical and functional findings after its removal., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Pharmacologic vitreolysis is a strategy used to treat anomalous posterior vitreous detachment, by weakening vitreoretinal adhesion with an intravitreal drug. Pharmacologic vitreolysis facilitates surgery, and abnormalities of the vitreoretinal interface including vitreomacular traction (VMT) and early stage macular hole (MH) could be resolved. Ocriplasmin is a recombinant protease, active against fibronectin and laminin, which are important components of the vitreoretinal interface. Ocriplasmin has been approved for symptomatic treatment of VMT and MH with visible traction, and it functions by dissolving the proteins that link the vitreous to the macula, thereby creating a complete posterior vitreous detachment (PVD)., Areas Covered: This paper reviews the current knowledge and status of investigations regarding the use of ocriplasmin for pharmacologic vitreolysis and its safety., Expert Opinion: Ocriplasmin is a non-specific enzyme; therefore, it dissolves vitreal proteins as well as possibly proteins associated with visual function in the retina, choroid, and lens. Ocular adverse events (OAEs) of ocriplasmin include transient visual loss, intraocular inflammation, vitreous floaters, lens opacification, zonular instability of the lens, and intraocular hemorrhage. The prevalence of the OAEs is very low; however, on rare occasions, they can result in widespread retinal dysfunction. Research into the acute and long-term safety of ocriplasmin is required.

The inner limiting membrane (ILM) is the basement membrane of the Müller cells and can act as a scaffold for cellular proliferation in the pathophysiology of disorders affecting the vitreomacular interface. The atraumatic removal of the macular ILM has been proposed for treating various forms of tractional maculopathy in particular for macular pucker. In the last decade, the removal of ILM has become a routine practice in the surgery of the epiretinal membranes (ERMs), with good anatomical results. However many recent studies showed that ILM peeling is a procedure that can cause immediate traumatic effects and progressive modification on the underlying inner retinal layers. Moreover, it is unclear whether ILM peeling is helpful to improve vision after surgery for ERM. In this review, we describe the current understanding about ILM peeling and highlight the beneficial and adverse effects associated with this surgical procedure.

Introduction: Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly prescribed medications and are routinely used for their analgesic, antipyretic, and anti-inflammatory properties. Because of their potent cyclooxygenase-inhibitory activity, they can inhibit pro-inflammatory prostaglandin synthesis, leading to complex inflammatory cascades. NSAIDs have been broadly used systemically for many decades and have recently become commercially available in the form of topical ophthalmic formulations. NSAIDs are weak acids with pKa values mostly between 3.5 and 4.5 and are poorly water-soluble. New, aqueous ophthalmic solutions of NSAIDs that afford better tissue penetration have recently been developed. In ophthalmological practice, topical NSAIDs are mostly used to stabilize pupillary dilation during intraocular surgery, manage postoperative pain and inflammation, and treat pseudophakic cystoid macular edema., Areas Covered: This review focuses on the vitreous penetration of topical NSAIDs and their potential clinical applications in the treatment of retinal diseases., Expert Opinion: A growing body of evidence suggests that NSAIDs may be beneficial in the treatment of age-related macular degeneration, diabetic retinopathy, and ocular tumors. Recent studies from our group and other authors have shown that the vitreous levels of NSAID exceed the median inhibitory concentration, which can significantly decrease vitreous PGE2 levels.

Subretinal neovascularization and pathologic ocular angiogenesis are common causes of progressive, irreversible impairment of central vision, and dramatically affect quality of life. Anti-vascular endothelial growth factor (anti-VEGF) therapy has improved the quality of life for many patients with age-related macular degeneration, diabetic retinopathy, and other ocular diseases involving neovascularization and edema. In these pathologies, the inhibition of intraocular VEGF is the only therapy that can preserve vision. Four anti-VEGF drugs are currently used to treat ocular neovascularization; pegaptanib, ranibizumab, and aflibercept have been approved for this condition, while bevacizumab can be used off-label. Anti-VEGF therapy is administered regularly for many months or years because its suspension or discontinuation may cause recurrence of neovascularization. On the other hand, VEGF is necessary for the survival of retinal and choroidal endothelial cells. Experimental studies in animal models have shown that local inhibition of VEGF causes thinning and atrophy of the choriocapillaris and degeneration of photoreceptors, primarily cones. These studies combined with clinical experience indicated that prolonged VEGF inhibition could impair retinal function. Moreover, anti-VEGF compounds can cross the blood-retina barrier, enter the systemic circulation, and inhibit serum VEGF. Since circulating VEGF protects blood vessel integrity, prolonged anti-VEGF treatment could induce thromboembolic adverse events from vascular causes such as heart attack and stroke, and even death. The ocular dosing regimen and systemic toxicity of anti-VEGF compounds are therefore central concerns. A better understanding of this topic requires knowledge of the metabolism, tissue distribution, and clearance of anti-VEGF compounds. This manuscript reviews the properties of anti-VEGF compounds following intravitreal administration.

Structural alterations of subcutaneous small-resistance arteries are associated with a worse clinical prognosis in hypertension and non-insulin-dependent diabetes mellitus. The effects of the direct renin inhibitor aliskiren on microvascular structure were never previously evaluated. Therefore, we investigated the effects of aliskiren in comparison with those of an extensively used angiotensin-converting enzyme inhibitor, ramipril, on peripheral subcutaneous small-resistance artery morphology, retinal arteriolar structure, and capillary density in a population of patients with non-insulin-dependent diabetes mellitus. Sixteen patients with mild essential hypertension and with a previous diagnosis of non-insulin-dependent diabetes mellitus were included in the study. Patients were then randomized to 1 of the 2 active treatments (aliskiren 150 mg once daily, n=9; or ramipril 5 mg once daily, n=7). Each patient underwent a biopsy of the subcutaneous fat from the gluteal region, an evaluation of retinal artery morphology (scanning laser Doppler flowmetry), and capillary density (capillaroscopy), at baseline and after 1 year of treatment. Subcutaneous small arteries were dissected and mounted on a pressurized micromyograph, and the media-to-lumen ratio was evaluated. A similar office blood pressure-lowering effect and a similar reduction of the wall-to-lumen ratio of retinal arterioles were observed with the 2 drugs. Aliskiren significantly reduced media-to-lumen ratio of subcutaneous small-resistance arteries, whereas ramipril-induced reduction of media to lumen ratio was not statistically significant. No relevant effect on capillary density was observed. In conclusion, treatment with aliskiren or ramipril was associated with a correction of microvascular structural alterations in patients with non-insulin-dependent diabetes mellitus., (© 2014 American Heart Association, Inc.)

Introduction: Anti-VEGF therapy improved the quality of life for millions of patients suffering from wet age-related macular degeneration (wet-AMD); unfortunately, this therapy involves multiple injections over many years. The administration of anti-VEGF can overcome the blood-retinal barrier with agents entering the systemic circulation and causing a significant decrease in VEGF serum concentration. Although circulating VEGF protects the integrity and patency of vessels, prolonged anti-VEGF treatment has the potential to increase the risk of thromboembolic events., Areas Covered: In this review, we discuss the safety data from recent trials involving available anti-VEGF drugs., Expert Opinion: During the 2 years of follow-up in the relevant clinical trials, the rates of serious adverse events such as stroke, heart attack and death were similar for patients treated with different anti-VEGF drugs. Moreover the arterial thrombotic risk appears sufficiently low when compared with the natural incidence of arterial thrombotic events in this category of elderly patients and acceptably balanced against the advantage of improved vision. Since the use of these drugs is likely to become increasingly widespread and prolonged, it is desirable that the scientific community improves the pharmacovigilance program on all anti-VEGF drugs, expanding knowledge with studies that compares head to head all four compounds belonging to anti-VEGF armamentarium.

Wall-to-lumen ratio of retinal arterioles might serve as an in vivo parameter of vascular damage. We analyzed the impact of brachial clinic blood pressure (BP), of central BP, and of 24-hour BP on wall-to-lumen ratio (WLR) of retinal arterioles. In 295 subjects (147 men; age range, 22-72 years; mean age, 54±7 years), WLR of retinal arterioles was assessed in vivo using scanning laser Doppler flowmetry. In addition, clinic and 24-hour BP values were measured. Central hemodynamics was assessed by pulse wave analysis. In treated patients with essential hypertension (n=100), a higher WLR (0.29±0.18 versus 0.23±0.13; P=0.009) was observed in comparison with normotensive individuals (n=119); no significant differences were observed between treated and untreated hypertensive patients (0.29±0.18 versus 0.28±0.18; P=0.7). WLR of retinal arterioles was significantly related to clinic systolic (r=0.18; P=0.002) and pulse pressure (r=0.20; P=0.001), to 24-hour systolic (r=0.25; P=0.0001) and pulse pressure (r=0.17; P=0.005), and to central systolic (r=0.16; P=0.006) and pulse pressure (r=0.18; P=0.002). Multiple regression analysis revealed that only mean systolic 24-hour BP was independently associated with an increased WLR of retinal arterioles. In this large group of hypertensive patients and normotensive individuals, 24-hour systolic BP seems to be the strongest determinant of increased WLR of retinal arterioles.