Age-Related Macular Degeneration and Cardiovascular Diseases: Revisiting the Common Soil Theory : The Asia-Pacific Journal of Ophthalmology

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Age-Related Macular Degeneration and Cardiovascular Diseases: Revisiting the Common Soil Theory

Mauschitz, Matthias M. MD, PhD; Finger, Robert P. MD, PhD

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Asia-Pacific Journal of Ophthalmology 11(2):p 94-99, March-April 2022. | DOI: 10.1097/APO.0000000000000496
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Age-related macular degeneration (AMD), a complex disease associated with aging, remains one of the leading causes of visual loss in high-income countries and its prevalence is expected to increase over the next decades. Polypoidal choroidal vasculopathy has been considered a variant of neovascular AMD and is highly prevalent in Asian populations. Similarly, cardiovascular disease (CVD)—another complex disease associated with aging—is a leading cause of morbidity and mortality in high-income countries and its prevalence is also expected to increase due to population aging. Previous studies reported an increased risk for CVD in AMD patients, indicating an underlying “common soil.” Reviewing the current literature, consistent evidence for common risk factors and mutual comorbidity was identified for both diseases. Cardiovascular risk factors include smoking, diet, and low levels of physical activity, which also play a role in AMD pathogenesis. Several studies demonstrated AMD patients to be at higher risk for CVD compared to the general older population. The complexity of both diseases, however, complicates research on their relation, and thus studies ought to be interpreted with caution. Herein we present an overview of selected studies and their main “take-home messages” on this topic, and hypothesize on the patho-etiologic “common ground” of these 2 diseases.

Age-related macular degeneration (AMD) is a chronic disease and one of the major causes of visual loss in the elderly worldwide, and due to population aging, incidence and prevalence are expected to increase significantly over the next decades. Previous studies reported an estimated prevalence of over 25% in subjects above the age of 60 years and a 15% increase in AMD incidence in individuals aged 75 years and older.1–3 Polypoidal choroidal vasculopathy (PCV), a disease highly prevalent in Asian populations, has been considered a variant of neovascular AMD and reported to share similar risk factors.4,5 AMD is a complex multifactorial disease with genetic and environmental risk factors.2,4–7 Besides aging as the main risk factor, lifestyle risk factors such as diet, smoking, and a sedentary lifestyle, chronic inflammation, and increased oxidative stress have been implicated in AMD etiology.7–11

Cardiovascular disease (CVD) affects the heart and vascular system and includes coronary heart disease (CHD) and cerebrovascular disease (stroke).12,13 Currently, CVD accounts for nearly half of noncommunicable diseases worldwide and nearly 50% of mortality in Europe.14 Globally, CVD is one of the leading causes of death, with an estimated 17.3 million deaths per year and projected to increase to 23.6 million deaths per year by 2030.15 Common risk factors are similar to those of AMD and include aging, diet and obesity, low levels of physical activity (PA), smoking, hypertension, and genetic predisposition.14–16

Early studies from the 1990 s reported a high intake of saturated fat and cholesterol to be associated with an increased risk for early AMD and hypothesized that atherosclerosis and its risk factors are related to AMD.12,17 Subsequently, various party-inconsistent studies have reported associations between CVD and respective risk factors with AMD and drew similarities to the “common soil” hypothesis of the relation between atherosclerosis and diabetes.18–21 A recent meta-analysis identified increased mortality due to CVD in persons with AMD.22 Against this background we reviewed the current literature on the associations of AMD and CVD, including any “common soil” theories.


We performed a nonsystematic review on PubMed during September and October 2021 using the following terms separately or in combination with one another: “age-related macular degeneration,” polypoidal choroidal vasculopathy,” “cardiovascular disease,” “coronary heart disease,” “cerebrovascular disease,” “atherosclerosis,” and “mortality.” All relevant abstracts were reviewed, and full-text articles and respective references were downloaded when indicated. We included observational and/or interventional studies, reviews, and meta-analyses on AMD, CVD, and respective risk factors published in English, and excluded case reports and case series. We reviewed methods of included studies for quality of study design, plausibility of results, and adherence to available reporting guidelines where available. If reported in the meta-analyses, we extracted aggregated data on the relation of AMD and CVD [namely relative risk (RR) and hazard ratio (HR)]. We did not limit our literature search to a specific period of time but aimed to report both, the earliest and the most current studies and potential evolvements of findings over time.


Early publications on the relation between traditional cardiovascular risk factors and AMD were published in the 1990 s and discussed potential similarities and overlaps in the causal pathways of AMD and CVD, which are depicted in the following.12,17,23 Subsequently, numerous studies have investigated mutual determinants of and associations between these diseases.

Age-Related Macular Degeneration and Cardiovascular Disease

Epidemiological studies from the 2000 s investigated and reported a link between CVD and AMD in different populations, but studies were inconsistent and partly contradictive.

Although 1 population study found AMD patients at higher risk for CHD [HR 1.57, 95% confidence interval (CI): 1.17–2.22] but not for stroke,24 another study did find an association with stroke (HR 1.85, 95% CI: 1.19–2.87)25 and the Rotterdam Study suggested an increased risk for cerebral hemorrhage but not cerebral infarction.26 Further studies reported mainly patients with late neovascular AMD to have an increased risk for CHD,27 myocardial infarction (MI)21,28 and stroke.28–31 In contrast, other studies found no association of AMD with CVD,32 MI,33 stroke,20,24 and general arterial thromboembolic events,20 or even reported lower rates of MI and stroke in late AMD patients.34

Subsequently, several meta-analyses investigated the relation between AMD and CVD as well as CVD mortality. A meta-analysis published in 2014 found a 15% increased RR for CVD (RR 1.15, 95% CI: 1.08–1.22), but no association with stroke in early AMD patients. In late AMD patients, the authors reported a borderline increased risk for CVD (RR 1.17, 95% CI: 0.98–1.40), which increased significantly when including prospective studies only (RR 1.66, 95% CI: 1.31–2.10). Similarly, late AMD was associated with an increased risk for stroke when including prospective studies only (RR 1.43, 95% CI: 1.02–2.00).35

Another meta-analysis published in 2016 found increased all-cause mortality (RR 1.08, 95% CI: 1.00–1.17) and borderline increased CVD mortality (RR 1.18,95% CI: 0.98–1.43) for AMD patients, and a higher risk for CHD (RR 1.17, 95% CI: 0.94–1.45) and stroke (RR 1.13, 95% CI: 0.93–1.36). Subgroup analyses on type of AMD showed an increased risk for stroke in early AMD patients only (RR 1.21, 95% CI: 1.03–1.42).36

In 2017, McGuinness and colleagues reported a 20% increased risk for all-cause mortality (HR 1.20, 95% CI: 1.02– 1.41) and a 46% increased rate of cardiovascular mortality (HR 1.46,95% CI: 1.13–1.89) for those with late AMD but not in early AMD.22 This is in line with the latest meta-analysis published to date in 2018, which reported a 28% increased risk of cardiovascular mortality in patients with late (HR 1.28, 95% CI: 1.04–1.57) but not with early AMD.37

Common Risk Factors Identified in AMD and CVD

Various modifiable and nonmodifiable risk factors have been reported to be associated with both AMD and PCV as well as CVD pathogenesis.7,14

Older age is one of the strongest nonmodifiable determinants and has been linked to higher risk for AMD, PCV, and CVD in many studies.7,13,14,38–40 Aging is associated with manifold structural and functional changes of the retina and modifies a number of other systemic risk factors over the life course.7,41

Hence, the association of aging with AMD and CVD is unspecific, likely confounded, and only explains parts of the relation.

Further metabolic and cardiovascular risk factors have frequently been investigated in the context of AMD and have been discussed to increase AMD risk. These include tobacco smoking that has been the most consistently reported modifiable risk factor for AMD and PCV incidence and progression,7,40,42–44 and a dominant risk factor in CVD development.14 Tobacco smoke was reported to contain numerous toxic chemicals that cause endothelial dysfunction and increase oxidative stress.7,45 In AMD, increased inflammation in retinal pigment epithelium (RPE) cells and vascular changes in the choroidal vessels have been discussed as contributing mechanisms.7 Former smokers have been shown to have a higher AMD risk than nonsmokers until 20 years after cessation,46 underscoring the importance of prevention and educational measures. In CVD, cessation was reported to be associated with a reduced risk after 5 years among heavy smokers, which, however, was still higher compared to neversmokers.47

Although debated and not consistent across all studies, a higher body mass index (BMI) and arterial hypertension have been linked to an increased AMD and PCV risk.7,42,48,49 Both of these modifiable risk factors play an important role in CVD.7,14

Ethnicity also seems to play a role in prevalence and incidence of AMD, PCV, and CVD. Prevalence of AMD is higher in Whites compared to African populations, which was hypothesized due to ultraviolet protection by increased melanin.7,50 In contrast, Asian and African populations are more likely affected by PCV,5,51 which is similar to CVD affecting Africans more frequently.52

Although AMD pathogenesis likely involves lipid metabolism, studies on the association of different serum lipids and AMD prevalence, incidence, and progression reported inconsistent results.7,48 Although most studies could not find an association between cholesterol levels and AMD, 1 study reported higher cholesterol to be associated with an increased incidence of late AMD.7,43 Although generally assumed, previous studies on the impact of cholesterol on CVD risk reported heterogeneous results and did not allow for general conclusions either.53 Similarly, although most studies failed to show an association with serum triglycerides levels, which are a risk factor for CVD,14,54 a recent large-scale study suggested a reduced risk of AMD with higher triglycerides levels.55 Interestingly, high levels of high-density lipoprotein (HDL) were reported to increase the risk of AMD,55,56 which seems contrary to the relation of HDL with CVD. Moreover, lipid-lowering drugs such as statins are frequently used in CVD patients14 and have recently been reported to reduce AMD risk.57,58 Although reduced low-density lipoprotein and cholesterol levels as well as lower oxidative stress seem to play a key role in this association, the underlying mechanismis still to be clarified.7,8

Only few studies exist on the relation between AMD and clinically diagnosed atherosclerosis, which is usually assessed using carotid ultrasonography and is operator-dependent.48,59 Data from the Rotterdam study suggested an increased prevalence of late AMD in participants with atherosclerosis and hence proposed a mutual etiology,60 while 2 other studies found no association of carotid plaques and carotid wall stiffness with AMD.61,62 In absence of objective ultrasonography assessments, some studies assumed the presence of atherosclerosis in patients with a history of angina pectoris, MI, or stroke. However, atherosclerosis and cardiovascular events have been reported not to always correlate well and hence this proxy ought to be interpreted with caution.48

Apart from these risk factors, several protective factors have been reported to decrease the risk of both AMD and CVD. A Mediterranean diet has been shown to reduce the risk of developing late AMD10,63 in 2 prospective studies and is considered as one of the main bases of CVD prevention.14 It consists of nutrient-rich foods such as fruits, vegetables, legumes, and fish, which are low in saturated fats and naturally rich in antioxidants, and that may explain its protective features. Notably, studies on diet often rely on accurate recalling of the individual nutrition, are sensitive to bias, and thus ought to be interpreted carefully.7,10,14 Apart from diet, several nutritional supplements have been discussed to be beneficial for AMD and CVD. For instance, supplements of folic acid and vitamins B6 and B12 have been discussed to lower levels of homocysteine, which is proinflammatory and was reported to induce vascular endothelial dysfunction.64–66 However, while intake of these supplements seemed to reduce the risk for AMD,67 an effect on CVD development could not be shown.68

Increased PA was reported to decrease the risk for both AMD7,9,11,48 and CVD14,48,69 in various studies. Regular PA directly reduces other risk factors such as existing vascular lesions, body weight, lipid levels, blood sugar, and blood pressure,14,54 and is hypothesized to increase antioxidant enzyme activity.7,11


Multiple studies reported an increased risk for CVD (CHD and stroke) and CVD mortality in AMD patients, with risks ranging between 15% to 57%. Moreover, previous studies identified common mutual risk factors that may explain some of these associations, with the strongest link between both being advancing age. Yet, both diseases are multifactorial and have a heterogeneous phenotype, and their respective pathogeneses have not been entirely elucidated, which makes it difficult to clearly identify common underlying patho-etiologic mechanisms.

The overlap in AMD and CVD pathogeneses has been postulated to comprise different systemic pathways. Particularly, lipid metabolism and increased inflammation seem to play an important role in both AMD and CVD etiology.7,14,54,70 Soft drusen are a hallmark retinal lesion of AMD and have been reported to consist of lipid metabolic products (eg, lipoproteins and apolipoproteins) similar to atherosclerotic plaques.22,71–74 Oxidized lipids interact with the RPE and macrophages and trigger inflammatory processes in the systemic and choroidal circulation.35,75 In the eye, downstream effects of increased oxidative stress and inflammation have been reported to involve altered structure of RPE, choroid, and choriocapillaris, and eventually resulting in retinal damage.48,76,77 In the systemic vasculature, inflammation promotes the formation of atherosclerosis and contributes to CVD development.78

In contrast to classical soft drusen under the RPE, subretinal drusenoid deposits (SDD) are located above the RPE79 and have been associated with CVD. Previous studies showed associations of SDD with coronary artery disease (CAD)80 and cardiovascular mortality.81 Moreover, studies on SDD patients reported thinner choroid and reduced perfusion of the choroid and choriocapillaris,74,75 which may contribute to advanced AMD phenotypes, such as (multilobular) geographic atrophy.82,83 Interestingly, reduced choroidal perfusion has also been linked to CAD, suggesting SDD as a potential biomarker in CAD patients.84,85 It remains unclear whether SDD and soft drusen are distinct diseases that only merge in advanced AMD and hence, inconsistency in previous studies may be caused by the lack of drusen-type differentiation. Further studies ought to discriminate the contribution of SDD and other lesion types to the association between AMD and CVD.

Increased inflammation seems to be one of the etiologic key factors in AMD, PCV, and CVD, and different inflammation markers have been shown to be strongly associated with both late AMD and CVD.5,7,22,86 Moreover, many of the aforementioned risk factors are associated with inflammation and vascular alterations. Several studies reported increased proinflammatory factors (eg, parts of the complement system and cytokines) and decreased protective carotenoids in persons with obesity.7,48,87 Although arterial hypertension was described to decrease choroidal blood flow and thus contribute to AMD progression,88 smoking was reported to increase oxidative stress and to be a source of free radicals damaging the vascular endothelium.7,89 Supportively, the protective effect of high PA and a Mediterranean diet was justified by decreased oxidative stress and increased antioxidant enzyme activity,7,9–11,63 and antioxidant nutrients have been named beneficial for AMD and CVD.7,90

Interestingly, increased HDL levels, which are protective for CVD development, seem to increase the risk for AMD. Lipoproteins were reported to be close to the complement system, and HDL has been shown to partially contain essential complement components such as C1, C2, C3, and C5,91,92 Hence, increased HDL may have proinflammatory characteristics and cause an imbalance of physiologic homeostasis in the retina contributing to AMD development.55,93,94 In contrast, the protective effect of HDL in CVD was not only linked to the transportation of cholesterol but also of lipid oxidation products, indicating an anti-inflammatory task in atherosclerosis and underscoring the complexity of the lipid metabolism.95

Several limitations of these studies on AMD and CVD need to be acknowledged. Because of the high mortality of CVD and the comparatively later onset age of AMD, a potential selection (survivorship) bias of more resilient patients in these studies may occur. Previously, survival bias has been reported to attenuate associations of risk factors and diseases of aging.96 Exemplary, 1 meta-analysis only found a higher risk in studies with mean participant age below 75 years, indicating that older persons at baseline may not survive long enough to find an association.35 This is reflected in the observation that more women tend to be diagnosed with AMD because men may die at an earlier stage of life.97 Moreover, associations of the different stages of AMD with CVD or its risk factors vary across studies. This is likely due to a population effect within individual studies and due to the large heterogeneity between included studies in any of the meta-analyses, which may have decreased statistical power, increased noise in the data and hence attenuated some effects.22,35–37 The assessment of certain risk factors such as diet and PA is challenging, as these variables may be subject to recall and social desirability bias and hence are likely less accurate than objective measurements. Lastly, different methodologic approaches within studies reduce comparability. This concerns study type (population vs case-control study), adjustment of confounders, assessments of risk factors, and outcome definition. In case of the latter, many studies use CVD mortality as proxy for CVD because these data are more easily obtained from death records. This, however, may cause an underestimation of overall CVD prevalence and/or a selection bias of more severe cases leading to CVD-caused mortality. Lastly, the lack of evidence for several cardiovascular risk factors for PCV as compared to AMD is likely due to much less studies investigating solely PCV or stratifying AMD into its subgroups including PCV.

In conclusion, there is consistent evidence for a relation between AMD and CVD. The complex underlying mechanisms seem to be entangled in various systemic pathways and concern among others the lipid metabolism and increased inflammation. Yet, this complexity complicates the design of studies and limits the ability to deduct common underlying patho-mechanisms. Nonetheless, prevention of mutual risk factors can contribute to both AMD and CVD prevention and thus ought to be a public health priority.


1. Bourne RRA, Stevens GA, White RA, et al. Causes of vision loss worldwide, 1990–2010: a systematic analysis. Lancet Glob Health 2013; 1:e339–e349.
2. Colijn JM, Buitendijk GHS, Prokofyeva E, et al. Prevalence of age-related macular degeneration in Europe: the past and the future. Ophthalmology 2017; 124:1753–1763.
3. Li JQ, Welchowski T, Schmid M, et al. Prevalence and incidence of age-related macular degeneration in Europe: a systematic review and meta-analysis. Br J Ophthalmol 2020; 104:1077–1084.
4. Chaikitmongkol V, Cheung CMG, Koizumi H, et al. Latest developments in polypoidal choroidal vasculopathy: epidemiology, etiology, diagnosis, and treatment. Asia Pac J Ophthalmol (Phila) 2020; 9:260–268.
5. Sahu Y, Chaudhary N, Joshi M, et al. Int Ophthalmol 2021; 41:753–765.
6. Choudhary M, Malek G. A review of pathogenic drivers of age-related macular degeneration, beyond complement, with a focus on potential endpoints for testing therapeutic interventions in preclinical studies. Adv ExpMed Biol 2019; 1185:9–13.
7. Heesterbeek TJ, Lorés-Motta L, Hoyng CB, et al. Risk factors for progression of age-related macular degeneration. Ophthalmic Physiol Opt 2020; 40:140–170.
8. Jarrett SG, Boulton ME. Consequences of oxidative stress in age-related macular degeneration. Mol Aspects Med 2012; 33:399–417.
9. McGuinness MB, Le J, Mitchell P, et al. Physical activity and age-related macular degeneration: a systematic literature review and meta-analysis. Am J Ophthalmol 2017; 180:29–38.
10. Merle BMJ, Colijn JM, Cougnard-Grégoire A, et al. Mediterranean diet and incidence of advanced age-related macular degeneration: the EYE-RISK Consortium. Ophthalmology 2019; 126:381–390.
11. Mauschitz MM, Schmitz M-T, Verzijden T, et al. Physical activity, incidence and progression of age-related macular degeneration: a multi-cohort study. Am J Ophthalmol 2021; 236:99–106.
12. Snow KK, Seddon JM. Do age-related macular degeneration and cardiovascular disease share common antecedents? Ophthalmic Epidemiol 1999; 6:125–143.
13. North BJ, Sinclair DA. The intersection between aging and cardiovascular disease. Circ Res 2012; 110:1097–1108.
14. Francula-Zaninovic S, Nola IA. Management of measurable variable cardiovascular disease’ risk factors. Curr Cardiol Rev 2018; 14:153–163.
15. Laslett LJ, Alagona P, Clark BA, et al. The worldwide environment of cardiovascular disease: prevalence, diagnosis, therapy, and policy issues: a report from the American College of Cardiology. J Am Coll Cardiol 2012; 60:S1–S49.
16. Aragam KG, Natarajan P. Polygenic scores to assess atherosclerotic cardiovascular disease risk: clinical perspectives and basic implications. Circ Res 2020; 126:1159–1177.
17. Mares-Perlman JA, Brady WE, Klein R, et al. Dietary fat and age-related maculopathy. Arch Ophthalmol 1995; 113:743–748.
18. Stern MP. Diabetes and cardiovascular disease. The “common soil” hypothesis. Diabetes 1995; 44:369–374.
19. Jarrett RJ. Type 2 (non-insulin-dependent) diabetes mellitus and coronary heart disease-chicken, egg or neither? Diabetologia 1984; 26:99–102.
20. Alexander SL, Linde-Zwirble WT, Werther W, et al. Annual rates of arterial thromboembolic events in medicare neovascular age-related macular degeneration patients. Ophthalmology 2007; 114:2174–2178.
21. Duan Y, Mo J, Klein R, et al. Age-related macular degeneration is associated with incident myocardial infarction among elderly Americans. Ophthalmology 2007; 114:732–737.
22. McGuinness MB, Karahalios A, Finger RP, et al. Age-related macular degeneration and mortality: a systematic review and meta-analysis. Ophthalmic Epidemiol 2017; 24:141–152.
23. Friedman E. The role of the atherosclerotic process in the pathogenesis of age-related macular degeneration. Am J Ophthalmol 2000; 130:658–663.
24. Sun C, Klein R, Wong TY. Age-related macular degeneration and risk of coronary heart disease and stroke: the Cardiovascular Health Study. Ophthalmology 2009; 116:1913–1919.
25. Wong TY, Klein R, Sun C, et al. Age-related macular degeneration and risk for stroke. Ann Internal Med 2006; 145:98–106.
26. Wieberdink RG, Ho L, Ikram MK, et al. Age-related macular degeneration and the risk of stroke: the Rotterdam study. Stroke 2011; 42:2138–2142.
27. Wong TY, Tikellis G, Sun C, et al. Age-related macular degeneration and risk of coronary heart disease: the Atherosclerosis Risk in Communities Study. Ophthalmology 2007; 114:86–91.
28. Tan JSL, Wang JJ, Liew G, et al. Age-related macular degeneration and mortality from cardiovascular disease or stroke. Br J Ophthalmol 2008; 92:509–512.
29. Hu CC, Ho JD, Lin HC. Neovascular age-related macular degeneration and the risk of stroke: a 5-year population-based follow-up study. Stroke 2010; 41:613–617.
30. Ikram MK, Mitchell P, Klein R, et al. Age-related macular degeneration and long-term risk ofstroke subtypes. Stroke 2012; 43:1681–1683.
31. Liao D, Mo J, Duan Y, et al. Is age-related macular degeneration associated with stroke among elderly americans? Open Ophthalmol J 2008; 2:37–42.
32. Fernandez AB, Wong TY, Klein R, et al. Age-related macular degeneration and incident cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis. Ophthalmology 2012; 119:765–770.
33. Golan S, Shalev V, Goldstein M, et al. The rate of myocardial infarction events among patients with age-related macular degeneration: a population-based study. Graefes Arch Clin ExpOphthalmol 2011; 249:179–182.
34. Nguyen-Khoa B-A, Goehring EL, Werther W, et al. Hospitalized cardiovascular diseases in neovascular age-related macular degeneration. Arch Ophthalmol 2008; 126:1280–1286.
35. Wu J, Uchino M, Sastry SM, et al. Age-related macular degeneration and the incidence of cardiovascular disease: a systematic review and meta-analysis. PloS one 2014; 9:e89600.
36. Wang J, Xue Y, Thapa S, et al. Relation between age-related macular degeneration and cardiovascular events and mortality: a systematic review and meta-analysis. Biomed Res Int 2016; 2016:8212063.
37. Xin X, Sun Y, Li S, et al. Age-related macular degeneration and the risk of all-cause and cardiovascular mortality: a meta-analysis of cohort studies. Retina (Philadelphia PA) 2018; 38:497–507.
38. Tikellis G, Robman LD, Dimitrov P, et al. Characteristics of progression of early age-related macular degeneration: the cardiovascular health and age-related maculopathy study. Eye (London England) 2007; 21:169–176.
39. Shim SH, Kim SG, Bae JH, et al. Risk Factors for progression of early age-related macular degeneration in Koreans. Ophthalmic Epidemiol 2016; 23:80–87.
40. Cackett P, Yeo I, Cheung CMG, et al. Relationship of smoking and cardiovascular risk factors with polypoidal choroidal vasculopathy and age-related macular degeneration in Chinese persons. Ophthalmology 2011; 118:846–852.
41. Ehrlich R, Harris A, Kheradiya NS, et al. Age-related macular degeneration and the aging eye. Clin Interv Aging 2008; 3:473–482.
42. Chakravarthy U, Wong TY, Fletcher A, et al. Clinical risk factors for age-related macular degeneration: a systematic review and meta-analysis. BMC Ophthalmol 2010; 10:31.
43. Tomany SC, Wang JJ, van Leeuwen R, et al. Risk factors for incident age-related macular degeneration: pooled findings from 3 continents. Ophthalmology 2004; 111:1280–1287.
44. Ueta T, Obata R, Inoue Y, et al. Background comparison of typical age-related macular degeneration and polypoidal choroidal vasculopathy in Japanese patients. Ophthalmology 2009; 116:2400–2406.
45. Kondo T, Nakano Y, Adachi S, et al. Effects of tobacco smoking on cardiovascular disease. Circ J 2019; 83:1980–1985.
46. Vingerling JR, Hofman A, Grobbee DE, et al. Age-related macular degeneration and smoking. The Rotterdam Study. Arch Ophthalmol 1996; 114:1193–1196.
47. Duncan MS, Freiberg MS, Greevy RA, et al. Association of smoking cessation with subsequent risk of cardiovascular disease. JAMA 2019; 322:642–650.
48. Connell PP, Keane PA, O’Neill EC, et al. Risk factors for age-related maculopathy. J Ophthalmol 2009; 2009:360764.
49. Sakurada Y, Yoneyama S, Imasawa M, et al. Systemic risk factors associated with polypoidal choroidal vasculopathy and neovascular age-related macular degeneration. Retina (Philadelphia PA) 2013; 33:841–845.
50. Age-Related Eye Disease Study Research Group. Risk factors associated with age-related macular degeneration. A case-control study in the age-related eye disease study: Age-Related Eye Disease Study Report Number 3. Ophthalmology 2000; 107:2224–2232.
51. Uyama M, Wada M, Nagai Y, et al. Polypoidal choroidal vasculopathy: natural history. Am J Ophthalmol 2002; 133:639–648.
52. Zhang L, Olalere D, Mayrhofer T, et al. Differences in cardiovascular risk, coronary artery disease, and cardiac events between Black and White individuals enrolled in the PROMISE Trial. JAMA Cardiol 2021; e215340Online ahead of print. doi:10.1001/jamacardio.2021.5340.
53. Berger S, Raman G, Vishwanathan R, et al. Dietary cholesterol and cardiovascular disease: a systematic review and meta-analysis. Am J Clin Nutr 2015; 102:276–294.
54. Perk J, de Backer G, Gohlke H, et al. European guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J 2012; 33:1635–1701.
55. Colijn JM, Hollander Alden, Demirkan A, et al. Increased high-density lipoprotein levels associated with age-related macular degeneration: evidence from the EYE-RISK and European Eye Epidemiology Consortia. Ophthalmology 2019; 126:
56. Cougnard-Gregoire A, Delyfer M-N, Korobelnik J-F, et al. Elevated high-density lipoprotein cholesterol and age-related macular degeneration: the Alienor study. PloS One 2014; 9:e90973.
57. Le Ma, Wang Y, Du J, et al. The association between statin use and risk of age-related macular degeneration. Sci Rep 2015; 5:18280.
58. Guymer RH, Baird PN, Varsamidis M, et al. Proof of concept, randomized, placebo-controlled study of the effect of simvastatin on the course of age-related macular degeneration. PloS One 2013; 8:e83759.
59. Tahmasebpour HR, Buckley AR, Cooperberg PL, et al. Sonographic examination of the carotid arteries. Radiographics 2005; 25:1561–1575.
60. Vingerling JR, Dielemans I, Bots ML, et al. Age-related macular degeneration is associated with atherosclerosis. The Rotterdam Study. Am J Epidemiol 1995; 142:404–409.
61. Klein R, Klein BEK, Marino EK, et al. Early age-related maculopathy in the cardiovascular health study. Ophthalmology 2003; 110:25–33.
62. Cheung N, Liao D, Islam FMA, et al. Is early age-related macular degeneration related to carotid artery stiffness? The Atherosclerosis Risk in Communities Study. Br J Ophthalmol 2007; 91:430–433.
63. Merle BMJ, Silver RE, Rosner B, et al. Adherence to a Mediterranean diet, genetic susceptibility, and progression to advanced macular degeneration: a prospective cohort study. Am J Clin Nutr 2015; 102:1196–1206.
64. Mukhtar S, Ambati BK. The value of nutritional supplements in treating Age-Related Macular Degeneration: a review of the literature. Int Ophthalmol 2019; 39:2975–2983.
65. Heuberger RA, Fisher AI, Jacques PF, et al. Relation of blood homocysteine and its nutritional determinants to age-related maculopathy in the third National Health and Nutrition Examination Survey. Am J Clin Nutr 2002; 76:897–902.
66. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 2002; 288:2015–2022.
67. Christen WG, Glynn RJ, Chew EY, et al. Folic acid, pyridoxine, and cyanocobalamin combination treatment and age-related macular degeneration in women: the Women's Antioxidant and Folic Acid Cardiovascular Study. Arch Intern Med 2009; 169:335–341.
68. Bazzano LA, Reynolds K, Holder KN, et al. Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. JAMA 2006; 296:2720–2726.
69. Warburton DER, Nicol CW, Bredin SSD. Health benefits of physical activity: the evidence. CMAJ 2006; 174:801–809.
70. Siri-Tarino PW, Krauss RM. Diet, lipids, and cardiovascular disease. Curr Opin Lipidol 2016; 27:323–328.
71. Curcio CA, Johnson M, Rudolf M, et al. The oil spill in ageing Bruch membrane. Br J Ophthalmol 2011; 95:1638–1645.
72. Li C-M, Chung BH, Presley JB, et al. Lipoprotein-like particles and cholesteryl esters in human Bruch's membrane: initial characterization. Invest Ophthalmol Vis Sci 2005; 46:2576–2586.
73. Ebrahimi KB, Handa JT. Lipids, lipoproteins, and age-related macular degeneration. J Lipids 2011; 2011:802059.
74. Erke MG, Bertelsen G, Peto T, et al. Cardiovascular risk factors associated with age-related macular degeneration: the Tromsø Study. Acta Ophthalmol 2014; 92:662–669.
75. Shaw PX, Zhang L, Zhang M, et al. Complement factor H genotypes impact risk of age-related macular degeneration by interaction with oxidized phospholipids. Proc Natl Acad Sci USA 2012; 109:13757–13762.
76. Anderson DH, Mullins RF, Hageman GS, et al. A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol 2002; 134:411–431.
77. Donoso LA, Kim D, Frost A, et al. The role of inflammation in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 2006; 51:137–152.
78. Senoner T, Dichtl W. Oxidative stress in cardiovascular diseases: still a therapeutic target? Nutrients 2019; 11:2090.
79. Spaide RF, Ooto S, Curcio CA. Subretinal drusenoid deposits AKA pseudodrusen. Surv Ophthalmol 2018; 63:782–815.
80. Cymerman RM, Skolnick AH, Cole WJ, et al. Coronary artery disease and reticular macular disease, a subphenotype of early age-related macular degeneration. Curr Eye Res 2016; 41:1482–1488.
81. Mano F, Sprehe N, Olsen TW. Association of drusen phenotype in age-related macular degeneration from human eye-bank eyes to disease stage and cause of death. Ophthalmol Retina 2021; 5:743–749.
82. Maguire P, Vine AK. Geographic atrophy of the retinal pigment epithelium. Am J Ophthalmol 1986; 102:621–625.
83. Xu L, Blonska AM, Pumariega NM, et al. Reticular macular disease is associated with multilobular geographic atrophy in age-related macular degeneration. Retina (Philadelphia PA) 2013; 33:1850–1862.
84. Ahmad M, Kaszubski PA, Cobbs L, et al. Choroidal thickness in patients with coronary artery disease. PloS One 2017; 12:e0175691.
85. Wang J, Jiang J, Zhang Y, et al. Retinal and choroidal vascular changes in coronary heart disease: an optical coherence tomography angiography study. Biomed Opt Express 2019; 10:1532–1544.
86. Hong T, Tan AG, Mitchell P, et al. A review and meta-analysis of the association between C-reactive protein and age-related macular degeneration. Surv Ophthalmol 2011; 56:184–194.
87. Nolan J, O’Donovan O, Kavanagh H, et al. Macular pigment and percentage of body fat. Invest Ophthalmol Vis Sci 2004; 45:3940–3950.
88. Metelitsina TI, Grunwald JE, DuPont JC, et al. Effect of systemic hypertension on foveolar choroidal blood flow in age related macular degeneration. Br J Ophthalmol 2006; 90:342–346.
89. Burke A, Fitzgerald GA. Oxidative stress and smoking-induced vascular injury. Prog Cardiovasc Dis 2003; 46:79–90.
90. McDermott JH. Antioxidant nutrients: current dietary recommendations and research update. J Am Pharm Assoc (Wash) 2000; 40:785–799.
91. Gordon SM, Deng J, Lu LJ, et al. Proteomic characterization of human plasma high density lipoprotein fractionated by gel filtration chromatography. J Proteome Res 2010; 9:5239–5249.
92. Rezaee F, Casetta B, Levels JHM, et al. Proteomic analysis of high-density lipoprotein. Proteomics 2006; 6:721–730.
93. Eren E, Yilmaz N, Aydin O. High density lipoprotein and it's dysfunction. Open Biochem J 2012; 6:78–93.
94. Hima BG, Rao VS, Kakkar VV. Friend turns foe: transformation of anti-inflammatory HDL to proinflammatory HDL during acute-phase response. Cholesterol 2011; 2011:274629.
95. Ahotupa M. Oxidized lipoprotein lipids and atherosclerosis. Free Radic Res 2017; 51:439–447.
96. McGuinness MB, Karahalios A, Kasza J, et al. Survival bias when assessing risk factors for age-related macular degeneration: a tutorial with application to the exposure of smoking. Ophthalmic Epidemiol 2017; 24:229–238.
97. Rastogi N, Smith RT. Association of age-related macular degeneration and reticular macular disease with cardiovascular disease. Surv Ophthalmol 2016; 61:422–433.

age-related macular degeneration; cardiovascular disease; epidemiology

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