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American Journal of Epidemiology Advance Access originally published online on June 24, 2007
American Journal of Epidemiology 2007 166(6):724-730; doi:10.1093/aje/kwm126
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American Journal of Epidemiology © The Author 2007. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

ORIGINAL CONTRIBUTIONS

Retinopathy and Survival in a Population without Diabetes

The Beaver Dam Eye Study

Flavio E. Hirai1,2, Scot E. Moss1, Michael D. Knudtson1, Barbara E. K. Klein1 and Ronald Klein1

1 Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI
2 Department of Ophthalmology, Federal University of Sao Paulo, Sao Paulo, Brazil

Correspondence to Dr. Ronald Klein, Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison School of Medicine and Public Health, 610 North Walnut Street #417 – WARF, Madison, WI 53726-2336 (e-mail: kleinr{at}epi.ophth.wisc.edu).

Received for publication November 29, 2006. Accepted for publication March 15, 2007.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Retinopathy is relatively common in nondiabetic populations, and its long-term prognostic implications are not certain. For this reason, the authors hypothesized that retinal alterations were associated with all-cause and cause-specific mortality in nondiabetic individuals participating in the Beaver Dam Eye Study in Wisconsin. Included in the analysis were 4,294 nondiabetic subjects aged 43–84 years examined at baseline (1988–1990). Retinopathy was classified into four groups by using retinal photographs: 1) no retinopathy, 2) presence of retinal hemorrhages only, 3) presence of retinal microaneurysms only, and 4) presence of moderate or worse retinopathy. The authors analyzed survival during 14 years of follow-up and in 5-year intervals by using time-varying covariates. Baseline prevalence of retinopathy was 7.7%. Adjusting for age, sex, and significant confounders, they observed that moderate retinopathy at baseline was associated with all-cause (hazard ratio = 1.76, 95% confidence interval: 1.16, 2.69) and ischemic heart disease (hazard ratio = 3.17, 95% confidence interval: 1.73, 5.78) mortality after 14 years of follow-up. In the 5-year-interval analysis, the presence of hemorrhages only was significantly related to increased all-cause (hazard ratio = 1.49, 95% confidence interval: 1.05, 2.12) and ischemic heart disease (hazard ratio = 2.43, 95% confidence interval: 1.48, 4.01) mortality. Study results suggest that retinal changes have possible prognostic implications regarding survival of persons without diabetes.

eye diseases; mortality; ophthalmology; retina; retinal hemorrhage

Abbreviations: CI, confidence interval; HR, hazard ratio; ICD, International Classification of Diseases


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Direct assessment of retinal signs during clinical examination and development of standardized methods of fundus photography grading permit the evaluation of retinal alterations as predictors of disease and mortality (1). Retinopathy, comprising microaneurysms, blot hemorrhages, soft exudates, and other retinal lesions, is relatively common in nondiabetic persons, with a prevalence varying from 3 percent to 10 percent (2–4). Its prognostic implications are not fully understood in people without diabetes. Data from earlier studies showed a relation to incident diseases such as hypertension and stroke (1, 5–14). However, the relation of retinopathy with mortality in nondiabetic persons has not been consistent (1, 7, 9, 11–13, 15). We hypothesized that retinal alterations in nondiabetic individuals were associated with increased mortality. Thus, we examined the relation of retinopathy with survival in a large, population-based study over a 14-year period of follow-up.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Study population
The Beaver Dam Eye Study is an ongoing prospective, population-based cohort study initiated in 1988–1990. After a private census was conducted between September 15, 1987, and May 4, 1988, 5,924 people were eligible to participate in the study. Eligibility included residing in the city or township of Beaver Dam, Wisconsin, and being aged 43–84 years at the time of the census. A total of 4,926 (83.1 percent) persons participated in the study between March 1, 1988, and September 14, 1990. Two hundred sixty-nine people (4.5 percent) permitted an interview only, 225 (3.8 percent) died before the examination, 91 (1.5 percent) moved out of the area, 23 (0.4 percent) could not be located, and 391 (6.6 percent) refused to participate. Comparisons between participants and nonparticipants have been reported elsewhere (16).

Deaths were ascertained by contacting family members and physicians, reviewing newspaper obituaries, and using vital status records. For cause-specific analyses, any mention on the death certificate was considered an event. Causes of death were defined according to the International Classification of Diseases (ICD), Ninth Revision and Tenth Revision. Ischemic heart disease mortality was defined according to codes 410.0–414.9 (ICD-9) and I20.0–I25.9 (ICD-10), and stroke mortality was defined according to codes 430.0–438.9 (ICD-9) and I60.0–I69.9 (ICD-10). The survival interval considered in the current analysis was a 14-year period from the beginning of the study until death or the date of last contact by December 31, 2002.

Informed consent was obtained from all participants. This research was conducted in accordance with the principles of the Declaration of Helsinki.

Procedures
Study protocols have been described previously (16, 17). Briefly, baseline and all follow-up examinations included detailed medical history with information about cancer and cardiovascular disease; questions about cigarette smoking and alcohol consumption; and measurements of blood pressure, height, weight, and waist and hip circumferences. Laboratory tests included serum glucose, glycosylated hemoglobin, and serum total and high density lipoprotein cholesterol levels. Urine tests were performed to determine the presence of gross proteinuria. Stereoscopic color retinal photographs were taken and were graded for retinopathy status.

Definitions
Diabetes was diagnosed if participants reported having the disease—confirmed by a random blood sugar level of >200 mg/dl—or being treated with insulin, pills, or diet or if their glycosylated hemoglobin value was greater than 2 standard deviations above the mean according to a given age-sex group (43–54 years of age: men, >9.5 percent; women, >9.6 percent; 55–64 years of age: men, >9.4 percent; women, >10.0 percent; 65–74 years of age: men, >9.6 percent; women, >9.6 percent; and 75 years of age or older: men, >9.5 percent; women, >9.6 percent).

Body mass index was calculated by dividing weight (kilograms) by squared height (meters). Participants were classified as normotensive if their systolic blood pressure and diastolic blood pressure were <140 mmHg and 90 mmHg, respectively, without use of antihypertensive medications; hypertensive if their systolic blood pressure or diastolic blood pressure were ≥140 mmHg or 90 mmHg, respectively, without use of antihypertensive medications; treated successfully if their systolic blood pressure and diastolic blood pressure were <140 mmHg and 90 mmHg, respectively, with use of antihypertensive medications; and treated unsuccessfully if their systolic blood pressure or diastolic blood pressure were ≥140 mmHg or 90 mmHg, respectively, even while using antihypertensive medications. History of cardiovascular disease was defined as having a positive history of angina, myocardial infarction, or stroke. Positive history of cancer was determined if participants reported any type of cancer. Participants who engaged in physical activity long enough to work up a sweat less than three times per week were considered sedentary. Cigarette smoking was analyzed as number of pack-years of smoking, and alcohol consumption was measured as average ethanol consumed per week from beer, wine, or liquor. Retinopathy status was classified by using a modified Airlie House Classification scheme (18) in four groups: 1) no retinopathy; 2) presence of retinal hemorrhages only; 3) presence of retinal microaneurysms only; and 4) presence of moderate retinopathy or worse, defined as the presence of retinal microaneurysms and blot hemorrhages or retinal microaneurysms and hard or soft exudates, intraretinal microvascular abnormalities, or venous beading in one or more fields or the presence of signs of proliferative retinopathy.

Statistical analysis
Continuous and categorical variables were compared by using the t test and {chi}2 test, respectively. Multivariate analyses were performed with the Cox proportional hazards model. First, we analyzed survival during 14 years of follow-up by using variables at baseline. Then, because some variables (e.g., retinopathy status) may have changed over time, we analyzed the data in each 5-year interval by using time-varying covariates (retinopathy status, pulse, diastolic blood pressure, pack-years of smoking, presence of proteinuria, history of cardiovascular disease, history of cancer, sedentary lifestyle, and use of diuretics) at the beginning of each period (baseline to 4-year follow-up; 5-year to 9-year follow-up; and 10-year follow-up until death or censoring on December 2002) (19). Previous values were used if that value was missing at the beginning of the interval. We decided that this approach would enable us to capture the presence/absence of retinal changes (e.g., blot hemorrhages, microaneurysms) more accurately than measuring them once. Thus, hazard ratios in this model show the risk of death in 5-year intervals according to retinopathy status at the beginning of each follow-up period. In addition, models were combined by using a generalized estimating equation approach to combine the hazards from each 5-year interval. Hazard ratios with 95 percent confidence intervals were estimated, and p values of less than 0.05 were considered significant. Analyses were performed with SAS software, version 9.1 (SAS Institute, Inc., Cary, North Carolina).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
After we excluded 446 individuals who had a diagnosis of diabetes at baseline, 86 without information about their diabetes status, 15 with retinal conditions not related to diabetes (e.g., retinal vein occlusion), 15 with isolated retinal lesions (e.g., soft/hard exudates or intraretinal microvascular abnormalities without microaneurysms), and 70 without information about their retinopathy status at baseline, 4,294 subjects were included in the study. After 14 years of follow-up (median, 13.3 years), 1,235 nondiabetic participants died.

Table 1 shows the baseline characteristics of the population in the current analysis. Those who died were more likely to be older and to have higher glycosylated hemoglobin levels, pack-years of smoking, and systolic blood pressure but lower diastolic blood pressure. In this group, the proportion of males was higher, as was history of cancer and cardiovascular disease, sedentary lifestyle, hypertension, presence of gross proteinuria, and history of use of diuretics, but a lower proportion of individuals had a history of alcohol consumption.


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  		TABLE 1. Baseline characteristics: survivors vs. deceased participants in the Beaver Dam Eye Study, Wisconsin, 1988–1990

 
The overall prevalence of retinopathy at baseline (table 2) was 7.6 percent (1.5 percent, hemorrhages only; 5.2 percent, microaneurysms only; 0.9 percent, moderate or more severe retinopathy). Statistically significant factors related to decreased survival were identified (table 3) and were used in models examining the associations of retinopathy with survival.


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  		TABLE 2. Baseline characteristics: survivors vs. deceased participants, by retinopathy status in the population without diabetes, Beaver Dam Eye Study, Wisconsin, 1988–1990

 

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  		TABLE 3. Variables at baseline significantly associated with decreased survival of participants in the Beaver Dam Eye Study, Wisconsin, 1988–1990

 
Table 4 shows the results of the Cox proportional hazards models for 14 years of follow-up adjusting for age and sex and adjusted to other significant variables: age, sex, pulse, diastolic blood pressure, pack-years of smoking, presence of proteinuria, history of cardiovascular disease, history of cancer, sedentary lifestyle, and use of diuretics. When adjusting for age and sex, there was increasing all-cause and ischemic heart disease mortality when individuals with moderate retinopathy were compared with those without retinopathy at baseline (adjusted hazard ratio (HR) = 1.76, 95 percent confidence interval (CI): 1.16, 2.69 and adjusted HR = 3.17, 95 percent CI: 1.73, 5.78, respectively). Moderate retinopathy was not associated with increased mortality from stroke in both age-sex and fully adjusted models (adjusted HR = 2.12, 95 percent CI: 0.67, 6.67 and adjusted HR = 2.34, 95 percent CI: 0.74, 7.40, respectively). Similar results were found when glycosylated hemoglobin was added to the hazard models (table 4). In addition, because some individuals could have developed diabetes during the study period, we added a time-to-diabetes covariate to all hazard models, and the results remained statistically significant for all-cause and ischemic heart disease mortality, supporting the idea that retinopathy is related to mortality independent of diabetes (table 4).


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  		TABLE 4. Association of retinopathy status*,{dagger} at baseline with decreased survival for participants in the Beaver Dam Eye Study for all-cause and cause-specific mortality, Wisconsin, 1988–1990

 
When the hazards of each 5-year interval were combined (table 5), the presence of retinal hemorrhages only was significantly related to increased all-cause mortality (adjusted HR = 1.49, 95 percent CI: 1.05, 2.12). Blot hemorrhages (adjusted HR = 2.43, 95 percent CI: 1.48, 4.01) and the presence of any retinopathy (adjusted HR = 1.83, 95 percent CI: 1.32, 2.52) were significantly associated with increased ischemic heart disease mortality. Analysis by 5-year intervals of stroke mortality was not possible because of the small number of cases.


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  		TABLE 5. Association of retinopathy status*,{dagger} with decreased survival for participants in the Beaver Dam Eye Study for all-cause and cause-specific mortality,{ddagger} Wisconsin, 1988–1990

 
The strong association of hypertension with both retinopathy and cardiovascular events is well described in the literature (1–3, 6, 20–24). To control for the influence of blood pressure, diastolic blood pressure was included in the models as a continuous variable. We tested the effect of hypertension status by using different definitions in all models, and no major differences in the associations were observed (data not shown). We also analyzed different cutoff levels of glycosylated hemoglobin (from 6.5 percent to 7.0 percent) in our definition of diabetes. Although additional individuals (4–11 percent) were excluded, no associations between retinopathy and mortality changed in our study (data not shown).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
We found an association of retinopathy with decreased survival in a population without diabetes. Moderate retinopathy, the most advanced stage of retinopathy found in this nondiabetic population at baseline, was significantly associated with increased mortality in 14 years of follow-up. The relation was stronger for ischemic heart disease mortality, with the risk of dying being about three times greater when compared with that for people without retinopathy, adjusted for age, sex, and other confounders. Witt et al. (11) reported an association of retinal vascular changes such as impaired bifurcation optimality and reduced arteriolar tortuosity with incident ischemic heart disease in the same population.

In persons with and without diabetes, retinal abnormalities were independently associated with cardiovascular disease mortality after controlling for relevant confounders (6, 7, 12, 14, 25–29). Few studies analyzed specifically the association of retinopathy with ischemic heart disease, and its relation is still not fully understood (25, 26, 29). Studies in diabetic populations (25, 27) showed an increased risk of death for those presenting with retinopathy compared with those without. Klein et al. (29) reported that the progression of retinopathy to proliferative stage was associated with ischemic heart disease mortality among individuals who developed diabetes after 30 years of age.

Besides the relation with cardiovascular disease, retinopathy has also been found to be associated with the development of chronic kidney disease (30–32). These associations might be due to the fact that retinal, renal, and cardiovascular diseases share common risk factors such as age and hypertension (26). In addition, others have speculated that micro- and macrovascular disease may share common pathways (5, 8, 33). For example, inflammation and endothelial dysfunction might play an important role in the development of both retinopathy and cardiovascular disease because systemic markers (e.g., C-reactive protein, soluble intercellular adhesion molecule-1) have been found to be associated with both diseases (33, 34).

Isolated retinal lesions such as microaneurysms and hemorrhages were associated with cardiovascular events in previous studies (7, 8, 14). Wong et al. (8) reported a significant association between the presence of retinopathy, as well as the presence of retinal hemorrhages, and incident congestive heart failure in the general population. Retinal hemorrhages were also associated with stroke among nondiabetic individuals in the Atherosclerosis Risk in Communities study (14). Mitchell et al. (7) reported similar findings in individuals without diabetes or severe hypertension in an Australian population. Although we found a positive hazard ratio, the association between retinal lesions and stroke was not statistically significant, possibly because of limited power.

Among the strengths of our study were its population-based design, the standardized fundus grading system, and its long follow-up. Limitations included possible misclassification of diabetes status and causes of death. Residual confounding could also have affected our association. In addition, we had limited power to examine some associations (e.g., retinopathy and stroke).

In summary, our study showed that the presence of retinal hemorrhages or moderate retinopathy in nondiabetic persons was independently associated with increased all-cause and ischemic heart disease mortality. These findings suggest that retinal changes have possible prognostic implications regarding survival for persons without diabetes.


   ACKNOWLEDGMENTS
 
National Institutes of Health grant EY06594 (R. K., B. E. K. K.) provided funding for the entire study, including collection and analyses of data, and Research to Prevent Blindness (R. K. and B. E. K. K., Senior Scientific Investigator Awards), New York, New York, and American Diabetes Association (R. K. Mentor Award), Alexandria, Virginia, provided, in part, funding for analyses of data.

R. K. was involved with conception and design, acquisition, analysis, and interpretation of data; drafting and critical revision of the manuscript; obtaining funding; and supervising the study. S. E. M. and M. D. K. were involved with analyses and interpretation of the data, critical revision of the manuscript for important intellectual content, and statistical expertise. F. E. H. was involved in acquisition of data; drafting and critical revision of the manuscript for important intellectual content; and administrative, technical, or material support. B. E. K. K. was involved with conception, design, and conduct of the study; drafting and critically revising the manuscript for important intellectual content; obtaining funding; and administrative support. All authors approved the final submitted manuscript.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

  1. Wong TY, McIntosh R. Systemic associations of retinal microvascular signs: a review of recent population-based studies. Ophthalmic Physiol Opt (2005) 25:195–204.[CrossRef][Web of Science][Medline]
  2. Klein R. Retinopathy in a population-based study. Trans Am Ophthalmol Soc (1992) 90:561–94.[Medline]
  3. Yu T, Mitchell P, Berry G, et al. Retinopathy in older persons without diabetes and its relationship to hypertension. Arch Ophthalmol (1998) 116:83–9.[Abstract/Free Full Text]
  4. Rajala U, Laakso M, Qiao Q, et al. Prevalence of retinopathy in people with diabetes, impaired glucose tolerance, and normal glucose tolerance. Diabetes Care (1998) 21:1664–9.[Abstract]
  5. Klein R, Sharrett AR, Klein BE, et al. Are retinal arteriolar abnormalities related to atherosclerosis? The Atherosclerosis Risk in Communities Study. Arterioscler Thromb Vasc Biol (2000) 20:1644–50.[Abstract/Free Full Text]
  6. Wong TY, Klein R, Klein BE, et al. Retinal microvascular abnormalities and their relationship with hypertension, cardiovascular disease, and mortality. Surv Ophthalmol (2001) 46:59–80.[CrossRef][Web of Science][Medline]
  7. Mitchell P, Wang JJ, Wong TY, et al. Retinal microvascular signs and risk of stroke and stroke mortality. Neurology (2005) 65:1005–9.[Abstract/Free Full Text]
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  9. van Hecke MV, Dekker JM, Stehouwer CD, et al. Diabetic retinopathy is associated with mortality and cardiovascular disease incidence: the EURODIAB prospective complications study. Diabetes Care (2005) 28:1383–9.[Abstract/Free Full Text]
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  12. van Hecke MV, Dekker JM, Nijpels G, et al. Retinopathy is associated with cardiovascular and all-cause mortality in both diabetic and nondiabetic subjects: the Hoorn Study. Diabetes Care (2003) 26:2958.[Free Full Text]
  13. Wong TY, Knudtson MD, Klein R, et al. A prospective cohort study of retinal arteriolar narrowing and mortality. Am J Epidemiol (2004) 159:819–25.[Abstract/Free Full Text]
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  30. Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med (2004) 351:1296–305.[Abstract/Free Full Text]
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  33. van Hecke MV, Dekker JM, Nijpels G, et al. Inflammation and endothelial dysfunction are associated with retinopathy: the Hoorn Study. Diabetologia (2005) 48:1300–6.[CrossRef][Web of Science][Medline]
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