Discussion
Within all cardiovascular and neurovascular diseases, we have identified certain HRVDs that are both high risk systemically for mortality and morbidity and also high risk for compromised ocular perfusion. The HRVDs are cardiac diseases (valve defects, MI, CABG, CHF) and stroke/TIA. Our data support the hypothesis that within AMD, only SDDs, with or without drusen, are biomarkers for coexistent HRVDs. In the literature, there is a historic finding of the Wisconsin Study that SDDs are associated with decreased longevity,15 compared with drusen. The association of SDDs, not drusen, with life-threatening HRVDs is consistent with and could now explain this finding. A specific HRVD is MI from CAD. The reduced systemic perfusion from the MI is a risk for compromised ocular perfusion. In 38 cardiovascular subjects with and without documented CAD and without known maculopathy, we found a significant association of CAD with SDDs on SD-OCT imaging.11 Recently, preliminary data (126 subjects) for the present study demonstrated a strong association between the broad category of CVD and stroke (not the specific HRVDs studied herein) and subjects with SDDs.22 To the best of our knowledge, this is the first demonstration of an association of vascular disease with a lesion of AMD.
We further hypothesise, and the data are also consistent with, a straightforward vascular mechanism for the association: the inadequate ophthalmic perfusion associated with HRVDs drives SDDs. SDDs form in the photoreceptor (PR) layer (figure 1), whose blood supply is the CC.10 The PRs, with the highest demand for O2, per unit mass in the body,23 are supplied by the choroid, which has the greatest blood flow per unit mass.24 We thus hypothesise that SDDs result from hypoxaemic damage to these vulnerable PRs due to HRVD-associated perfusion deficits.
Because the ophthalmic artery (OA) is the main blood supply of the retina and choroid, our hypothesis also includes inadequate OA perfusion. The fact that the CC is particularly vulnerable to inadequate OA perfusion adds physiological consistency to these hypotheses. As demonstrated by Hayreh, the choroid is an end-arterial system supplying CC lobules10 without adjacent anastomoses. This places these lobules at particular risk. Second, the retinal circulation derives protection from inadequate OA perfusion by autoregulation, which is not present in the choroid.25 The literature also confirms choroidal abnormalities in the setting of CAD. We showed CAD was associated with generalised choroidal thinning,12 confirmed by a later study with OCTA that also documented CC insufficiency.26
Inadequate OA perfusion in AMD was demonstrated by magnetic resonance angiography, with further reduction in advanced AMD,27 consistent with our vascular hypothesis. Further direct evidence came from improved choroidal vascular indices following ipsilateral carotid endarterectomy.28 Even more directly, OA angioplasty has been performed for advanced AMD with good results reported, again consistent with our hypothesis.29
However, relationships of SDDs to CC insufficiency30 remain controversial. Hence, although we have proposed combining CC insufficiency and SDDs as the reticular macular disease phenotype of AMD,11 we have confined this report to SDDs and associations with HRVD, without claiming, or depending on, any mechanism. Hence, all statistical results and risk models from the data are also independent of the proposed mechanism.
In this paradigm HRVD and SDDs share risk factors, for example, hypertension, but do not share mechanisms: the mechanism of an HRVD may be atherosclerotic disease (ASD), but the HRVD, in turn, is the perfusion-based mechanism for SDDs. Thus, ASD is quite rare in the OA itself,31 but perfusion of the OA, the first intracranial branch of the internal carotid artery (ICA), is vulnerable to plaque in the ICA.
Bilateral SDDs in this study were also found associated with compromised cardiac output from causes other than ASD. There was one case of idiopathic CHF and 14 of valvular disease (table 1). To the best of our knowledge, this is the first reported association of any AMD lesion with cardiac valve defects.
Cholesterol has roles in both AMD and ASD. However, drusen dynamics are now correctly associated with local lipid pathways and lipid genetics,9 and not with atherosclerosis. The risk marker of low-serum HDL for ASD actually runs contrary for AMD, with higher HDL increasing AMD risk.32 This may now be clarified: high HDL was only established as a risk for drusen, because prior studies used colour photography, which is sensitive to drusen but not SDD.32 Low HDL is a risk for ASD, which in its HRVD forms is a risk for SDD, the other iAMD lesion. Hence, low HDL is a risk for SDDs, as demonstrated. Thus, HDL effect on AMD depends on the AMD lesion, drusen or SDD. The well-known risk of high LDL for ASD, however, translated into statin use if needed in our private clinics, without multivariate significance.
The further finding that lower HDL and SDDs are significantly and independently associated with HRVD is consistent with cardiovascular literature: increasing HDL confers increasing protection against ASD between HDL levels 35 and 60, but not beyond.33 No other covariates showed risks for the presence of HRVD with multivariate adjustment. The corresponding risk model displayed good accuracy, sensitivity and specificity. Future work should consider all the main vascular serum risks, which may vary in significance across age, gender and ethnicity.
Many lines of evidence suggest SDDs are markers for a retinal disease distinct from drusen22 and may even, like diabetic retinopathy, be a retinal disease driven by systemic vascular disease. Examples of pure SDDs from the three major HRVDs are shown in figures 2–4, respectively. The vascular paradigm for SDDs also helps explain the preponderance of women (~85%) among older AMD subjects with SDDs.11 18 The significantly earlier death of men from HRVD1 and the strong linkage of HRVD with SDDs found herein would make female preponderance of SDDs in later years more likely.
The study has several limitations. Selection bias against elderly and infirm subjects was discouraged but may have reduced CVD and stroke numbers. These, however, totalled 81/200, with 47/200 HRVD, spread across multiple disorders, which supported robust associations. The elderly mean age of ~80 years in both SDD and pure drusen groups also suggests our policies were effective. The multivariate regression model for HRVD has not yet been tested on a separate dataset. This would be required for population screening. For example, the results from this moderate-sized, mostly Caucasian elderly cohort invite replication in larger and diverse cohorts, for example, in Asians, with the prevalent polypoidal vasculopathy form of AMD,34 and in the disadvantaged, with excess CAD mortality.35 LDL might well have a stronger association with HRVD in the underserved. Vascular histories were patient reported, and HRVDs were verified from medical records. However, disease metrics such as cardiac ejection fraction and per cent ICA stenosis would have helped interpreting the results and should be included in future studies.
Strengths of this cross-sectional study at two tertiary retina referral centres include rigorous patient selection and AMD phenotyping with high-quality multimodal imaging for drusen and SDD, and contemporaneous lipid levels. The strong associations found between HRVD and SDDs suggest that the targeted subsets of vascular disease and AMD were the correct ones to answer old questions.3–5 Further, these associations can all be explained by a single vascular mechanism: systemic vasculopathy driving CC insufficiency. However, the data, which strongly associated HRVD with the presence of SDDs after the correction for multiple known risks, are independent of a particular mechanism. Hence, larger and detailed studies from both the ophthalmic and vascular perspectives are warranted to explore the mechanism and assess the full impact of these findings. In particular, the detection of SDDs in women could prompt evaluation for undiagnosed CAD, a serious issue in women’s health.36 37
In summary, the strong associations found herein between HRVD and SDDs in AMD subjects warrant validation on larger and varied cohorts, which in turn might lead to inexpensive screening for HRVD in population and eye clinics. The care of HRVD might likewise include retinal imaging for SDDs, with their high risk of AMD progression.13–15 Such programmes could be high impact initiatives in public health for the reduction of mortality, morbidity and blindness.
