Quantifying cardiac dysfunction and valvular heart disease associated with subretinal drusenoid deposits in age-related macular degeneration.

BACKGROUND/AIMS: Demonstrate through objective multidisciplinary imaging that subretinal drusenoid deposits (SDDs) in age-related macular degeneration (AMD) are linked to both coexistent valvular heart disease (VHD) and reduced systemic perfusion via cardiac index (CI). METHODS: Post-hoc analysis of cross-sectional study. 200 intermediate AMD (iAMD) subjects were assigned by masked readers to two groups: SDD (with or without drusen) and drusen (only) based on multimodal ophthalmic imaging. 65 transthoracic echocardiograms (TTEs) reports were available for cardiologist evaluation of VHD severity of the four cardiac valves and the presences of precursor lesions of aortic sclerosis (ASc) and mitral annular calcification (MAC). Necessary parameters to calculate CI were also obtained. Univariate testing was performed using Fisher's Exact test and t-test. RESULTS: 82.6% (19/23) of the iAMD subjects with at least one moderate/severe VHD had concurrent SDDs (p = 0.0040). All cases of aortic regurgitation (6/6, p = 0.0370) and mitral regurgitation (13/13, p = 0.0004) were found with coexisting SDDs. Stenotic VHD was not significantly associated with SDDs, however 70.7% of subjects with ASc (29/41, p = 0.0108) and 76.0% of subjects with MAC (19/25, 0.0377) had coexisting SDDs. CI was available in 48 subjects and was significantly below normal levels in the SDD cohort (mean CI SDD 1.95 ± 0.60 L/min/m2, non-SDD 2.71 ± 0.73 L/min/m2, p = 0.0004). CONCLUSIONS: Several specific VHDs have been found associated with the SDD form of AMD. Decreased systemic perfusion as measured by CI was also associated with SDDs, which supports a perfusion hypothesis of SDD pathogenesis. Further research is warranted to understand the relationship between cardiovascular disease and SDDs.

Correlation between ellipsoid zone thickness and the presence of subretinal drusenoid deposits in age-related macular degeneration.

PURPOSE: Subretinal drusenoid deposits (SDDs) in age-related macular degeneration (AMD) are associated with systemic vascular diseases that compromise ocular perfusion. We demonstrate that SDDs are associated with decreased ellipsoid zone (EZ) thickness, further evidence of hypoxic damage. METHODS: Post hoc analysis of a cross-sectional study. 165 AMD subjects (aged 51-100; 61% women). Spectral-domain optical coherence tomography was obtained in both eyes. Masked readers assigned subjects to three groups: drusen only, SDD+drusen (SDD+D) and SDD only. EZ thickness was measured subfoveally and 2000 µm nasally, temporally, superiorly and inferiorly from the fovea. Univariate testing was performed using two-tailed t-tests with Bonferroni correction. RESULTS: The mean EZ thickness differences between the SDD+D and drusen-only groups were (in µm) 1.10, 0.67, 1.21, 1.10 and 0.50 at the foveal, nasal, temporal, superior and inferior locations, respectively (p=0.08 inferiorly, otherwise p≤0.01); between the SDD-only and drusen-only groups, the differences were 3.48, 2.48, 2.42, 2.08 and 1.42 (p≤0.0002). Differences in EZ thicknesses across all subjects and between groups were not significantly different based on gender, race or age. CONCLUSION: Subjects with SDDs (±drusen) had thinner EZs than those with drusen only, and the inferior EZ was least affected. EZs were thinnest in SDD-only subjects. This thinning gradation is consistent with progressive destruction of highly oxygen-sensitive mitochondria in the EZ from hypoxia. These findings support the reduced ophthalmic perfusion hypothesis for the formation of SDDs secondary to high-risk systemic vasculopathy.

Internal Carotid Artery Stenosis and Ipsilateral Subretinal Drusenoid Deposits.

Purpose: Subretinal drusenoid deposits (SDDs) in age-related macular degeneration (AMD) are strongly associated with vasculopathies such as myocardial infarction and ischemic stroke. This study evaluates ischemic stroke subjects for SDDs to determine whether ocular hypoperfusion from internal carotid artery (ICA) stenosis is associated with ipsilateral SDDs. Methods: A cross-sectional study at Mount Sinai Hospital recruited 39 subjects with ischemic stroke (aged 52-90; 18 women, 21 men); 28 completed all study procedures. Computed tomography (CT) of the head and neck evaluated 54/56 ICAs for stenosis criteria: none (n = 33), mild (n = 12), moderate (n = 3), severe (n = 3), and complete (n = 3). Spectral-domain optical coherence tomography (SD-OCT) scans were read to consensus by two masked graders for soft drusen, SDDs and choroidal thickness (CTh; choroidal thinning = CTh < 250 µm). Univariate testing was done with Fisher's exact test. Multivariate logistic regression models tested age, gender, and ICA stenosis as covariates. Results: Moderate or more ICA stenosis (≥50%-69%) was significantly associated with ipsilateral choroidal thinning (P = 0.021) and ipsilateral SDDs (P = 0.005); the latter were present distal to six of nine stenosed ICAs versus five of 33 normal ICAs. Mild ICA stenosis (≥1%-49%) was not significantly associated with ipsilateral SDDs. Multivariate regression found that older age (P = 0.015) and moderate or more ICA stenosis (P = 0.011) remained significant independent risks for ipsilateral SDDs. Conclusions: At least moderate ICA stenosis (≥50%-69%) is strongly associated with ipsilateral SDDs and choroidal thinning, supporting downstream ophthalmic artery and choroidal hypoperfusion from ICA stenosis as the mechanism for SDD formation. SDDs may thus serve as sensitive biomarkers for ischemic stroke and other vascular diseases.

Subretinal drusenoid deposits, age-related macular degeneration, and cardiovascular disease.

Decades of studies on age-related macular degeneration (AMD), cardiovascular disease and stroke have not found consistent associations between AMD and systemic vascular disease. This study suggests that there is in fact no general relationship, but instead a strong, specific association between only the subretinal drusenoid deposit (SDD) phenotype of AMD on retinal imaging and certain co-existent vascular diseases that are high risk for compromised cardiac output or internal carotid artery stenosis. Future screening initiatives for these high -risk vascular diseases (HRVDs) with fast, inexpensive retinal imaging could make a significant contribution to public health and save lives. Likewise, screening patients with known HRVDs for unrecognized AMD of the SDD form could enable needed treatment and save vision.

SUBRETINAL DRUSENOID DEPOSITS AND SOFT DRUSEN: Are They Markers for Distinct Retinal Diseases?

PURPOSE: Soft drusen and subretinal drusenoid deposits (SDDs) characterize two pathways to advanced age-related macular degeneration (AMD), with distinct genetic risks, serum risks, and associated systemic diseases. METHODS: One hundred and twenty-six subjects with AMD were classified as SDD (with or without soft drusen) or non-SDD (drusen only) by retinal imaging, with serum risks, genetic testing, and histories of cardiovascular disease (CVD) and stroke. RESULTS: There were 62 subjects with SDD and 64 non-SDD subjects, of whom 51 had CVD or stroke. SDD correlated significantly with lower mean serum high-density lipoprotein (61 ± 18 vs. 69 ± 22 mg/dL, P = 0.038, t-test), CVD and stroke (34 of 51 SDD, P = 0.001, chi square), ARMS2 risk allele (P = 0.019, chi square), but not with CFH risk allele (P = 0.66). Non-SDD (drusen only) correlated/trended with APOE2 (P = 0.032) and CETP (P = 0.072) risk alleles (chi square). Multivariate independent risks for SDD were CVD and stroke (P = 0.008) and ARMS2 homozygous risk (P = 0.038). CONCLUSION: Subjects with subretinal drusenoid deposits and non-SDD subjects have distinct systemic associations and serum and genetic risks. Subretinal drusenoid deposits are associated with CVD and stroke, ARMS2 risk, and lower high-density lipoprotein; non-SDDs are associated with higher high-density lipoprotein, CFH risk, and two lipid risk genes. These and other distinct associations suggest that these lesions are markers for distinct diseases.

Quantitative and qualitative spectral domain optical coherence tomography analysis of subretinal deposits in patients with acute central serous retinopathy.

PURPOSE: To perform qualitative and quantitative analyses of subretinal protein deposits (PDs), seen in acute central serous retinopathy (CSR) patients, using high-resolution spectral domain optical coherence tomography (SD-OCT), in order to investigate whether the present PDs have any significant impact on best corrected visual acuity (BCVA). METHODS: Patients diagnosed with acute CSR were included. Using SD-OCT, the following distances/heights were measured: central total retinal thickness, central neurosensory retinal thickness, the vertical and horizontal length of subfoveal subretinal fluid and subfoveal thickness of the PD layer, if present and could be measured. RESULTS: Thirty-eight patients with acute CSR were included. A significant correlation was found between the subfoveal thickness of the PD layer and baseline/final visual acuities in the eyes (r = 0.60, p ≤ 0.001 and r = 0.45, p = 0.008, respectively). CONCLUSIONS: The thickness of subfoveal PDs at baseline appears to be an important parameter related to the BCVA and time of CSR resolution.

Suggestive association between PLA2G12A single nucleotide polymorphism rs2285714 and response to anti-vascular endothelial growth factor therapy in patients with exudative age-related macular degeneration.

PURPOSE: The use of anti-vascular endothelial growth factor (anti-VEGF) therapy, with drugs such as ranibizumab and bevacizumab, to treat neovascular age-related macular degeneration (nAMD) produces an effective but widely variable response. Identifying markers that predict differentiated response could serve as a valuable assay in developing more personalized medicine. This study aimed to identify single nucleotide polymorphisms (SNPs) that influence the outcome of treatment with anti-VEGF therapy for AMD. METHODS: One hundred six patients with nAMD were treated with either ranibizumab or bevacizumab as needed over a period of 12 months. Visual acuity and the presence of macular fluid were measured with optical coherence tomography at baseline, six months, and 12 months. Patients were then classified as good or poor responders based on change in visual acuity and macular fluid on follow-up visits. DNA extracted from blood was genotyped with a TaqMan-based allelic discrimination SNP assay for 21 SNPs in six candidate genes (PLAG12A, IL23R, STAT3, VEGFA, KDR, and HIF1A). The SNPs were primarily selected based on previously reported associations with AMD and functional involvement in angiogenesis pathways. SNPs shown to be promising for association with anti-VEGF therapy were then assessed in an independent AMD case-control cohort. RESULTS: Of the 106 patients with nAMD, 77 were classified as good responders and 29 as poor responders. For rs2285714 (PLA2G12A), the frequency of minor allele T was 40.1% for good responders compared to 51.7% for poor responders (odds ratio: 1.60, 95% confidence interval of odds ratio: 0.87-2.94, p=0.13). Genetic model analysis of rs2285714 (PLA2G12A) demonstrated an association between rs2285714 (PLA2G12A) and therapy response in a dominant genotypic model. Patients carrying at least one T allele of rs2285714 were 2.79 times (95% confidence interval=1.02-7.69, p<0.05) more likely to be poor responders (79.3% of poor responders) than good responders (57.3% of good responders). However, after adjusting for multiple testing by the false discovery rate or Bonferroni correction, the initially observed association was no longer statistically significant. No association was identified between the remaining SNPs and response status. The SNP rs2285714 of PLA2G12A was not significantly associated with AMD in an independent AMD case-control cohort. CONCLUSIONS: Data suggest a possible weak association between rs2285714 (PLA2G12A) and response to anti-VEGF therapy, but the association must be confirmed in additional cohorts with larger patient samples. Identifying factors that predict the differentiated response could provide a valuable assay for developing approaches in personalized medicine.

Qualitative spectral OCT/SLO analysis of drusen change in dry age-related macular degeneration patients treated with Copaxone.

PURPOSE: High-resolution spectral domain OCT/SLO (SD-OCT) has become an increasingly useful tool for differentiating drusen morphologic parameters such as shape, internal reflectivity, homogeneity, and presence of overlying hyperreflective foci. Our purpose was to evaluate which types of drusen may respond to Copaxone (glatiramer acetate) treatment of dry age-related macular degeneration (AMD) patients by shrinking or disappearing. METHODS: A prospective and interventional clinical trial of patients with dry AMD who received subcutaneous treatment with Copaxone or sham injections was conducted. SD-OCT images were used for analysis of drusen ultrastructure. Morphologic characteristics for specific drusen within the macular region were assessed with serial studies. Pre- and posttreatment statuses of drusen were compared. Main outcome measure was a change of drusen morphologic parameters in Copaxone-treated and sham-treated dry AMD patients between baseline and 12 weeks of treatment. RESULTS: Three hundred eleven drusen from 26 eyes of 14 dry AMD patients were evaluated. One hundred seventy-two drusen from 14 eyes (7 patients) of Copaxone-treated and 139 drusen from 12 eyes sham-treated (7 patients) were included. Overall, between baseline and 12-week visit, the percentage of drusen that disappeared/shrank in the Copaxone-treated group was 19.2% versus 6.5% in the sham-treated group (P = 0.13). The percentage of convex drusen that shrank or disappeared after 12 weeks of treatment was significantly higher in the Copaxone-treated group (27.8%) in comparison with the sham-treated group (6.8%) (P = 0.008). The difference between the groups was found to be statistically significant for drusen with low and medium internal reflectivity (P = 0.019 and P = 0.036, respectively). CONCLUSIONS: Convex shape and low/medium internal reflectivity were found to be favorable parameters in prediction of drusen reduction in the Copaxone-treated patients. This study represents a preliminary attempt to identify SD-OCT features of drusen that may predict susceptibility to Copaxone treatment and therefore help clinicians decide which patients to treat.

Urinary 6-sulfatoxymelatonin level in age-related macular degeneration patients.

PURPOSE: Melatonin is a potent antioxidant and free radical scavenger. It has been reported that serum melatonin level is relevant to certain aging diseases. The purpose of this study was to investigate melatonin levels in age-related macular degeneration (AMD) patients by measurement of 6-sulfatoxymelatonin levels (aMT6s), the major metabolite of melatonin in urine, and compare it with a group of age- and gender-matched controls. METHODS: The first urine of the morning was collected from 43 AMD patients and 12 controls who did not have AMD. The level of aMT6s in specimens was measured by a commercial 6-sulfatoxymelatonin ELISA kit. The assay was performed by researchers, who were masked to the clinical information. To adjust for variation in the diluteness of urine, urinary creatinine level was measured and aMT6s levels were expressed as aMT6s/creatinine. RESULTS: The level of urinary aMT6s/creatinine (mean+/-SD) in AMD (6.24+/-3.45 ng aMT6s/mg creatinine) was significantly lower than that of the controls (10.40+/-4.51, p=0.0128). After adjustment for various factors (age, smoking, cancer, and coronary heart disease) that may influence the aMT6s level, the odds-ratio of urinary aMT6s comparing AMD patients to controls was 0.65 (95% confidence interval=0.48-0.88, p=0.0036), indicating that urinary aMT6s level in AMD patients was lower than in controls even after multivariate adjustment. CONCLUSIONS: Urinary aMT6s level in AMD patients was 40% lower than in age- and gender-matched controls. This difference between AMD patients and controls is present after adjustment for the factors of age, smoking, and histories of cancer and coronary heart disease. The significance of this result and the role of melatonin in the occurrence of AMD require further investigation.