Participants in the Multi-Ethnic Study of Atherosclerosis (MESA) with age-related macular degeneration (AMD), computed tomography (CT) scans, and spirometry.
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Klein R, Knudtson MD, Klein BEK, Wong TY, Cotch MF, Barr G. Emphysema, Airflow Limitation, and Early Age-Related Macular Degeneration. Arch Ophthalmol. 2010;128(4):472–477. doi:10.1001/archophthalmol.2010.25
Copyright 2010 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2010
To describe the associations of lung function and emphysema, measured with spirometry and computed tomography (CT), with early age-related macular degeneration (AMD) in a sample of white, black, Hispanic, and Chinese subjects.
Three thousand three hundred ninety-nine persons aged 45 to 84 years residing in 6 US communities participated in a period cross-sectional study. Age-related macular degeneration was measured from digital retinal photographs at the second Multi-Ethnic Study of Atherosclerosis (MESA) examination. Forced expiratory volume in 1 second (FEV1) and FEV1 to forced vital capacity (FVC) ratio were measured at the third or fourth MESA examination. Percent emphysema was measured from cardiac CT scans at baseline. Apical and basilar lung segments were defined as the cephalad or caudal regions of the lung on the cardiac CT scan. Logistic regression models were used to examine the association of lung function and structure with AMD, controlling for age, sex, and other factors.
The prevalence of early AMD was 3.7%. Early AMD was not associated with FEV1 (odds ratio [OR], 0.82; 95% confidence interval [CI], 0.58-1.15; P = .25), FEV1:FVC ratio (OR, 0.92; 95% CI, 0.76-1.12; P = .43), percent emphysema (OR, 1.13; 95% CI, 0.91-1.40; P = .26), and apical-basilar difference in percent emphysema (OR, 1.14; 95% CI, 0.95-1.37; P = .17). Associations were stronger in smokers. Apical-basilar difference in percent emphysema was significantly associated with early AMD among those who ever smoked (OR, 1.28; 95% CI, 1.02-1.60; P = .03). Associations were not modified by race/ethnicity.
Lung function and emphysema on CT scan were not cross-sectionally associated with AMD; this might be explained by the relatively low smoking exposure in this cohort.
Age-related macular degeneration (AMD) is an important cause of visual loss in Americans 65 years of age or older.1 Its pathogenesis remains poorly understood. Aside from age, smoking, and genetic factors, few risk factors have been found to be consistently associated with this condition in epidemiological studies.1-3 Two population-based studies have reported poorer respiratory function and a history of physician diagnosis of emphysema to be associated with the risk of AMD.4-6 In the Framingham Eye Study, decreased forced vital capacity (FVC) and a history of pulmonary symptoms were associated with AMD.4 In the Beaver Dam Eye Study, a self-reported history of emphysema at baseline was associated with the 15-year incidence of retinal pigment epithelium (RPE) depigmentation and exudative AMD (odds ratio [OR], 3.0; 95% confidence interval [CI], 1.0-8.4; P = .04).6 These associations were independent of smoking and other factors.
These findings were hypothesized to be related to systemic inflammation and/or decreased oxygenation associated with chronic obstructive pulmonary disease (COPD). However, 2 prior case-control studies failed to find such relationships,7,8 possibly owing to problems with the ascertainment of COPD. Given the growing recognition of the role of inflammation and genes involved in inflammatory regulation in the development and progression of AMD and COPD, we examined the associations of functional measures of obstructive lung disease on spirometry and anatomical measures of percent emphysema on computed tomography (CT) scans with signs of AMD in the Multi-Ethnic Study of Atherosclerosis (MESA).
The MESA is a prospective cohort study of men and women aged 45 to 85 years without a history of clinical cardiovascular disease (CVD) living in 6 US communities.9 The objectives of MESA were to identify risk factors for subclinical CVD, progression of subclinical CVD, and transition from subclinical to clinical CVD. Selection of the study population has been reported in detail elsewhere.9 At the first examination, carried out from July 17, 2000, to August 29, 2002, there were 6814 participants: 1086 from Baltimore, Maryland, 1164 from Chicago, Illinois, 1077 from Forsyth County, North Carolina, 1319 from Los Angeles County, California, 1102 from New York, New York, and 1066 from St Paul, Minnesota. Tenets of the Declaration of Helsinki were followed, and institutional review board approval was granted at each study site. Written informed consent was obtained from each participant.
Fundus photography using a 45°, 6.3-megapixel, nonmydriatic digital camera was performed at the second examination immediately following the baseline examination from September 9, 2002, to February 7, 2004, at each site, using a standardized protocol.10,11 Two photographic fields were taken of each eye, the first centered on the optic disc (Early Treatment Diabetic Retinopathy Study [ETDRS] field 1) and the second centered on the fovea (ETDRS field 2).12 Images were obtained from 6176 participants.
Capture and grading of digital images and quality control have been described in detail elsewhere.13,14 Each image was graded twice (a preliminary and a detail grade) online using a modification of the Wisconsin Age-Related Maculopathy Grading System.14 For the purposes of this article, there were 5887 (98.9%) persons photographed with at least 1 eye that could be evaluated for AMD (right eye [n = 211], left eye [n = 200], and both eyes [n = 5476]). Of these, 3399 subjects had lung data and are included in the analyses (Figure). There were no statistically significant differences in gradability for AMD among the 4 racial/ethnic groups in the study (data not shown).
The AMD features evaluated were drusen size, type and area, increased retinal pigment, RPE depigmentation, pure geographic atrophy, and signs of exudative macular degeneration (ie, subretinal hemorrhage, subretinal fibrous scar, RPE detachment, and/or serous detachment of the sensory retina or laser or photodynamic treatment for neovascular AMD). Soft distinct drusen were defined by size (63-300 μm in diameter) and appearance (sharp margins and a round nodular appearance with a uniform density [color] from center to periphery). Soft indistinct drusen were the same size as the soft distinct drusen but have indistinct margins and a softer, less solid appearance. Increased retinal pigment appeared as a deposition of granules or clumps of gray or black pigment in or beneath the retina. Retinal pigment epithelial depigmentation was characterized by faint grayish-yellow or pinkish-yellow areas of varying density and configuration without sharply defined borders. Early AMD was defined by either the presence of any soft drusen (distinct or indistinct) and pigment abnormalities (either increased retinal pigment or RPE depigmentation) or the presence of a large, soft drusen 125 μm or larger in diameter with a large drusen area (>500 μm in diameter circle) or large (≥125 μm in diameter), soft indistinct drusen in the absence of signs of late AMD. Late AMD was defined by the presence of any of the following: geographic atrophy or pigment epithelial detachment, subretinal hemorrhage or visible subretinal new vessels, subretinal fibrous scar, or laser treatment scar for AMD.
When 2 eyes of a participant were discrepant for the severity of a lesion, the grade assigned to the participant was that of the more severely involved eye. For example, in assigning the prevalence of soft drusen, if soft drusen were present in one eye but not the other, the participant was considered to have soft drusen. When drusen or signs of AMD could not be graded in an eye, the participant was assigned a score equivalent to that in the other eye.
Functional measures of obstructive lung disease were quantified by spirometry conducted in the third and fourth MESA examinations as part of the MESA-Lung Study in accordance with the American Thoracic Society/European Respiratory Society guidelines.15 The MESA-Lung Study enrolled 3965 MESA participants of 4484 who were sampled randomly among those who consented to genetic analyses (99%), underwent baseline measures of endothelial function (89%), and attended an examination during the MESA-Lung recruitment period (91%) in 2004-2006. Asians were oversampled. All participants performed at least 3 acceptable maneuvers on a dry-rolling–sealed spirometer with software that performed automated quality checks in real time (Occupational Marketing Inc, Houston, Texas). One investigator reviewed all spirometry examinations and each test was graded for quality.16 The intraclass correlation coefficients of both the forced expiratory volume in 1 second (FEV1) and FVC on a random 10% replicate testing was 0.99. The FEV1 and FEV1:FVC ratio were treated as the primary measures of airflow obstruction. For the current analysis related to obstructive lung disease, we excluded 322 participants with a restrictive pattern of spirometry, defined as an FVC less than the lower limit of normal,17 with an FEV1:FVC ratio above 0.70.
Quantitative anatomical measures of emphysema were performed on the lung fields of cardiac CT scans, which captured approximately 70% of the lung volume from the carina to the lung bases. Cardiac CT scans were performed at full inspiration on multidetector and electron-beam CT scanners in the first MESA examination following a standardized protocol.18 Two scans were performed on each participant; because these measures are affected by level of inspiration, the scan with the higher air volume was used for analyses except in cases of discordant scan quality, in which case the higher-quality scan was used.19
Image attenuation was assessed using the modified Pulmonary Analysis Software Suite20-23 at a single reading center by trained readers without knowledge of other participant information. Attenuation of air was measured outside the chest on a random sample of scans to confirm scanner calibration at −1000 Hounsfield units. Percent of emphysema-like lung (also known as percent low attenuation area and hereafter referred to as percent emphysema) was defined as the percentage of the total voxels (pixels × slice thickness) in the lung that fell below −910 Hounsfield units. This threshold was chosen based on pathology comparisons24 and the generally mild degree of emphysema in the sample. The intraclass correlation coefficient of the 100% replicate scanning was 0.94.
Percent emphysema measures from the carina to the lung base are highly correlated (r = 0.99) with full-lung measures on the same full-lung scans in smokers.25 Emphysema measures from cardiac CT scans correlated with those from full-lung scans from the same MESA participants (eg, 0.93 on a multi-detector CT scanner).19 The apical and basilar lung segments were defined as the cephalad or caudal regions of the lung divided along the z-axis scan coverage of the cardiac CT scan.
Participants underwent an interview and assessment of cardiovascular risk factors during the course of the study.9,26 Other variables or confounders were based on data collected at the first or fourth examination. Resting blood pressure was measured 3 times with participants in the seated position (Dinamap model Pro 100 automated oscillometric sphygmomanometer; Critikon, Tampa, Florida). The mean of the last 2 measurements was used. Hypertension was defined as systolic blood pressure of 140 mm Hg or higher, diastolic blood pressure of 90 mm Hg or higher, or current use of antihypertensive medications. Height and weight were measured with participants wearing light clothing and no shoes, and body mass index was calculated as weight in kilograms divided by height in meters squared.
A detailed questionnaire was used to obtain information about medical history (eg, hypertension, diabetes, asthma, arthritis, and emphysema), cigarette smoking and alcohol consumption (defined as current or past/never), and medication use. Cotinine was measured by immunoassay (Immulite 2000 Nicotine Metabolite Assay; Diagnostic Products, Los Angeles, California).
Logistic regression was used to estimate the OR and its 95% CI for early and specific AMD lesions associated with different lung function measurements. Each lung function measure was entered into a separate model. Odds ratios for continuous variables are presented per SD increase. Interactions between race/ethnicity, sex, and smoking status and AMD were tested by including an interaction term in the logistic regression models. In the CT analysis, we adjusted for covariates measured at baseline, while for the spirometry measures, we adjusted for covariates at the time of that examination. Two logistic regressions are presented for each risk factor. With measures collected at baseline, model 1 for the CT measures included age, sex, racial/ethnic group, height, body mass index, and study site. Model 2 for the CT measures included model 1 and additional adjustment for smoking status, pack-years smoked, serum cotinine level, and CT protocol. Using measures collected at spirometry examination, model 1 for the spirometry measures included age, sex, racial/ethnic group, height, and study site. Model 2 for the spirometry measures included model 1 and additional adjustment for body mass index, smoking status, pack-years smoked, and asthma prior to the age of 45 years. Version 9.1 of SAS (SAS Institute Inc, Cary, North Carolina) was used for all analyses.
Selected characteristics, including risk factors and potential confounders for the AMD and lung disease relationship for the full cohort and each of the 4 racial/ethnic groups among participants with available data (n = 3399 at baseline), are shown in Table 1. There were 1196 (35.2%) white, 558 (16.4%) Chinese, 896 (26.4%) black, and 749 (22.0%) Hispanic subjects in the cohort. Fifty-three percent of the cohort never smoked, 35% smoked in the past, and 12% smoked currently. Among those who ever smoked (ever-smokers) the median number of pack-years was 17.8.
There were significant differences in the frequency and distribution of most characteristics among the racial/ethnic groups. For example, black participants were more likely to be current cigarette smokers, while Chinese participants were least likely to have a history of asthma before 45 years of age and to have the lowest body mass index. White subjects had the lowest FEV1:FVC ratio, indicating obstructive lung disease.
Early AMD was present in 3.7%, late AMD in 0.4%, large drusen in 9%, soft drusen in 17%, increased pigment in 2%, RPE depigmentation in 0.8%, exudative AMD in 0.3%, and geographic atrophy in 0.2% of the cohort. Because of the small number of persons with signs of late AMD, associations of pulmonary factors with this end point are not examined.
Table 2 shows no statistically significant associations of functional measures of airflow obstruction and anatomic measures of emphysema with early AMD for the whole cohort while controlling for age, sex, race/ethnicity, height, and study site. There were also no associations of airflow obstruction and percent emphysema with size, type, or area of drusen and pigmentary abnormalities in the whole cohort (data not shown). However, all associations were in the hypothesized directions (Table 2).
These associations were modified by smoking status (Table 3). Apical-basilar differences in percent emphysema was associated with early AMD in ever-smokers (OR, 1.28; 95% CI, 1.02-1.60; P = .03) but not in never-smokers (OR, 0.93; 95% CI, 0.69-1.26, P = .66; interaction, P = .11). The association of apical-basilar difference in percent emphysema with early AMD remained statistically significant (P = .04) while further controlling for pack-years smoked in ever-smokers. There were no statistically significant interactions of airflow obstruction and percent emphysema with AMD end points by age, sex, or race (data not shown).
The MESA provided a unique opportunity to examine the relationship of anatomical and functional measures of lung disease to AMD in a large, multiethnic cohort without clinical CVD at the baseline examination.9 After controlling for age, sex, race, height, and study site in multivariate models, we found no statistically significant associations to early AMD in the whole cohort. However, one association was modified by smoking history, and apical-basilar emphysema was associated with early AMD in ever-smokers.
Findings in MESA contrast with those from the 2 earlier population-based studies.4-6 As noted above, in the Framingham Eye Study, decreased FVC and a history of lung infection were associated with AMD, and in the Beaver Dam Eye Study, a self-reported history of emphysema at baseline was associated with the 15-year incidence of RPE depigmentation (OR, 2.5; 95% CI, 1.3-4.8; P = .006) and exudative AMD (OR, 3.0; 95% CI, 1.0-8.4; P = .04).4,6 The associations in the Beaver Dam Eye Study remained after controlling for smoking and other factors. Additionally, in the Beaver Dam Eye Study, a history of respiratory symptoms (cough/phlegm/wheezing), first obtained at the 10-year follow-up, was associated with the 5-year incidence of exudative AMD (OR, 3.6; 95% CI, 1.4-9.3; P = .01) and progression of AMD (OR, 2.9; 95% CI, 1.4-6.0; P = .004), independent of a history of smoking. While controlling for age, smoking status, and a history of emphysema, peak expiratory flow rate was inversely associated with the 5-year incidence of 2 signs of early AMD, large drusen (fourth vs first quartile, OR, 0.4; 95% CI, 0.2-0.7; P = .001) and soft drusen (OR, 0.5; 95% CI, 0.3-0.9; P = .01), and progression of AMD (OR, 0.5; 95% CI, 0.2-1.0; P = .04). These prior cohort studies suggest that airflow obstruction and COPD may be a risk factor for AMD. We did not, in general, confirm these findings cross-sectionally in MESA, using lung function and novel measures of percent emphysema on CT scan. Because the association of airflow obstruction and emphysema appear to be modified by smoking history, this difference may be due to underlying differences in the smoking history of the 3 cohorts. The MESA cohort had no clinical cardiovascular disease at baseline, and participants in the current sample had to survive to participate in the third and fourth MESA examinations. The current sample is thus drawn from a “healthy” population, and the smoking exposure is less than in other previously studied cohorts.
Consistent with this notion, arguably the most sensitive of these available measures for smoking-related damage to the lung, apical-basilar difference in emphysema, was associated with early AMD in ever-smokers. Classically, smoking preferentially damages the apices of the lung, and this difference in degree of emphysema is detectable on CT scans. Interestingly, many prior studies of inflammatory and genetic risk in COPD have found stronger associations for apical-basilar difference in emphysema than for diffuse emphysema.27
Although our study has many strengths (eg, objective grading of AMD, spirometry, and a validated measure of percent emphysema, which is novel in a population-based multiethnic cohort), caution must be exercised when interpreting the findings for several reasons. We examined many variables. The significance of the one association of lung density and early AMD found in persons with a history of smoking may have been due to the large number of analyses and may have led to chance findings or type I error. In addition, the infrequency of late AMD (0.5%) limited us from analyzing lung factors with this end point. Thus, we could not examine the association of emphysema with exudative AMD as reported in the Beaver Dam Eye Study. The period cross-sectional nature of the study design (a single eye examination 2 years after or before the risk factors were measured) limits our ability to detect associations with factors, which may manifest subsequently as pathologic changes over some different interval of time. Another possible cause of concern is the possibility of misclassification of AMD status because of the use of minified 45° nonstereoscopic fundus images in the analyses compared with 30° stereoscopic images. However, we have no reason to believe that this will result in systemic biases in evaluating associations. Furthermore, the emphysema measures were drawn from cardiac rather than full-lung scans, though we have previously validated these measures against full-lung scans.19 Finally, we cannot determine whether there were biases caused by nonparticipation or selective mortality that affected the relationships.
In summary, these data from MESA show no statistically significant associations between pulmonary function or emphysema and early AMD signs in the whole cohort. In a secondary but potentially important analysis, apical-basilar difference in percent emphysema was associated with early AMD among ever-smokers. While our data suggest that these factors are not related to early AMD in a general, predominantly nonsmoking cohort without clinical signs of cardiovascular disease, the reader should be cautious regarding the implications of applying our findings to the general population, which has a higher proportion of smokers and persons with respiratory and cardiovascular disease. Longitudinal data in samples of larger size with greater frequency of smoking and late AMD will be important in further investigating the possibility of a causal relationship between lung structure and function and AMD.
Correspondence: Ronald Klein, MD, MPH, Department of Ophthalmology and Visual Sciences, University of Wisconsin–Madison, 610 N Walnut St, 450 WARF, Madison, WI 53726-2397 (email@example.com).
Submitted for Publication: June 29, 2009; final revision received October 9, 2009; accepted October 29, 2009.
Financial Disclosure: None reported.
Funding/Support: This research was supported by contracts N01-HC-95159 through N01-HC-95165 and N01-HC-95169 from the National Heart, Lung and Blood Institute; National Institutes of Health Intramural Research program award Z01000403 from the National Eye Institute (Dr Cotch); and grants HL69979-03 (Drs R. Klein and Wong) and HL077612 (Dr Barr) from the National Institutes of Health.
Additional Contributions: We thank the other investigators, the staff, and the participants of MESA for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org.
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