Study links AMD to higher cardiovascular disease mortality in high-risk patients

(Image Credit: AdobeStock/New Africa)

Australian researchers identified in a recent study an association between age-related macular degeneration (AMD) and cardiovascular disease (CVD): they showed that the presence of AMD predicted an increased risk of all-cause and CVD mortality in patients with a high risk of CVD, even in the early stages of AMD,¹ according to Richard Kha, first author and medical student from the Centre for Vision Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia.

Kha was joined in this study by researchers from the Department of Cardiology, Westmead Hospital, Westmead, and the Department of Cardiology, Bankstown Hospital, Sydney, both in New South Wales, Australia.

The research team explained that while numerous studies have evaluated the relationship between AMD and CVD, no consensus was reached and the results were inconsistent.^2-10 Because there are no data that evaluated the impact of AMD on mortality in a high CVD risk cohort, they undertook a prospective cohort study that included 1,545 patients who presented with acute coronary syndrome.

Importantly, they emphasized the high impact the two diseases have. AMD affects the central retina¹¹ resulting in an increased risk of falls,¹² fractures,¹³ depression,¹⁴ and loss of independence.¹⁵

CVD is the leading cause of mortality despite advances in cardiac diagnosis and management and accounts for in excess of 30% of all deaths globally.¹⁶

“It has been hypothesized,” they noted, “that AMD shares a similar risk profile to CVD.^17,18 Many CVD risk factors that lead to shorter survival, such as advanced age, smoking, obesity, ethnicity, hypertension, and elevated serum cholesterol levels are also associated with AMD.^17,18

All study patients underwent coronary angiography and fundus photography; the photographs were graded as any, early, and late AMD. The investigators’ stated goal was “to improve the current understanding of whether AMD is a useful prognostic indicator for identifying adults with a lower chance of survival in a population that already has a higher baseline risk of mortality. They hypothesized that patients with AMD in a high-risk cohort will have an increased risk of CVD-specific mortality.”

What was the relationship between AMD and CVD?

Kha and colleagues reported the presence of any AMD in 107 (6.9%) participants, including those with early (n = 86) and late AMD (n = 21).

“Over 9 years of follow-up, 234 (15.1%) participants had died, including 174 (11.3%) participants from fatal CVD events. After controlling for age, sex, body mass index, total cholesterol, smoking status, history of diabetes, hypertension, myocardial infarction, stroke, and macrovascular coronary artery disease severity using the Gensini score, there was an increased rate of all-cause mortality for those with any AMD (HR, 2.37; 95% confidence interval [CI], 1.54–3.64), early AMD (HR, 2.42; 95% CI, 1.48–3.94), and late AMD (HR, 2.25; 95% CI, 1.08–4.71),” they said.

They also found that any AMD (HR, 2.62; 95% CI, 1.61–4.26) and early AMD (HR, 2.61; 95% CI, 1.50–4.64) also were associated with a greater likelihood of CVD mortality. However, late AMD was not associated with CVD mortality.

Discussing possibilities

Currently, the mechanisms underlying the association between AMD and CVD mortality are not clear.

“It is possible that AMD shares common antecedents with macrovascular diseases such as CVD. Chronic inflammation, oxidative stress, atherosclerosis, and abnormal lipid homeostasis are common biological mechanisms implicated in the development of AMD and CVD.^19,20 In AMD, oxidative stress, inflammation, and complement pathway activation lead to retinal pigment epithelial cell death and drusen formation.²¹ Drusen consist of lipids and apolipoproteins, and the mechanism behind drusen formation is thought to be similar to that of atherosclerotic plaques.²² Oxidized lipids interact with macrophages, initiating an inflammatory cascade resulting in atherosclerosis.²³ The excessive formation of arterial plaques increases the risk of adverse CVD events, such as stroke or fatal myocardial infarction,” the authors theorized.

Other factors are the strong association between genetic variants of complement factors and development of AMD,²⁴ and the activation of the complement pathway that predicts CVD and stroke risk.^25,26 In the systemic vasculature, interactions between oxidative stress, inflammation, and atherosclerosis lead to CVD and its adverse events.²⁷ In addition, the presence of reticular pseudodrusen, which is linked with the Y402H and ARMS2 69S alleles, has also been found to be associated with CVD and higher mortality rates.^28,29

The authors concluded, “AMD is a complex multifactorial disease that shares similar processes with CVD, and the association between AMD and CVD mortality is likely to be a combination of multiple factors rather than a single shared risk factor or biological pathway. Future research should seek to clarify the impact of reticular pseudodrusen and genetic variations in the complement pathway on AMD and CVD events.”

References

1. Kha R, Burlutsky G, Thiagalingam A, et al. Association between age-related macular degeneration and mortality in a high cardiovascular risk cohort: a prospective cohort study. Ophthalmol Retina. 2025;9:821-7.https://www.ophthalmologyretina.org/article/S2468-6530(25)00094-6/fulltext

2. Gopinath B, Liew G, Burlutsky, G, et al. Age-related macular degeneration and risk of total and cause-specific mortality over 15 years. Maturitas. 2016;84:63-67.

3. Fisher DE, Jonasson F, Eiriksdottir G, et al. Age-related macular degeneration and mortality in community-dwelling elders: the age, gene/environment susceptibility Reykjavik study. Ophthalmology. 2015;122:382-390.

4. Tan JS, Wang JJ, Liew G, et al. Age-related macular degeneration and mortality from cardiovascular disease or stroke. Br J Ophthalmol. 2008;92:509-512.

5. Clemons TE, Kurinij N, Sperduto RD, et al. AREDS Research Group. Associations of mortality with ocular disorders and an intervention of high-dose antioxidants and zinc in the age-related eye disease study: AREDS Report No. 13. Arch Ophthalmol. 2004;122:716-726.

6. Wang P, Wang J, Ma J, et al. The association between age-related macular degeneration and the risk of mortality. BioMed Res Int. 2017;2017:3489603.

7. Borger PH, van Leeuwen R, Hulsman CA, et al. Is there a direct association between age-related eye diseases and mortality? The Rotterdam study. Ophthalmology. 2003;110:1292-1296

8. Thiagarajan M, Evans JR, Smeeth L, et al. Cause-specific visual impairment and mortality: results from a population-based study of older people in the United Kingdom. Arch Ophthalmol. 2005;123:1397-1403.

9. Wang YX, Zhang JS, You QS, et al. Ocular diseases and 10-year mortality: the Beijing Eye Study 2001/2011. Acta Ophthalmol. 2014;92:e424-e428.

10. Siantar RG, Cheng CY, Gemmy Cheung CM, et al. Impact of visual impairment and eye diseases on mortality: the Singapore Malay Eye Study (SiMES). Sci Rep. 2015;5:16304

11. Mitchell P, Liew G, Gopinath B, et al. Age-related macular degeneration. Lancet. 2018 392:1147-1159.

12. Wood JM, Lacherez P, Black AA, et al. Risk of falls, injurious falls, and other injuries resulting from visual impairment among older adults with age-related macular degeneration. Invest Ophthalmol Vis Sci. 2011;52:5088-5092.

13. Chong EW, Wang Y, Robman LD, et al. Age related macular degeneration and total hip replacement due to osteoarthritis or fracture: Melbourne collaborative cohort study. PLoS One. 2015;10:e0137322

14. Tolman J, Hill RD, Kleinschmidt JJ, et al. Psychosocial adaptation to visual impairment and its relationship to depressive affect in older adults with age-related macular degeneration. Gerontologist. 2005; 45:747-753.

15. Wang JJ, Mitchell P, Smith W, et al. Impact of visual impairment on use of community support services by elderly persons: the Blue Mountains Eye Study. Invest Ophthalmol Vis Sci. 1999;40:12-19.

16. Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the global burden of disease study 2010. Lancet. 2012;380:2095-2128.

17. Tan JS, Mitchell P, Smith W, et al. Cardiovascular risk factors and the long-term incidence of age-related macular degeneration: the Blue Mountains Eye Study. Ophthalmology. 2007;114:1143-1150.

18. Delcourt C, Michel F, Colvez A, et al. Associations of cardiovascular disease and its risk factors with age-related macular degeneration: the POLA study. Ophthalmic Epidemiol. 2001;8:237-249.

19. Jun S, Datta S, Wang L, et al. The impact of lipids, lipid oxidation, and inflammation on AMD, and the potential role of miRNAs on lipid metabolism in the RPE. Exp Eye Res. 2019;181:346-355.

20. Yang X, Li Y, Li Y, et al. Oxidative stress-mediated atherosclerosis: mechanisms and therapies. Front Physiol. 2017;8:600.

21. Romero-Vazquez S, Llorens V, Soler-Boronat A, et al. Interlink between inflammation and oxidative stress in age-related macular degeneration: role of complement factor H. Biomedicines. 2021;9:763.

22. Li CM, 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.

23. Bentzon JF, Otsuka F, Virmani R, et al. Mechanisms of plaque formation and rupture. Circ Res. 2014;114:1852-1866.

24. Baird PN, Islam FM, Richardson AJ, et al. Analysis of the Y402H variant of the complement factor H gene in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2006;47:4194-4198.

25. Kardys I, de Maat MP, Uitterlinden AG, et al. C-reactive protein gene haplotypes and risk of coronary heart disease: the Rotterdam study. Eur Heart J. 2006;27:1331-1337.

26. Jylhävä J, Eklund C, Jylhä M, et al. Complement factor H 402His variant confers an increased mortality risk in Finnish nonagenarians: the vitality 90+ study. Exp Gerontol. 2009;44:297-299.

27. Steven S, Frenis K, Oelze M, et al. Vascular inflammation and oxidative stress: major triggers for cardiovascular disease. Oxid Med Cell Longev. 2019;2019:7092151

28. Klein R, Meuer SM, Knudtson MD, et al. The epidemiology of retinal reticular drusen. Am J Ophthalmol. 2008;145:317-326.

29. Smith RT, Sohrab MA, Busuioc M, et al. Reticular macular disease. Am J Ophthalmol. 2009;148:733-743.e2