Background/aims To describe the prevalence of early, late and any age-related macular degeneration (AMD) in a clinical cohort (Australian Heart Eye Study, AHES) and to determine whether associations exist between extent and severity of coronary artery disease (CAD) and AMD, independent of traditional cardiovascular risk factors.
Methods The AHES is an observational study that surveyed 1680 participants between 2009 and 2012 who presented to a tertiary referral hospital for the evaluation of potential CAD by coronary angiography. Severity and extent of CAD was assessed using three scoring systems: (1) segment/vessel scores, (2) Gensini and (3) extent scores.
Results Prevalence of early and late AMD was 5.8% (n=86) and 1.4% (n=21), respectively. After multivariable adjustment, patients with stenosis >50% in any coronary artery segment (vessel score) had approximately twofold higher odds of early AMD, OR 1.95 (95% CI 1.07 to 3.57). Patients with obstructive coronary stenosis in all three main coronary arteries (segment score) had greater than twofold higher likelihood of early AMD, OR 2.67 (95% CI 1.24 to 5.78). Participants in the highest versus lowest tertile of Gensini scores were also twice as likely to have early AMD, multivariable-adjusted OR 2.27 (95% CI 1.12 to 4.58). Extent scores were not associated with AMD. There was no significant association between CAD and late AMD.
Conclusions Severity of coronary stenosis and the presence of stenotic lesions were independently associated with early AMD. These findings could have potential clinical significance as they suggest that individuals with evidence of CAD may be screened for early AMD.
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Age-related macular degeneration (AMD) is the leading cause of blindness and low vision in older adults.1 A wide range of risk factors have also been identified, ranging from demographic (ethnicity, gender) to dietary (vitamins, dietary fat, fish and alcohol) and environmental (smoking, sun exposure) factors.2–6
It has long been noted that AMD shares many risk factors with cardiovascular disease (CVD).7 For example, individual studies have reported associations between AMD and some clinical (hypertension, myocardial infarction, stroke and hyperlipidaemia),8–13 subclinical (carotid artery plaques and intima-medial thickness, MRI cerebral white matter lesions),11 ,14–16 inflammatory (C reactive protein)16 ,17 and genetic (apolipoprotein E gene, complement factor H polymorphism)18 ,19 risk factors of CVD.
However, in a systematic review and meta-analysis of 18 cross-sectional studies and six case–control studies that examined the link between late AMD and both general and CVD-specific risk factors, only one of the factors that demonstrated consistent and strong associations with AMD was also a risk factor for CVD. This was current cigarette smoking, the other risk factors being age, previous cataract surgery and a family history of AMD.20 Although consistent and moderate associations were found between AMD and a history of CVD, hypertension and higher body mass index (BMI), other CVD risk factors such as history of cerebrovascular disease, diabetes and hyperlipidaemia were found to have relatively weak and inconsistent associations with AMD.20
Most studies have examined the link between CVD and AMD through risk factors for CVD, including family history and markers of atherosclerosis or inflammation. To our best knowledge, no study has examined the relationship between the extent and severity of coronary artery disease (CAD) estimated by quantitative coronary angiography (QCA) and AMD.
Thus, the aims of this study were to (1) describe the prevalence of early, late and any AMD in a unique clinical cohort of high-risk patients presenting for coronary angiography (the Australian Heart Eye Study, AHES), (2) compare the age-standardised prevalence of AMD in the AHES with baseline prevalence from the Blue Mountains Eye Study (BMES), (3) determine whether associations exist between the extent and severity of CAD and prevalent early, late and any AMD, independent of traditional CVD risk factors and (4) investigate such associations in sex-stratified subanalyses.
Study population and data collection
The AHES is a clinical cohort study of 1680 participants who presented to a major tertiary referral hospital servicing the greater Western Sydney area (Westmead Hospital, Sydney, Australia) between June 2009 and January 2012 to evaluate potential CAD by coronary angiography.
All eligible patients presenting for assessment of suspected CAD were included in this study. Exclusion criteria were patients with a history of coronary artery bypass graft or coronary artery stent. These patients were excluded because the Gensini and extent scoring systems used have not been validated in this group. Participants were also excluded if they had incomplete information on AMD signs or absent Gensini or extent scores.
Ethics approval for the AHES was obtained from the Western Sydney Local Health Network Human Research Ethics Committee (Westmead). All patients provided written informed consent to participate in the study.
Assessment of AMD
All participants had digital retinal photographs taken after pharmacological mydriasis. Seven standard Early Treatment Diabetic Retinopathy Study (ETDRS) 45° fields were taken on a digital camera (Canon CR-DGI, Tokyo, Japan). Digital images were viewed at high resolution before being graded (masked) for the presence of early and late AMD using the Wisconsin AMD Grading System.21 Intergrader and intragrader reliability showed good agreement in the identification of individual lesions.22
‘Early AMD’ prevalence was defined as the absence of late AMD and presence of either large (0.125 mm diameter) indistinct soft or reticular drusen or both large distinct soft drusen and retinal pigmentary abnormalities (hyperpigmentation or hypopigmentation). Similarly, ‘late AMD’ prevalence was defined as the presence of either neovascular or atrophic AMD in that eye. Neovascular AMD was defined as the presence of serous or haemorrhagic detachment of the retinal pigment epithelium (RPE) or sensory retina, presence of subretinal or sub-RPE haemorrhages or subretinal fibrosis. Atrophic AMD was defined as a discrete area, at least 175 µm in diameter, of retinal depigmentation characterised by a sharp border and presence of visible choroidal vessels.23
‘Any AMD’ prevalence was defined as the presence of either early or late AMD. A retinal specialist (PM) adjudicated all uncertain retinal pathology and confirmed all late AMD cases.4
Assessment of CAD
Routine diagnostic coronary angiography was performed after 6 h fasting via either the femoral or the radial artery using a catheter of known dimension (5Fr to 7Fr). Selective coronary injections of Ultravist (Schering) were filmed in standard projections on a Siemens Bi-Plane radiographic unit (Siemens Healthcare, Germany).
All angiograms were analysed offline by a trained cardiologist masked to the results of the adjunctive investigations and retinal grading. The coronary artery segments were defined using the Syntax system, which divides the arterial tree into 16 segments, based on the modified American Heart Association classification.24 For each segment, the severity of obstruction was documented using several grades: normal, 1%–25%, 25%–50%, 50%–74%, 75%–99% and 100% (occluded). Each lesion that was visually scored as >50% luminal obstruction in a vessel that was ≥1.5 mm diameter was further analysed using quantitative coronary angiography (QCA). QCA was performed using validated computerised edge-detection software (QCAPLUS, Sanders data Systems, Palo Alto, California, USA).
Coronary angiograms were scored according to the three methods to document both the severity and the extent of CAD:
Vessel and segment score (severity score): Vessel scores were calculated based on the number of vessels with significant obstructive coronary disease. The American College of Cardiology taskforce definition from 2011 uses 50% stenosis to define significant vessel disease.25 This definition was used for the left main coronary, right coronary, left anterior descending and left circumflex arteries. Scores ranged from 0 to 4, depending on the vessels with >50% stenosis.26 Left main artery stenosis was scored as double vessel disease, as per the Coronary Artery Surgery Study scoring system.27 The segment score was reported based on the number of obstructive lesions present in the 16 segments.
Gensini score (severity score): This has been described previously.28 Briefly, the coronary arterial tree was divided into segments with multiplying factors according to the functional importance of any given segment (5 for the left main trunk to 0.5 for the most distal segments) and the percentage reduction in luminal diameter of each narrowing was assigned a score (0, 1, 2, 4, 8, 16 or 32), according to the degree of stenosis. The sum of the scores of all segments gives the Gensini score, which places emphasis on the severity of the disease.26
Extent score: The extent score was proposed by Sullivan et al29 to define the proportion of the coronary arterial tree with angiographically detectable coronary atheroma. The proportion of each vessel involved by atheroma, identified by lumen irregularity, was multiplied by a factor for each vessel, which is related to the length of that vessel. The scores for each vessel were added to give a total score out of 100. This percentage represents the proportion of the coronary intimal surface area containing coronary atheroma.26
All analyses were performed using SAS statistical software (V.9.2, SAS Institute, Cary, North Carolina, USA).
Multivariate analyses using χ2 statistics and logistic regression models adjusted for age, sex, ethnicity, BMI, mean arterial blood pressure (MABP) and history of smoking, diabetes mellitus or acute myocardial infarction (AMI) were used to determine associations between prevalent AMD (study outcome) and the following variables: vessel score, segment score, Gensini score and extent score.
These tests were repeated in subgroup analyses by sex. Gender differences were postulated to be biologically plausible, given that the morphological aetiology and clinical signs and symptoms of ischaemic heart disease in women have been shown to differ from men.30
Comparisons between the BMES-1 and AHES were performed in patients aged 50 years and above. Both early and late AMD prevalence in the BMES-1 were age-standardised and weighted according to the age-specific sample sizes of the BMES. Statistical significance was defined as p<0.05.
AMD prevalence among participants with suspected CAD
A total of 1545 participants had information on AMD prevalence and complete data on CAD extent and severity and thus were included in the analyses. The mean age of participants was 61.06±11.62 years (range 23–92 years). Table 1 compares study characteristics of participants and non-participants.
The prevalence of early AMD was 5.8% (n=86), after excluding patients with late AMD in either eye. The overall prevalence of late AMD was 1.4% (n=21), including 0.5% (n=7) neovascular AMD and 0.7% (n=10) atrophic AMD. The prevalence of mixed AMD (neovascular AMD in one eye, with geographic atrophy in the other eye) was 0.3% (n=4). The prevalence of any AMD was 6.9% (n=107). Figures 1 and 2 show the prevalence of early, late and any AMD, stratified by age and sex, respectively.
Table 2 shows that the prevalence of early AMD in the AHES was significantly higher than the BMES baseline (BMES-1) prevalence rates for early AMD. The age-standardised prevalence in the AHES was 7.7% (95% CI 6.2% to 9.2%), whereas the age-standardised prevalence in the BMES-1 was 5.0% (95% CI 4.2% to 5.8%). Table 2 also indicates that the prevalence of late AMD was similar between the AHES and BMES samples (2.0% and 2.3%, respectively) although these were based on small numbers.
Associations between the presence of stenotic lesions and prevalence of AMD
After adjusting for age, sex, ethnicity, BMI, MABP, history of smoking, diabetes mellitus and AMI, patients with stenosis >50% in any coronary artery segment (segment score) had approximately twofold higher odds of having early AMD than patients without stenosis >50% in any segment, OR 1.95 (95% CI 1.07 to 3.57, p=0.03).
Patients with obstructive coronary stenosis in all three main coronary arteries (vessel score) compared with patients without any obstructive coronary stenosis had greater than twofold higher likelihood of early AMD, multivariable-adjusted OR 2.67 (95% CI 1.24 to 5.78, p=0.01). There was no significant association between the presence of stenotic lesions and prevalent late or any AMD.
Similar results were found when the above analyses were repeated for men only. Men with stenosis >50% (segment score) in any coronary artery segment had approximately twofold higher odds of having early AMD, OR 2.18 (95% CI 1.11 to 4.26, p=0.02). Men with obstructive coronary stenosis in all three main coronary arteries (vessel score) had approximately threefold higher likelihood of early AMD, multivariable-adjusted OR 3.10 (95% CI 1.19 to 8.11, p=0.02). There were no significant associations between the presence of stenotic lesions and early AMD in women.
Associations between extent and severity of CAD and prevalence of AMD
There was a significant association between Gensini scores and prevalence of early AMD. Table 3 shows that participants in the highest versus lowest tertile of Gensini scores were twice as likely to have early AMD, multivariable-adjusted OR 2.36 (95% CI 1.16 to 4.79, p=0.02).
Again, similar results were found when the above analyses were repeated for men. In men, each unit increase in Gensini score was associated with ∼1% increase in the prevalence of early AMD, multivariable-adjusted OR 1.01 (95% CI 1.00 to 1.02, p=0.01). In women, participants in the highest versus lowest tertile of Gensini scores were five times more likely to have early AMD, multivariable-adjusted OR 4.97 (95% CI 1.32 to 18.65, p=0.02). All associations between extent scores and prevalent AMD were non-significant.
This study is the first to show a significant association between clinically significant CAD and early AMD, through the use of coronary angiographic findings in a symptomatic population. The non-standardised prevalence of early and late AMD in this study was 5.8% and 1.4%, respectively. Prevalence from a large-scale international meta-analysis of AMD studies conducted across seven population-based studies from the USA, Europe and Australia reported a similar early AMD prevalence (6.12%) and a similar late AMD prevalence (1.47%) among participants aged above 40 years.31 Other population-based cohort studies have reported late AMD prevalence ranging from 1.46% in the Beaver Dam Eye Study (BDES) to 1.66% in the Rotterdam Study.20
However, the age-standardised prevalence of early AMD (7.7%) in the AHES was substantially higher than corresponding age-standardised baseline prevalence from a large Australian population-based cohort study, the BMES (5.0%). In most age strata apart from persons aged 70–79 years, the age-standardised prevalence in AHES was about twice that in the BMES. This difference, together with the significant associations we report between CAD and early AMD, suggests that patients with CAD are more likely to have early AMD. However, the age-standardised prevalence of late AMD (2.0%) in the AHES was comparable with age-standardised baseline prevalence rates in the BMES (2.3%).32
Our study showed that quantification of the severity of clinically significant CAD in terms of coronary angiographic measurements is independently associated with prevalence of early AMD. Multiple coronary angiographic measures of CAD were analysed to document the severity (vessel, segment, Gensini scores) and the extent of CAD.
The extent score is a measure of the burden of coronary atheroma, regardless of the severity of a stenosis.29 Interestingly, our study did not find an association between the extent of CAD and early AMD. However, there is as yet no consensus over which scoring system may serve as a ‘gold standard’ in the quantification of CAD, despite or because of potential correlations between them.33 Given that our study is the first to report on the association between specific measures of CAD burden and AMD, it was thus particularly important to comprehensively assess this association using multiple scoring systems.
The significant association between CAD and early AMD suggests that there is added importance in the screening and early diagnosis of AMD, especially among patients with clinically significant coronary atheroma. The fact that this study did not find an association between CAD and late AMD is plausible, as the mechanisms behind the development of early AMD are not likely to be the same as those involved in the progression from early to late AMD.34 We hypothesise that the lack of association is also due to the small sample size of participants who manifested both conditions concurrently. This is suggested by the observation that the mean age of patients with CAD tends to be lower than the age of peak prevalence of late AMD. For instance, the mean age of participants with clinically significant CAD was 60.7 years, whereas the peak prevalence of late AMD lay in the age groups of 70–79 years and 80+ years.
The associations found in women were inconsistent, with women in the highest versus the lowest tertile of Gensini scores (indexing the severity of CAD) manifesting a fivefold increased risk of early AMD, but with no other associations between specific angiographic signs of CAD and early AMD. In contrast, risk of early AMD in men was associated with all three scoring systems of obstructive CAD (Gensini, segment and vessel scores).
Past studies have indicated significant gender-specific differences in the pathology and presentation of ischaemic heart disease. The relevant disease aetiology in women is thought to be more multifactorial than in men. This warrants additional risk assessments, such as examination of blood inflammatory markers and predictors of plaque burden, to reflect any potential underlying pathology mediated by reproductive hormones, particularly oestrogen.30
Previous studies have suggested that diagnostic tests of ischaemic heart disease in women based on evidence of obstructive disease may not be as effective as the examination of prognostic risk, such as atherosclerotic risk burden or the presence of ischaemia.30 ,35 ,36 However, the present study did not find an association between extent scores, the only scoring system based on the degree of atheroma (rather than obstruction) in the coronary arteries, and the prevalence of AMD, in either men or women. Further studies with greater sample sizes may therefore be warranted to explore sex-specific differences in the pathology and presentation of CAD and their associations with AMD, as these issues have broad clinical implications for the diagnosis, treatment and prognosis of men and women with both cardiovascular and ocular conditions.
Extant studies have varied widely in their respective designs and methodologies. Although previous population-based studies have examined cross-sectional and longitudinal associations between CVD and AMD, the current study is the first to examine the associations between specific clinical signs of CAD and AMD in a symptomatic clinical cohort. Meta-analysis of pooled estimates from prospective and cross-sectional studies has failed to find strong, consistent associations between vascular disease and AMD.20 This is especially true of early AMD. For instance, the Atherosclerosis Risk in Communities (ARIC) study reported an association between early AMD and risk of stroke in middle-aged participants,37 but did not find associations between early AMD and incident coronary heart disease (CHD) or all-cause mortality.37 In contrast, Sun et al7 reported an increased likelihood of CHD in participants with early AMD, but failed to find an association between stroke and either early or late AMD.
Many population-based studies, including the BDES,12 ARIC study38 and Cardiovascular Health Study,7 were often limited to mortality outcomes and incident CVD in their quantification of CAD and CVD. For instance, Tan et al39 using BMES data found that participants with early AMD had approximately twofold higher odds of CHD mortality compared with adjusted controls. This makes it difficult to draw specific conclusions about the associations between AMD and CAD pathology. In the present study, the clinical markers associated with AMD are specific to the coronary arteries and reflect actual atherosclerotic pathology, with the vessel, segment, Gensini and extent scoring systems all being well-established measures of CAD extent and severity.
Study strengths and weaknesses
Strengths of this study include its direct quantification of CAD through routine coronary angiography, the evaluation of AMD through a reproducible photographic grading system and its unique clinical cohort consisting of patients symptomatic for CVD.
One limitation of the study is the bias that is introduced when drawing comparisons between two discrete studies, the AHES and BMES. However, comparison of both early and late AMD prevalence was age-standardised against the BMES.
Another limitation of the study is its cross-sectional design, which renders it difficult to infer causal relationships. Furthermore, participants compared with non-participants differed in several study characteristics such as age, gender distribution, ethnicity, smoking status and history of hypertension and diabetes; hence, there is the possibility of selection bias here. Finally, there is the potential for residual confounding effects from unmeasured or unknown parameters, such as inflammatory markers or endothelial dysfunction, which were not adjusted for in this study.
In summary, this study has demonstrated that the severity of coronary stenosis and the presence of stenotic lesions in the coronary tree are independently associated with the prevalence of early AMD. This study also found that the presence of three-vessel CAD is associated with the prevalence of any AMD. In addition, there was a doubling of the age-adjusted prevalence of early AMD in patients with symptomatic CAD. These findings have potential clinical significance as they highlight the importance of monitoring individuals with evidence of CAD for signs of early AMD, at a time when preventive strategies to delay progression to late stages of the disease can be introduced.
Contributors All eight authors are justifiably credited with authorship, according to the authorship criteria. In detail: SBW contributed in analysis and interpretation of data, drafting of manuscript, final approval given; PM, JC, GL, AJHP, AT and BG in conception, design, data acquisition, critical revision of manuscript, final approval given and GB in the analysis and interpretation of data, critical revision of manuscript, final approval given.
Competing interests None.
Patient consent Obtained.
Ethics approval Western Sydney Local Health Network Human Research Ethics Committee (Westmead).
Provenance and peer review Not commissioned; externally peer reviewed.