Do age-related macular degeneration and cardiovascular disease share common antecedents?

125Age-related macular degeneration and cardiovascular disease

Correspondence andreprint requests to:Johanna M. Seddon, MDMassachusetts Eye & Ear InfirmaryEpidemiology Unit243 Charles StreetBoston, MA 02114U.S.A.Tel.: +1 (617) 573-4010Fax: +1 (617) 573-3570E-mail:[email protected]

Review article

Ophthalmic Epidemiology0928-6586/99/US$ 15.00

Ophthalmic Epidemiology– 1999, Vol. 6, No. 2,pp. 125-143© Æolus Press 1999

Accepted 11 January 1999

Do age-related macular degeneration andcardiovascular disease share common

antecedents?

Kristin K. Snow, M.S.1,2

Johanna M. Seddon, M.D., S.M.1,2,3

1Epidemiology Unit, Massachusetts Eye and Ear Infirmary,2Department of Epidemiology, Harvard School of Public Health,and 3Department of Ophthalmology, Harvard Medical School,

Boston, MA

Abstract Age-related macular degeneration (AMD) is the leadingcause of irreversible vision loss and blindness in elderly Americans.The etiology of this condition remains unknown and treatment optionsare limited. Some epidemiological findings point to a cardiovascularrisk profile among persons with AMD. Documented risk factors forcardiovascular disease (such as age, smoking, hypertension, hypercho-lesterolemia, post-menopausal estrogen use, diabetes, and dietary in-take of fats, alcohol and antioxidants) have also been associated withAMD in some studies. This raises the possibility that the causal path-ways for cardiovascular disease and AMD may share similar risk fac-tors. Future research on this hypothesis could lead to important insightsinto etiologic factors for AMD. Research could also identify modifiablerisk factors and suggest new treatment options which could preventAMD, slow its progression, or reduce visual loss. Susceptible individ-uals could then be targeted for improved health promotion and diseaseprevention measures for this disabling and highly prevalent disorder.

Key words Age-related macular degeneration; cardiovascular dis-ease; risk factors

Introduction Age-related macular degeneration (AMD) is the mostcommon cause of irreversible vision loss and blindness in the U.S. andother developed countries. Among people aged 75 and older, more thanone-quarter have signs of age-related maculopathy and 6-8% have ad-vanced forms of maculopathy with visual loss.1 Despite the high pre-valence and the public health impact, the etiology of AMD remainsunknown and its epidemiology is poorly understood.2,3 A large numberof clinical and epidemiological studies have focused on a host of pos-sible risk factors. Although there is not complete agreement, severalcardiovascular risk factors may underlie the mechanisms for the devel-opment of AMD. In this paper we review the literature on this topicand examine the possibility that cardiovascular disease risk factors may

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K.K. Snow & J.M. Seddon126

influence the development of AMD, with recommendations for futureresearch.

Definitions and overview of age-related macular de-generation AMD is characterized by clinically recognizable ocu-lar findings in the choroid, retina, and retinal pigment epithelium (RPE)that can lead to blindness. Although there are no universally accepteddiagnostic criteria, AMD has most often been defined as the presenceof drusen, RPE disturbance, geographic atrophy, RPE detachment, sub-retinal or choroidal neovascularization, and/or disciform scarring. Someresearchers use the terms age-related maculopathy (ARM), early AMD,or background AMD when describing early symptoms of the disease,and use the terms late ARM or advanced AMD for the forms that aremost likely to cause visual loss, including geographic atrophy andexudative disease. Some studies classify the ocular condition as AMDonly if there is visual acuity loss attributable to the AMD.4

AMD manifests in two forms: dry, present in 80-90% of cases, andexudative, neovascular, or wet, present in the remaining cases. There isno established prevention or treatment for dry AMD. The only modi-fiable risk factors for wet AMD that have been identified are curtailingcigarette smoking and possibly increasing antioxidant dietary intake,5,6

although there is no prospective evidence to date that a dietary inter-vention will lead to a beneficial effect.7 Less than 20% of wet AMDlesions can be treated with laser photocoagulation to reduce the risk ofvision loss.8 However, laser treatment is not considered a cure becausemany cases are not suitable for treatment and the beneficial effectsdecrease as time passes.9 The modest effectiveness of photocoagulationand scant preventive options underscore the need to identify additionaletiologic factors. These may lead to primary preventive treatments oradditional therapeutic regimens for this disabling disorder.

Definitions and risk factors of cardiovascular diseaseCardiovascular disease (CVD) includes both coronary heart disease(CHD) and cerebrovascular disease (stroke). CHD is the leading causeof mortality in the US for both men and women. It accounts for approx-imately 600,000 deaths per year, or one-third of all deaths. Strokeaccounts for another 150,000 deaths per year.10 Atherosclerosis is theunderlying cause of most ischemic events and can result in angina,myocardial infarction, congestive heart failure, cardiac arrhythmias, orsudden cardiac death. Risk factors for CVD have been extensivelyreviewed elsewhere.11,12 For the purposes of this review, we present abrief overview of the topic.

CHD is uncommon in men under 40 and premenopausal women, butrisk increases exponentially with advancing age in men and post-meno-pausal women.10 Most stroke-related mortality occurs in persons aged65 and older.13

Smoking more than doubles the incidence of CHD and increasesmortality from CHD by 70%.14,15 For current smokers, a clear and verystrong dose-response relationship exists between the number of ciga-rettes ever smoked and the risk of CVD,16 with a relative risk of 5.5 forfatal CHD in the heaviest smokers in the Nurses’ Health Study.17

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Smoking also acts synergistically with other coronary risk factors. Theincreased risk associated with smoking and diabetes, hypercholester-olemia, and hypertension are more than additive.11 Cessation of smok-ing leads to both immediate benefits and long-term declines in excessrisk of CHD,18 with risk declining to levels of non-smokers within twoto five years after cessation.11

Hypertension is a strong and modifiable risk factor for CHD and isthe chief predisposing factor to stroke.19 Hypertension is present in anestimated 43 million Americans and is more common in older adults.20

Mortality due to CHD begins to increase at blood pressures above 110mmHg systolic or 70 mmHg diastolic, although hypertension is usuallydefined as a systolic blood pressure of 140 mmHg or higher and adiastolic blood pressure of 90 mmHg or higher.21 Hypertension increas-es cardiovascular morbidity and mortality two- to four-fold.19

Elevated blood cholesterol is another major modifiable cause of CHD.Substantial research supports a causal relationship between blood lipidlevels, atherosclerosis, and the manifestations of coronary artery dis-ease.22 CHD risk increases in a dose-response fashion, beginning withcholesterol levels as low as 150-180 mg/dL.23 During middle age, each1% increase in total cholesterol is associated with a 3% increase in riskfor CHD.24 CHD risk is associated positively with total cholesterol andthe low-density lipoprotein (LDL) fraction and is associated inverselywith the high-density lipoprotein (HDL) fraction.25 Dietary, environ-mental, and genetic factors all appear to determine cholesterol levels.11

Dietary lipid intake is primarily responsible for raising or loweringserum lipids. Diets that are high in saturated and trans-unsaturated fatsare associated with an increased risk for CHD, whereas higher intakesof mono-unsaturated and polyunsaturated fats are associated with a de-creased risk as a result of a net change in LDL.26,27

Approximately 14 million Americans have diabetes mellitus, with95% having Type II (non-insulin dependent) diabetes. Diabetes accel-erates atherosclerosis and independently increases the risk of myocar-dial infarction, particularly in women.11 Age-adjusted mortality ratesfor CHD are two to three times higher in diabetic men and three toseven times higher in diabetic women. Further, diabetes exacerbatesthe effects of other known risk factors for CVD.28 Diabetes may alsolead to diabetic retinopathy which is the leading cause of blindness inAmericans aged 20 to 64.29

One-third of Americans are considered obese.30 Obesity is a well-established cause of diabetes mellitus, hypertension, and dyslipidemia.Direct positive associations between obesity and the risk for CHD havebeen demonstrated in a number of prospective studies.31 In prospectivestudies, the risk of CHD was two to three times higher in obese sub-jects as compared to lean subjects.11,12

Risk for CVD has been shown to be inversely related to physicalactivity in more than 30 studies completed in the past four decades.32

The relative risk of death from CHD is approximately two times higherin sedentary persons than in active persons.12 Therefore, a sedentarylifestyle may be considered an important and modifiable risk factor forCHD. Unfortunately, more than half of all Americans maintain a sed-entary lifestyle.33

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Moderate alcohol consumption has been found to reduce the risk ofCVD by about 30-70% in various studies. Persons who are never orrare drinkers have slightly increased risk of CVD, while heavier drink-ers have higher risks for accidental injuries. The protective effect ofmoderate alcohol intake appears to be independent of the type of alco-holic beverage consumed.34,35

Post-menopausal women have higher rates of CVD than pre-meno-pausal women, but this excess risk can be reduced by taking post-menopausal hormones. The reduction in risk of CHD due to use ofpost-menopausal hormone therapy was estimated to be 44% in theNurses’ Health Study.36

Findings from the Physicians’ Health Study showed that regular useof low-dose aspirin reduced the risk for first myocardial infarction by44%, although the findings on risk of death from stroke were inconclu-sive.37 Other studies have found a modest reduction in incidence ofstroke and death from cardiovascular causes in regular users of aspirin,although there is some concern that aspirin may increase the risk ofhemorrhagic stroke, particularly in women.38

Dietary and supplemental intake of antioxidants have been repeatedlyassociated with a small to moderate reduction in the development ofatherosclerosis and risk of cardiovascular events. It is hypothesized thatantioxidants (such as vitamin C, vitamin E, flavonoids, and carotenoids)inhibit oxidative modification of low-density lipoprotein (LDL), there-by preventing or slowing the progression of atherosclerosis. Epidemi-ologic evidence is strongest for vitamin E, while some studies alsosuggest a protective effect for vitamin C, flavonoids, and beta-caro-tene.39-43

Review of epidemiological research regarding riskfactors associated with CVD and AMD As early as the1970’s, researchers wondered if AMD may be part of an underlyingsystemic vascular process or a result of factors that also influence thedevelopment of cardiovascular disease (CVD).44,45 Two case-controlstudies have found a relationship between AMD and a history ofCVD.45,46 A cross-sectional study, NHANES-1, reported a positiveassociation between AMD and cerebrovascular disease, but positiveassociations with other vascular diseases did not reach statistical sig-nificance.47 However, other studies have found that persons who re-ported a history of CVD did not have a significantly greater risk ofAMD.48-54

One recent etiologic model hypothesizes that hemodynamic factorsincrease resistance of the choroidal circulation. The resulting decreasein choroidal perfusion would lead to dry AMD, or alternatively, anincreased choroidal pressure would lead to wet AMD. Therefore, AMDmay be a vascular disorder manifested by lipid infiltration which wouldbe called atherosclerosis if it involved organs in the cardiovascular orcerebrovascular systems.55 Also, foveolar choroidal blood flow (ChB-Flow) has been shown to decrease with age,56 and the average ChB-Flow in subjects with dry AMD is lower than in age-matched con-trols.57 This may suggest that ChBFlow may play a role in thedevelopment of wet AMD. In another study, slow choroidal filling was

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one of several factors found to be associated with progression of AMD.58

Additional research is required to further elucidate this hypothesis.57

Some studies have suggested an association between AMD and clin-ical manifestations of CVD. The Framingham Eye Study reported apositive association with left ventricular hypertrophy, but did not adjustfor age.44 In a large population-based study, plaques in the carotidbifurcation were associated with a 4.7 times increased odds of preva-lent AMD, and persons with plaques in the common carotid arteryshowed a 2.5 times increased odds. Lower extremity arterial diseasewas also associated with a 2.5 times increased odds of AMD.59 Impairedocular blood flow and increased scleral rigidity, which may reflect thedegree of arteriosclerotic changes in the choroidal vasculature, havebeen reported to be increased among persons with AMD.60-63 A Finnishstudy reported a significant correlation between occurrence of AMDand the severity of retinal arteriosclerosis.64

There is consistent epidemiologic evidence that several risk factorsfor AMD are also associated with CVD. Risk factors common to bothAMD and CVD, as well as those worth exploring further, are discussedbelow.

age Several epidemiological studies have provided valuable infor-mation on the prevalence and incidence of AMD at various ages. Thesestudies have shown that all signs of macular degeneration are associ-ated with increasing age, hence the inclusion of the term “age-related”in the condition’s name.1,44,47,50,64-66 The Framingham Eye Study estimat-ed that 10% of their study population aged 52-85 had visual loss dueto some form of AMD. Prevalence increased dramatically with age sothat 28% of persons aged 75-85 were affected.44,65 More recently, theBeaver Dam Eye Study reported that the prevalence of any signs ofearly AMD rose from 8.4% in persons aged 43-54 to 29.7% in personsage 75 and older. Advanced AMD was present in 7.8% of women and5.6% of men age 75 years and older, but in only 0.1% of those aged43-54.1

The incidence of AMD has also been estimated. The Beaver DamStudy found higher incidence of drusen, RPE changes, geographic at-rophy, and exudative disease with increasing age in their population of3583 adults aged 43-86. Five-year cumulative incidence of advancedAMD in either eye was 0.9%, rising from 0% in those younger than 55to 3.2% in those 75 and older.67 In the Melton Mowbray Eye Study ofpersons aged 77-90, seven-year cumulative incidence in eyes withoutany signs of the lesion at baseline was 30.6% for drusen, 54.5% forRPE degeneration, 1.3% for geographic atrophy, and 1.3% for subret-inal hemorrhage.68

smoking The preponderance of epidemiological evidence indicates astrong positive association between both wet and dry AMD and smok-ing. Two large prospective cohort studies have evaluated the relation-ship between smoking and wet AMD and dry AMD associated with avisual loss.6,69,70 In the Nurses’ Health Study, women who currentlysmoked 25 or more cigarettes per day had a relative risk of 2.4, andwomen who were past smokers had a relative risk of 2.0 for AMD

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compared with women who never smoked.6 Risk increased as pack-years of smoking increased, indicating a dose-dependent relationship.Risk for AMD remained elevated for many years after smoking cessa-tion. Results were consistent for various definitions of AMD, includingwet AMD, dry AMD with different levels of visual loss, and for dif-ferent definitions of smoking. Among women, it was estimated that29% of the AMD cases in that study could be attributed to smoking.6

These results were supported by a study among men participating in thePhysicians’ Health Study,70 suggesting that smoking is an important,independent, avoidable cause of AMD.6

Several cross-sectional and case-control studies have also shown anincreased risk for wet AMD among smokers.44,50,51,71-75 Some studies,however, have found no relationship.44,48,64,76-78 or an inverse relation-ship.79 Risk of dry AMD was somewhat elevated in two studies,50,74 butnot in others.64,72,75 Despite equivocal results in these types of studies,the strong positive relationship between smoking and AMD seen inprospective studies is persuasive.6,69,70,80 We conclude that AMD is yetanother smoking-related condition.

blood pressure and hypertension The role of blood pressurein the etiology of AMD remains unclear. There was a small and con-sistent statistically significant relationship between AMD and systemichypertension in two cross-sectional population-based studies.47,81 Onesmall case-control study found that persons with AMD were signifi-cantly more likely to be taking anti-hypertensive medication.49 A largecase-control study reported that persons with systemic hypertensionhad increased risk for AMD.46 A significant relationship was foundbetween AMD and diastolic blood pressure measured several yearsbefore the eye examination in the Framingham Eye Study,44 and in asmall Israeli study.82 The Beaver Dam Study reported that systolic bloodpressure was associated with incidence of RPE depigmentation.52 Inanother study, there was an increased incidence of wet AMD in thesecond eye among hypertensives with wet AMD in one eye at base-line.78

Several case-control and cohort studies have found no relationshipbetween systolic or diastolic blood pressure, presence or history ofhypertension, or use of anti-hypertensive therapies and development ofadvanced AMD.45,48,52,54,64,73,76,77 The Eye Disease Case-Control Studydid not show a significant relationship between either hypertension orcurrent treatment with anti-hypertensive medication and wet AMD,although a trend for increased risk with higher systolic blood pressurewas evident.51

Taken together, the evidence suggests a possible mild to moderateassociation between elevated blood pressure and AMD. Assessment ofthis relationship could be enhanced by evaluating the duration of hy-pertension and its subsequent effects on onset and progression of mac-ulopathy.

cholesterol levels and dietary fat intake There is someevidence linking cholesterol level to AMD, but not all studies are con-sistent. The Eye Disease Case-Control Study (EDCCS) reported a sta-tistically significant four-fold increased odds of having wet AMD in

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the group with the highest total serum cholesterol level, and a two-foldincreased odds in the middle cholesterol level group, compared withthe lowest cholesterol level group, controlling for other factors.51 Nosignificant association was noted between AMD and cholesterol levelin the Framingham Eye Study,44 the Blue Mountains Eye Study,54 andfour other, small studies.76,83-85 A study of plasma cholesterol and fattyacid levels found no difference between 65 cases of wet AMD andcontrol pairs.86 The Beaver Dam Study found that early AMD wasrelated to low total serum cholesterol levels in women and men overage 75. Further, men with early AMD had higher high density lipopro-tein-cholesterol (HDL-C) and lower total cholesterol/HDL-C ratios.52,87

Slightly, but not significantly, increased risk of wet AMD was seenwith increasing triglyceride level in the EDCCS,51 but this finding wasnot confirmed in the Rotterdam Study or the Beaver Dam Study.52,59

Dietary fat intake was associated with a slightly elevated risk of wetAMD in the EDCCS. This association was primarily due to vegetablefat rather than animal fat. For omega-3 fatty acid intake, an inverseassociation was suggested in the multivariate model.88 In the BeaverDam Study, persons in the highest quintile of saturated fat and choles-terol intake compared to the lowest quintile had 80% and 60% in-creased odds, respectively, for early AMD. Results for advanced AMDregarding total fat intake were in the same direction but were not sta-tistically significant.89

Based on the study results to date, one could speculate that choles-terol and other lipid levels may have a different effect on CVD thanthey have on AMD.90 Alternatively, cholesterol levels may only berelated to wet AMD.51 Exposure misclassification may be of concernsince serum cholesterol measurement likely followed the initiation ofthe disease process. However, the possible association between AMDand dietary fat and cholesterol intake, particularly from vegetable anddairy sources, may indicate a relationship with atherosclerosis.55,91

Longitudinal follow-up studies are necessary to delineate the effects ofserum lipid levels and dietary lipid intake on subsequent developmentand progression of AMD.

diabetes and hyperglycemia Many studies have investigated therelationship between diabetes and/or hyperglycemia and AMD, but fewhave found any significant relationships.44,45,51,54,64,76-78 Three studies sug-gested a possible positive association. A small case-control study founda non-significantly increased odds of AMD related to a history of di-abetes.48 Another small study reported a positive association betweenserum glucose levels and the mean area affected by drusen only infemales without diabetes.82 The Beaver Dam Study found no overallassociation between dry or wet AMD and diabetes or glycosylatedhemoglobin, a measure of glycemia. A positive association was foundbetween glycosylated hemoglobin and wet AMD only in older men;however, this finding could have been due to chance since sample sizesin these subgroup analyses were very small.92 Therefore, the associa-tion between hyperglycemia or diabetes and AMD, if any, is probablyweak.93 One problem with these studies may be the difficulty withdiagnosing AMD in the presence of diabetic retinopathy. Also, many

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studies of AMD exclude persons with diabetic retinopathy. This couldresult in attenuated relationships between AMD and diabetes in pub-lished studies.

obesity and physical inactivity Literature on the relationshipbetween obesity or physical activity and AMD is scarce. In the EyeDisease Case-Control Study, there was a suggestion of higher risk ofwet AMD in persons with a body mass index (BMI) over 30.0 and withincreasing BMI categories, and there was a trend towards lower risk forwet AMD in persons who reported higher levels of physical activity.51

The Beaver Dam Study found no relationship between BMI and ad-vanced AMD,52 but did report slightly increased odds for progressionof retinal pigmentation with increasing BMI.85 A Finnish study report-ed that a BMI over 27.5 was predictive for wet AMD, and for earlyAMD in men only.64 The Blue Mountains Eye Study found that a BMIoutside the normal range of 20 to 25 was associated with a significantlyincreased risk of early AMD, and an increased risk of late AMD whichwas not statistically significant.54 A Danish case-control study found noassociation between physical inactivity during work and AMD.50 Addi-tional research is necessary to evaluate these relationships.

alcohol intake Studies which have examined the relationship be-tween AMD and alcohol consumption have produced mixed results. Inthe Eye Disease Case-Control Study, no significant relationship be-tween alcohol intake and wet AMD was noted in univariate analyses,but an inverse association could not be ruled out in multivariate anal-yses.51,94 Another case-control study found a non-significant associationbetween current daily alcohol intake and AMD, although there was asuggestion of a non-linear trend with higher odds of AMD in personswho had 5 or more drinks per day, and lower odds in persons who had1-2 drinks per day compared to non-drinkers.50 In a case-control studyusing NHANES-1 data, moderate wine consumption was associatedwith decreased odds of developing AMD, although the analysis did notcontrol for the potentially confounding effects of smoking.95 In twopopulation-based cross-sectional studies, evidence for an associationbetween alcohol and AMD was weak. The Beaver Dam Study reportedslightly increased odds for retinal pigment degeneration in persons whoconsumed beer in the past year.96 However, in the Beaver Dam inci-dence study, beer drinking was only associated with incident retinaldrusen in men.97 The Blue Mountains Eye Study found increased oddsof dry AMD only in current liquor drinkers.98 Neither study foundincreased odds for AMD related to total alcohol intake. In a largeprospective study, there was no support for a protective associationbetween moderate alcohol consumption and risk of AMD, althoughthere was a suggestion of a modest increased risk of AMD in heavierdrinkers.99 In summary, the evidence to date suggests that alcohol in-take has little effect on AMD.

post-menopausal hormone use and menopause Only fourstudies have examined whether AMD may be related to use of post-menopausal hormones or type of menopause. In the Eye Disease Case-

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Control Study, former and current users of post-menopausal estrogenshad significantly reduced odds of developing wet AMD.51 Alternative-ly, the Beaver Dam Study reported no strong relationship betweenpresence of dry or wet AMD and premenopausal or post-menopausalestrogen use. However, this study had only 40 women with wet AMDwhich limited the power to detect an effect.100 A nested case-controlstudy found a nearly four-fold increased odds of AMD only in womenwho had oophorectomies leading to menopause before age 45.101 TheBlue Mountains Eye Study reported a small but significant decrease inthe odds of early AMD with increasing number of years betweenmenarche and menopause, but no difference in odds of early or lateAMD among women who had used hormone replacement therapy orwho had early menopause.102 Although the evidence is sparse, a protec-tive effect of estrogen on AMD cannot be ruled out, and further re-search is warranted.

aspirin use Only one cross-sectional study has addressed aspirinuse and the risk for AMD. Comparing aspirin users to non-users, nodifference in prevalence of AMD was found in a Finnish population of478 persons over age 70, which included 199 cases of dry or wetAMD.64 Additional investigations are needed to explore the relation-ship between aspirin use and different forms of AMD will remain un-known.

nutritional factors The possible role of antioxidant vitamins inthe pathogenesis of AMD has received a great deal of attention.5,7 An-tioxidants such as vitamin C (ascorbic acid); vitamin E (alpha-toco-pherol); and the carotenoids, including alpha-carotene, beta-carotene,cryptoxanthin, lutein and zeaxanthin; may be relevant to AMD due totheir physiologic functions and the location of some of these nutrientsin the retina. Trace minerals like zinc, selenium, copper, and manga-nese may also be involved in antioxidant functions of the retina.3,103

Theoretically, antioxidants could prevent oxidative damage to theretina, which could, in turn, prevent development of AMD.7,104 Damageto retinal photoreceptor cells could be caused by photo-oxidation or byfree radical induced lipid peroxidation.105 This could lead to impairedfunction of the retinal pigment epithelium and, eventually, to degener-ation involving the macula.7,105,106 The deposition of oxidized compoundsin healthy tissue may result in cell death because they are indigestibleby cellular enzymes.105,107 One possible mechanism involved in thepathogenesis of AMD may be the inability to prevent the deposition orthe removal of these non-digestible compounds from healthy eye tis-sue.103 Some experimental data support this theory. Age-related chang-es in the macula may lead to increased susceptibility to oxidative damagedue to lipid peroxidation.106 Antioxidants may scavenge, decompose, orreduce the formation of harmful oxidants. Hopefully, a dietary inter-vention that increases consumption of antioxidant nutrients could be-come a primary prevention method for controlling oxidative damagethat may lead to AMD. However, results of prospective studies andrandomized clinical trials are needed.103

The Eye Disease Case-Control Study (EDCCS) reported that personswith higher serum levels of carotenoids (sum of serum lutein/zeaxan-

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thin, beta-carotene, alpha-carotene, cryptoxanthin, and lycopene levels)had markedly reduced risks of wet AMD.51 Persons with higher serumlevels of lutein/zeaxanthin, beta-carotene, alpha-carotene, and cryptox-anthin had reduced risks of wet AMD. The study did not find a statis-tically significant protective effect for serum levels of vitamin C, vita-min E, or selenium individually, but when these were combined into anantioxidant index with carotenoids, there was a significant reduction inrisk of wet AMD with increasing levels of the index.108 In the DietaryIntake Study of the EDCCS, an inverse association between wet AMDand dietary intake of carotenoids was observed. High intake of greenleafy vegetables containing the carotenoids lutein and zeaxanthin wasassociated with a reduction in risk of wet AMD. Intake of vitamin Cwas associated with a small but non-significant reduction in risk. Intakeof vitamin A or vitamin E was not associated with a reduction in risk.5

A cross-sectional study using NHANES-1 data examined the rela-tionship between the prevalence of any AMD and vitamins A and Cintake. A weak protective effect was seen with increased consumptionof fruits and vegetables rich in carotenoids which lead to formation ofvitamin A.47 The Beaver Dam Study found no effect for supplementalantioxidant vitamins alone or in combination on early or late AMD.109

However, in a case-control study nested within the Beaver Dam Study,a low serum level of one carotenoid, lycopene, was associated withpresence of any AMD.110 In the Beaver Dam incidence study, an in-verse association was seen between pro-vitamin A carotenoids and largedrusen.111 Another study reported a protective effect for any AMDamong those who had higher serum vitamin E and among those whohad higher values for an antioxidant index of vitamins C, E, and beta-carotene, but no protective effect was seen for vitamin supplementa-tion.112 A study of plasma levels of vitamins A and E and five caro-tenoids found no relationship with wet AMD in 65 case-control pairs.86

A small randomized trial demonstrated less visual loss due to AMDand less accumulation of drusen in the group of 97 patients assigned tohigh-dose zinc supplementation, compared to 84 patients in the placebogroup.113 Another small randomized trial found that zinc supplementa-tion had no short-term effect on the course of disease in 112 patientswith wet AMD.114 The Beaver Dam Study found a weak protectiveeffect of zinc intake on early AMD,109 and incidence of pigmentaryabnormalities.111 The EDCCS did not find any significant relationshipsbetween serum zinc levels or zinc supplementation and risk of wetAMD.51 In a small case-control study, an inverse association was notedbetween serum selenium levels and AMD.85

Overall, the results suggest that diets rich in antioxidant-rich fruitsand vegetables may be related to a lower risk of wet AMD. Increasedblood levels of carotenoids and antioxidant vitamins were also relatedto decreased risk of wet AMD in some studies. However, these rela-tionships need to be confirmed with prospective studies. The effect ofdietary intake of antioxidants on dry AMD has not yet been sufficientlystudied. Supplementation with antioxidant vitamins or minerals has notbeen shown to reduce the risk of AMD. This is currently under inves-tigation in a large randomized clinical trial among subjects with andwithout AMD at baseline, the Age-Related Eye Disease Study spon-sored by the National Eye Institute.115 This study is evaluating whether

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supplementation with high dose zinc or antioxidant vitamins C, E, andbeta-carotene reduces the incidence or progression of dry or wet AMD,as well as lens opacities.

Summary of the evidence to date Epidemiologic studieswhich have evaluated risk factors that are common to both CVD andAMD suggest the possibility of a causal relationship between CVDmechanisms and AMD, with some possible differences in the mecha-nisms for dry and wet AMD. Among factors common to both diseases,increasing age and cigarette smoking are most consistently associatedwith AMD. Low antioxidant intake has been associated with an in-creased risk of AMD in some studies. Risk factors such as hyperten-sion, hypercholesterolemia, high saturated fat intake, and diabetes havealso been associated with AMD in some, but not all studies. Risk fac-tors that have not been well studied with regard to AMD include obe-sity, increased physical activity, alcohol consumption, post-menopausalestrogen use, and aspirin use. Additional research into these areas maylead to important insights into etiologic factors for AMD, and maypossibly identify new methods for preventing or slowing the progres-sion of AMD in susceptible individuals.

Biomarkers and avenues for future research Based onthe above research, we may better understand the mechanisms involvedin the development of AMD by evaluating several biomarkers of car-diovascular disease and oxidative stress. Homocysteine, B vitamins,apolipoproteins, lipoproteins, and fatty acids have all been implicatedeither as risk factors for CVD or in oxidative processes. These biom-arkers and the potential role of genetic factors are discussed below.

homocysteine and B vitamins The amino acid homocysteineappears to be a powerful independent risk factor for CVD.116-122 Morethan 75 clinical and epidemiologic studies have consistently linkedelevated blood levels of homocysteine with an increased risk of variouscardiovascular endpoints.117,120,123-126 Vitamins B6, B12, and folate areinvolved as cofactors in the metabolism of homocysteine, so that lowlevels of these vitamins may lead to high levels of homocysteine, es-pecially in the elderly127 and smokers.128 In addition, elevated homocys-teine levels can often be normalized by modest doses of folate andvitamins B6 and B12.129 Recent studies have raised the strong possibil-ity that fortification or supplementation with vitamins B6, B12, andfolate may reduce the risk of cardiovascular diseases.117-119,121,125,130 Itmay be fruitful to begin research on the association between homocys-teine levels and incidence or progression of AMD. Finding a positiverelationship between homocysteine levels and AMD could lead to newpreventive strategies involving B-vitamin supplementation.

apolipoproteins and lipoproteins Measurement of lipoproteinsand apolipoproteins can supplement information from total cholesterolanalysis.131,132 Low levels of high-density lipoprotein (HDL) cholesteroland high levels of low-density lipoprotein (LDL) cholesterol have beenassociated with an increased risk of CVD in many studies.133 Decreased

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levels of apolipoprotein A-I and increased levels of apolipoprotein Bhave also been identified as independent risk factors for CVD in sev-eral studies.132,133 Apolipoprotein E has three common alleles whichhave a major impact on total and LDL cholesterol levels, with partic-ularly increased odds for CHD with the e4 allele.134 High lipoprotein(a)levels have been associated with CHD.133,135-137 Research is warrantedinto the relationship between levels of HDL, LDL, apolipoproteins A-1, B, and E, and lipoprotein(a) and AMD given the current interest instudying these factors in relation to CVD.

fatty acids Some fatty acids also seem to be involved in athero-genic processes. Increased intake of fish oil which is high in omega-3fatty acids has been associated with reduced risk of CHD in manystudies.138,139 On the other hand, trans-fatty acid intake, primarily fromeating processed vegetable oil, has been associated with a two-foldincreased risk for CHD.27 The omega-3 polyunsaturated fatty aciddocosahexanoic acid (DHA) is a major component of neural tissues andcomprises as much as 50% of the fatty acids in the retinal rod outersegments.140 A number of studies have reported a decrease in plasmalevel of DHA in persons with retinitis pigmentosa, indicating that re-duced DHA levels may be a sign of oxidative stress.141,142 Given therelationship between increased susceptibility of older human maculasto lipid peroxidation, and the importance of DHA to the retina, it seemsreasonable to speculate that lipid peroxidation and related fatty acidsmay also play some role in AMD. The role that DHA and other omega-3 fatty acids may play in the pathogenesis of AMD warrants investiga-tion.

C-reactive protein C-reactive protein (CRP) is considered one ofseveral acute phase proteins that are related to inflammatory activitydue to the injury of cells and tissues.143,144 CRP has been demonstratedto be a short-term biomarker of risk of myocardial infarction in patientswith unstable angina.145 In the European Concerted Action on Throm-bosis study, after two years of follow-up, those patients with an acutecoronary event had CRP levels that were 20% higher than those ofcontrols. The Multiple Risk Factor Intervention Trial (MRFIT) indicat-ed that there was a significant association between the available distri-bution of CRP and the subsequent coronary heart disease mortality insmokers.143 The Physicians’ Health Study found that elevated baselineplasma concentration of CRP predicted the risk of future myocardialinfarction and ischemic stroke independently of other risk factors.146 Ina meta-analysis of seven published prospective studies, individuals withCRP values in the top third had nearly double the risk of CHD com-pared with those in the bottom third.147 There has also been some dis-cussion that AMD may have an inflammatory component,148 and infact, some physicians have attempted to treat AMD with steroids.149

Histopathologic study has demonstrated the presence of inflammatoryand reparative responses in the retina of patients with choroidal neovas-cularization. Clinical trials are beginning at the National Eye Instituteto study the effects of various anti-inflammatory therapies on the de-velopment and progression of the previously untreatable wet forms of

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AMD.150 Investigation of the association between C-reactive proteinlevels and the development or progression of AMD is justified.

genetic factors It has long been speculated that AMD or a sus-ceptibility toward developing it may be at least partially inherited, andthere is some evidence in the literature for a genetic component. Anearly study suggested that persons with AMD were three times morelikely to report a positive family history than were age-matched controlsubjects.45 A segregation analysis suggested that a single major gene isresponsible for about 90% of the genetic variability, or about 56% ofthe total variability, in AMD.151 Using a different methodology whichcompared families rather than patients, a two-fold to three-fold in-crease in risk was found among first degree relatives of patients withAMD compared with first degree relatives of control subjects.152 Familialaggregation was also demonstrated in another study population usingsimilar methodology.153 Thirteen different alterations were discoveredin one allele of the ABCR gene in 26 of 167 unrelated AMD patients,154

and additional studies are underway to evaluate this relationship. Re-ports of concordance for AMD in a few monozygotic twin pairs alsosuggest a role of genetic factors in the origin of AMD.155,156 A largepopulation-based twin study is currently underway which will provideestimates of heritability for various forms of age-related maculopa-thy.157

Reasons for the observed familial aggregation have not been delineat-ed, and could include a shared genetic susceptibility to AMD amongfamily members, as well as exposure to similar environmental riskfactors that are associated with this disease. Gene-environment interac-tions may also play a role. It is possible that some persons may begenetically predisposed to develop AMD and these susceptible individ-uals will manifest signs of this disease only when they are exposedduring their lifetimes to certain environmental or biologic influences.152

Many CVD risk factors (and possibly AMD risk factors) are also likelyto be under genetic control. As advances are made in the knowledgeand understanding of the genetic predisposition to both AMD and CVD,it may be possible to target susceptible individuals for increased sur-veillance and offer preventive as well as better therapeutic measures inthe future. A therapeutic approach that combines biologic, environmen-tal, lifestyle (smoking, diet) and pharmacologic modalities may mini-mize the impact of genetic susceptibility and reduce visual loss.

Conclusions and recommendations Age-related macular de-generation is the leading cause of irreversible vision loss among elderlyAmericans who make up the fastest growing segment of the US pop-ulation. To date, the etiology of this condition is unknown, and treat-ment options are limited. Current epidemiological findings point to apossible cardiovascular risk profile among some persons with AMD,and it seems possible that the two conditions may in some way beinterrelated. One could speculate that the dry form of AMD might beexacerbated by retinal pigment epithelial damage induced by local is-chemia caused by the same risk factors that induce atherosclerosis. Thewet form of AMD may simply carry that process a step further with the

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addition of vascular endothelial growth factor (VEGF)158 induced cho-roidal neovascularization stimulated by local ischemia.

If this hypothesis proves true, then searching for common mecha-nisms for the two diseases could help us to better understand the patho-physiology of AMD. Research aimed at investigating the associationsbetween serum lipids, vascular processes, and oxidative mechanismsand AMD could help elucidate potential correlates and mechanisms ofAMD. Biomarkers such as homocysteine, fatty acids, and certain otherlipids may also be associated with AMD. Similar inquiries into biom-arkers for CVD have led to better understanding of mechanisms ofCVD as well as targeting of high risk groups for interventions.

Identification of modifiable risk factors for AMD may improve ourability to identify and treat persons who are at high risk of either de-veloping AMD or of progressing to more severe forms of AMD. Suchefforts could also facilitate the search for various susceptibility geneswhich may predispose some persons to AMD development if they areexposed to certain environmental or biologic influences.152 Susceptibleindividuals could then be targeted for improved health promotion anddisease prevention measures as well as new therapeutic strategies forthis disabling and highly prevalent disorder. As we learn more aboutthe possible interrelated effects of risk factors for AMD and CVD,opportunities may emerge for coordinated preventive measures aimedat reducing the harmful effects of both conditions.

Acknowledgments The work was supported in part by Researchto Prevent Blindness. Dr. Seddon is a Lew R. Wasserman Merit Awardeefrom Research to Prevent Blindness.

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Do age-related macular degeneration and cardiovascular disease share common antecedents?