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

Abstract

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.

METHODS

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.

RESULTS

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 AMD^10,63 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 AMD^7,9,11,48 and CVD^14,48,69 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

DISCUSSION

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.