October 2014
Volume 55, Issue 10
Letters to the Editor  |   October 2014
Author Response: Geographic Atrophy and Cardiovascular Disease
Author Notes
Investigative Ophthalmology & Visual Science October 2014, Vol.55, 6263-6264. doi:https://doi.org/10.1167/iovs.14-15598
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      Monika Fleckenstein, Steffen Schmitz-Valckenberg, Frank G. Holz; Author Response: Geographic Atrophy and Cardiovascular Disease. Invest. Ophthalmol. Vis. Sci. 2014;55(10):6263-6264. doi: https://doi.org/10.1167/iovs.14-15598.

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      © ARVO (1962-2015); The Authors (2016-present)

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We are very grateful for Dr Smith's 1 important comments on our article 2 on a specific subtype of geographic atrophy (GA), the so-called “diffuse-trickling” phenotype. We demonstrated, among other findings, that this GA phenotype compared with other GA variants, has a significantly younger age of onset and a significantly higher rate of myocardial infarction (MI) in the age group younger than 65. Further evaluation revealed that in the age group younger than 65, 54% of patients with “diffuse trickling” had been hospitalized due to cardiovascular diseases (CVD), including hypertensive crisis, angina, and MI. Furthermore, analysis of subfoveal choroidal thickness (SCT) revealed a significantly thinner SCT in “diffuse-trickling” compared with “non–diffuse-trickling” GA. We concluded that the results may indicate an association of “diffuse-trickling” GA with systemic CVD in the younger study population, and that together with the ocular morphological characteristics, including a lobular appearance and a thin choroid, a vascular insufficiency at the level of the choroid may play a pathogenetic role in this distinct GA phenotype. 
Theodore Smith 1 in his comment emphasizes the possible role of choroidal insufficiency in the pathogenesis of specific phenotypic manifestations of macular degeneration. Theodore Smith and coworkers have made essential contributions in the area of dry AMD and reticular pseudodrusen (RPD) (they introduced the term “reticular macular disease”), and in his comment he highlights their important findings regarding the relationship between RPD, choroidal compromise, CVD, and GA. 1  
In 2009, Dr Smith and coworkers 3 confirmed the observation of indocyanine green (ICG) angiography hypofluorescence topographically corresponding to RPD as initially reported by Arnold et al. 4 They verified that the ICG lesions were in precise registration with the RPD and with the lesions of reticular fundus autofluorescence. These findings implicated choriocapillaris in addition to potential RPE involvement as suggested by fundus autofluorescence findings. In their comprehensive review in 2012, they hypothesized that the reticular pattern identified as “reticular macular disease” in different imaging modalities is related to an alteration in choriocapillaris blood flow. 5 Furthermore, they reported significantly more hypertension among men with RPD than without RPD, and a trend to more angina among all subjects with RPD than without RPD, and more angina among women with RPD than without RPD, whereas no significant differences were found with respect to smoking history, MI, or diabetes. 6 Later they reported on a greater frequency of hypertension in patients with RPD without large soft drusen as compared with patients with large soft drusen without RPD. 7  
Interestingly, in our study we found, as an incidental finding, that patients with “diffuse-trickling” GA always showed the presence of RPD. However, we would not share the view that the “diffuse-trickling” phenotype is a “severe manifestation” or continuum of “reticular macular disease.” There is increasing evidence that RPD represents a nonspecific finding that has been noted in association also with retinal diseases other than exudative and nonexudative AMD (e.g., pseudoxanthoma elasticum). 8 Herein, “diffuse trickling” can be clearly distinguished from other diseases/GA phenotypes by means of retinal imaging. 9,10  
We further would like to point out that “multilobular” (or multifocal) GA in AMD does not necessarily indicate the “diffuse-trickling” phenotype, although there is resemblance at first glance. In fact, a recent analysis of the Fundus Autofluorescence in Age-related Macular Degeneration (FAM) Study (ClinicalTrials.gov Identifier: NCT00393692) database revealed that 71.5% of eyes with GA had a “multifocal” configuration, whereas only 13.2% exhibited the “diffuse-trickling” phenotype (unpublished data, 2014). The presence of RPD in 65.1% of GA eyes in the FAM study cohort (unpublished data, 2014) and 62% of patients with GA in the Natural History of Geographic Atrophy Progression (GAP) Study (ClinicalTrials.gov Identifier: NCT00599846), 11 irrespective of the GA subtype, further points to a more complex relationship between RPD and phenotypic variants of GA. 
The purpose of the current study was to compare demographics, choroidal thickness, and the association with CVD between “diffuse-trickling” GA and other GA subtypes. Herein, the “non–diffuse-trickling” group also included eyes with RPD and/or multifocal GA. Therefore, we cannot conclude an association of CVD and RPD based on our data. However, the finding that eyes with the “diffuse-trickling” phenotype analyzed in this study always presented with RPD may further underscore a potential link between choroidal perfusion and RPD as highlighted and proposed early on by Theodore Smith and coworkers. 5  
Smith RT. Geographic atrophy and cardiovascular disease. Invest Ophthalmol Vis Sci . 2014; 55: 6262. [CrossRef] [PubMed]
Fleckenstein M Schmitz-Valckenberg S Linder M The “diffuse-trickling” fundus autofluorescence phenotype in geographic atrophy. Invest Ophthalmol Vis Sci . 2014; 55: 2911–2920. [CrossRef] [PubMed]
Smith RT Sohrab MA Busuioc M Barile G. Reticular macular disease. Am J Ophthalmol . 2009; 148: 733–743.e2. [CrossRef] [PubMed]
Arnold JJ Quaranta M Soubrane G Sarks SH Coscas G. Indocyanine green angiography of drusen. Am J Ophthalmol . 1997; 124: 344–356. [CrossRef] [PubMed]
Martillo MA Marsiglia M Lee MD Pumariega N Bearelly S Smith RT. Is reticular macular disease a choriocapillaris perfusion problem? Med Hypothesis Discov Innov Ophthalmol . 2012; 1: 37–41. [PubMed]
Smith RT Merriam JE Sohrab MA Complement factor H 402H variant and reticular macular disease. Arch Ophthalmol . 2011; 129: 1061–1066. [CrossRef] [PubMed]
Boddu S Lee MD Marsiglia M Marmor M Freund KB Smith RT. Risk factors associated with reticular pseudodrusen versus large soft drusen. Am J Ophthalmol . 2014; 157: 985–993.e2. [CrossRef] [PubMed]
Zweifel SA Imamura Y Freund KB Spaide RF. Multimodal fundus imaging of pseudoxanthoma elasticum. Retina . 2011; 31: 482–491. [CrossRef] [PubMed]
Holz FG Bindewald-Wittich A Fleckenstein M Dreyhaupt J Scholl HP Schmitz-Valckenberg S. Progression of geographic atrophy and impact of fundus autofluorescence patterns in age-related macular degeneration. Am J Ophthalmol . 2007; 143: 463–472. [CrossRef] [PubMed]
Fleckenstein M Schmitz-Valckenberg S Martens C Fundus autofluorescence and spectral-domain optical coherence tomography characteristics in a rapidly progressing form of geographic atrophy. Invest Ophthalmol Vis Sci . 2011; 52: 3761–3766. [CrossRef] [PubMed]
Schmitz-Valckenberg S Alten F Steinberg JS Reticular drusen associated with geographic atrophy in age-related macular degeneration. Invest Ophthalmol Vis Sci . 2011; 52: 5009–5015. [CrossRef] [PubMed]

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