Faculty Bibliography

There are nearly 65 million people with chronic heart failure (CHF) globally, with no treatment directed at the pathologic cause of the disease, the loss of functioning cardiomyocytes. We have an allogeneic cardiac patch comprised of cardiomyocytes and human fibroblasts on a bioresorbable matrix. This patch increases blood flow to the damaged heart and improves left ventricular (LV) function in an immune competent rat model of ischemic CHF. After 6 months of treatment in an immune competent Yucatan mini swine ischemic CHF model, this patch restores LV contractility without constrictive physiology, partially reversing maladaptive LV and right ventricular remodeling, increases exercise tolerance, without inducing any cardiac arrhythmias or a change in myocardial oxygen consumption. Digital spatial profiling in mice with patch placement 3 weeks after a myocardial infarction shows that the patch induces a CD45^pos immune cell response that results in an infiltration of dendritic cells and macrophages with high expression of macrophages polarization to the anti-inflammatory reparative M2 phenotype. Leveraging the host native immune system allows for the potential use of immunomodulatory therapies for treatment of chronic inflammatory diseases not limited to ischemic CHF.

PURPOSE/OBJECTIVE:The aim of this study was to report trends in keratoplasty techniques and indications in the United States from 2015 to 2020. METHODS:This retrospective review of annual reports from the Eye Bank Association of America assessed domestic corneal graft distribution and surgical indication data for various types of keratoplasty. Trends in procedure volume and indications from 2015 to 2020 were analyzed using the Cochran-Armitage test. RESULTS:The total number of corneal transplants increased from 47,903 in 2015 to 49,143 in 2019, with a decline to 42,257 in 2020, most likely due to COVID-19. Penetrating keratoplasty (PK) volume decreased from 2015 to 2020 (19,160-15,402, 40% to 36.4%, P < 0.001), continuing a trend from the previous decade. Descemet membrane endothelial keratoplasty as a percentage of all keratoplasty procedures increased (9.8%-27.8%, P < 0.001), whereas Descemet stripping automated endothelial keratoplasty (47%-33.9%, P < 0.001) and anterior lamellar keratoplasty (ALK) decreased (2.3%-1.2%, P < 0.001).From 2017 to 2020, repeat corneal transplant was the most common specific indication for PK while ectasias/thinnings decreased in prevalence (15.6%-11.5%, P < 0.001). Ectasias/thinnings and endothelial dystrophy remained the leading indications for ALK and endothelial keratoplasty, respectively. CONCLUSIONS:From 2015 to 2020, keratoplasty trends in the United States showed a continuation of the decrease in PK and increase in Descemet membrane endothelial keratoplasty observed in the previous decade. The most common domestic indications from 2017 to 2020 have been repeat corneal graft, endothelial dystrophy, and ectasias/thinnings for PK, EK, and ALK, respectively.

PURPOSE:To describe specific clinical, multimodal imaging, and natural history features of an unusual variant of acute zonal occult outer retinopathy. METHODS:Retrospective, observational, longitudinal, multicenter case series. Patients exhibiting this unusual clinical condition among cases previously diagnosed with acute zonal occult outer retinopathy were included. Multimodal imaging, laboratory evaluations, and genetic testing for inherited retinal diseases were reviewed. RESULTS:Twenty eyes from 10 patients (8 females and 2 males) with a mean age of 54.1 ± 13.3 years (range, 38-71 years) were included. The mean follow-up duration was 13.1 ± 5.3 years (range, 8-23 years). Presenting symptoms were bilateral in 7 patients (85% of eyes) and included scotomata and photopsia. All patients had bilateral lesions at presentation involving the peripapillary and far peripheral retina. Baseline optical coherence tomography showed alteration of the retinal pigment epithelium and photoreceptor layers corresponding to zonal areas of fundus autofluorescence abnormalities. Centrifugal and centripetal progression of the peripapillary and far-peripheral lesions, respectively, occurred over the follow-up, resulting in areas of complete outer retinal and retinal pigment epithelium atrophy. CONCLUSION:Initial alteration of photoreceptors and retinal pigment epithelium and a stereotypical natural course that includes involvement of the far retinal periphery, characterize this unusual condition. It may represent a variant of acute zonal occult outer retinopathy or may be a new entity. We suggest to call it multizonal outer retinopathy and retinal pigment epitheliopathy .

PURPOSE:To perform an unsupervised machine learning clustering of patients with punctate inner choroidopathy (PIC) and provide new insights into the significance of pachychoroid disease features in PIC eyes. METHODS:Retrospective multicenter study, including 102 eyes from 82 patients diagnosed with PIC. Demographics, clinical data, and multimodal imaging, including fundus photography, optical coherence tomography, and indocyanine green angiography, were collected. Clusters of eyes were identified, and multilevel logistic regression analysis was performed to compare between-group differences. RESULTS:Using 17 clinical features, two distinct clusters of patients with PIC were identified. Cluster 1 patients were characterized by older age, high myopia, myopic maculopathy features, thin choroids, multiple lesions, and a higher likelihood of developing patchy chorioretinal atrophy. Cluster 2 consisted of younger age, emmetropia or low myopia, thick choroids, choroidal vascular hyperpermeability on late-phase indocyanine green angiography, and high prevalence of focal choroidal excavation. These features exhibited significant differences ( P < 0.05) between the two clusters. CONCLUSION:While PIC typically affects young myopic female patients with thin choroids, a subset of patients with PIC exhibits features associated with pachychoroid disease. Considering the potential influence of choroidal venous insufficiency on PIC manifestations and secondary complications, we propose the term "punctate inner pachychoroidopathy" to characterize this distinct subtype of PIC.

BACKGROUND:Imaging indicators of macular neovascularization risk can help determine patient eligibility for new treatments for geographic atrophy secondary to age-related macular degeneration. Because type 1 macular neovascularization includes inflammation, we assessed by histology the distribution of cells with inflammatory potential in two fellow eyes with age-related macular degeneration. METHODS:Two eyes of a White woman in her 90's with type 3 macular neovascularization treated with antivascular endothelial growth factor were prepared for high-resolution histology. Eye-tracked spectral domain optical coherence tomography applied to the preserved donor eyes linked in vivo imaging to histology. Cells were enumerated in the intraretinal, subretinal, and subretinal retinal pigment epithelium (RPE)-basal lamina compartments on 199 glass slides. Cells with numerous organelles were considered to RPE-derived; cells with sparse RPE organelles were considered non-RPE phagocytes. RESULTS:Both eyes had soft drusen and abundant subretinal drusenoid deposit. In the retina and subretinal space, RPE-derived cells, including hyperreflective foci, were common (n = 125 and 73, respectively). Non-RPE phagocytes were infrequent (n = 5 in both). Over drusen, RPE morphology transitioned smoothly from the age-normal layer toward the top, suggesting transdifferentiation. The sub-RPE-basal lamina space had RPE-derived cells (n = 87) and non-RPE phagocytes (n = 49), including macrophages and giant cells. CONCLUSION:Numerous sub-RPE-basal lamina cells of several types are consistent with the documented presence of proinflammatory lipids in drusen and aged Bruch's membrane. The relatively compartmentalized abundance of infiltrating cells suggests that drusen contents are more inflammatory than subretinal drusenoid deposit, perhaps reflecting their environments. Ectopic RPE occurs frequently. Some manifest as hyperreflective foci. More cells may be visible as optical coherence tomography technologies evolve.

PURPOSE/UNASSIGNED:Fluid presence and dynamism is central to the diagnosis and management of neovascular age-related macular degeneration. On optical coherence tomography (OCT), some hyporeflective spaces arise through vascular permeability (exudation) and others arise through degeneration (transudation). Herein we determined whether the histological appearance of fluid manifested this heterogeneity. METHODS/UNASSIGNED:Two eyes of a White woman in her 90s with anti-vascular endothelial growth factor treated bilateral type 3 neovascularization secondary to age-related macular degeneration were osmicated, prepared for submicrometer epoxy resin sections, and correlated to eye-tracked spectral domain OCT. Examples of intraretinal tissue fluid were sought among similarly prepared donor eyes with fibrovascular scars, in a web-based age-related macular degeneration histopathology resource. Fluid stain intensity was quantified in reference to Bruch's membrane and the empty glass slide. RESULTS/UNASSIGNED:Exudative fluid by OCT was slightly reflective and dynamically responded to anti-vascular endothelial growth factor. On histology, this fluid stained moderately, possessed a smooth and homogenous texture, and contained blood cells and fibrin. Nonexudative fluid in degenerative cysts and in outer retinal tubulation was minimally reflective on OCT and did not respond to anti-vascular endothelial growth factor. By histology, this fluid stained lightly, possessed a finely granular texture, and contained mainly tissue debris. Quantification supported the qualitative impressions of fluid stain density. Cells containing retinal pigment epithelium organelles localized to both fluid types. CONCLUSIONS/UNASSIGNED:High-resolution histology of osmicated tissue can distinguish between exudative and nonexudative fluid, some of which is transudative. TRANSLATIONAL RELEVANCE/UNASSIGNED:OCT and histological features of different fluid types can inform clinical decision-making and assist in the interpretation of newly available automated fluid detection algorithms.

In this review we highlight emerging immune regulatory functions of lumican, keratocan, fibromodulin, biglycan and decorin, which are members of the small leucine-rich proteoglycans (SLRP) of the extracellular matrix (ECM). These SLRPs have been studied extensively as collagen-fibril regulatory structural components of the skin, cornea, bone and cartilage in homeostasis. However, SLRPs released from a remodeling ECM, or synthesized by activated fibroblasts and immune cells contribute to an ECM-free pool in tissues and circulation, that may have a significant, but poorly understood foot print in inflammation and disease. Their molecular interactions and the signaling networks they influence also require investigations. Here we present studies on the leucine-rich repeat (LRR) motifs of SLRP core proteins, their evolutionary and functional relationships with other LRR pathogen recognition receptors, such as the toll-like receptors (TLRs) to bring some molecular clarity in the immune regulatory functions of SLRPs. We discuss molecular interactions of fragments and intact SLRPs, and how some of these interactions are likely modulated by glycosaminoglycan side chains. We integrate findings on molecular interactions of these SLRPs together with what is known about their presence in circulation and lymph nodes (LN), which are important sites of immune cell regulation. Recent bulk and single cell RNA sequencing studies have identified subsets of stromal reticular cells that express these SLRPs within LNs. An understanding of the cellular source, molecular interactions and signaling consequences will lead to a fundamental understanding of how SLRPs modulate immune responses, and to therapeutic tools based on these SLRPs in the future.

BACKGROUND/UNASSIGNED:In properly selected patients, combined face and whole eye transplantation (FWET) may offer a more optimal aesthetic and potentially functional outcome while avoiding the complications and stigma of enucleation and prosthetics. This study presents the most comprehensive cadaveric assessment for FWET to date, including rehearsal allograft procurement on a brain-dead donor. METHODS/UNASSIGNED:Over a 2-year period, 15 rehearsal dissections were performed on 21 cadavers and one brain-dead donor. After identification of a potential recipient, rehearsals assessed clinical feasibility and enabled operative planning, technical practice, refinement of personalized equipment, and improved communication among team members. Operative techniques are described. RESULTS/UNASSIGNED:Facial allograft procurement closely followed previously described face transplant techniques. Ophthalmic to superficial temporal (O-ST) vessel anastomosis for globe survival was assessed. Craniectomy allowed for maximal optic nerve and ophthalmic vessel pedicle length. Appropriate pedicle length and vessel caliber for O-ST anastomosis was seen. Research procurement demonstrated collateral blood flow to the orbit and surrounding structures from the external carotid system as well as confirmed the feasibility of timely O-ST anastomosis. Personalized cutting guides enabled highly accurate bony inset. CONCLUSIONS/UNASSIGNED:This study formalizes an approach to FWET, which is feasible for clinical translation in judiciously selected patients. O-ST anastomosis seems to minimize retinal ischemia time and allow perfusion of the combined allograft on a single external carotid pedicle. Although restoration of vision likely remains out of reach, globe survival is possible.

OBJECTIVES/OBJECTIVE:To determine the relationship between treatment frequency with intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents and visual acuity (VA) outcomes in eyes with macular oedema (MO) secondary to branch retinal vein occlusion (BRVO) in US clinical practice. METHODS:Study eyes that initiated anti-VEGF injections between January 2012 and May 2016 were followed for ≥1 year in a retrospective analysis of medical records (Vestrum Health database). Eyes were analysed in 2 cohorts by treatment duration (years 1 and 2) and then in 2 subcohorts by injection frequency (≤6 or ≥7 injections/year). RESULTS:Among 3099 eyes with MO secondary to BRVO, 1197 (38.6%) received ≤6 injections (mean injections, 4.6; baseline mean VA, 53 letters) and 1902 (61.4%) received ≥7 injections through 1 year (mean injections, 8.8; baseline mean VA, 52 letters). At year 1, mean VA gain from baseline was 10.4 versus 13.9 letters in eyes receiving ≤6 versus ≥7 injections (p < 0.001). At year 2, mean VA in eyes receiving ≤6 (n = 42) versus ≥7 injections (n = 227) was 64 versus 68 letters, respectively (p = 0.19). Mean VA change between the start and end of year 2 in eyes receiving ≥7 injections in year 1 and ≤6 in year 2 differed significantly from that of eyes receiving ≥7 injections in both years (-3.0 vs 0.7 letters, respectively; p < 0.001). CONCLUSIONS:In routine clinical practice, more frequent dosing with anti-VEGF agents was associated with greater visual benefits in eyes with MO secondary to BRVO.