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Aortic stiffness and systemic inflammation changes predict clinical response to intravitreal anti-vascular endothelial growth factor therapy in patients with age-related macular degeneration


Aortic stiffness and systemic inflammation are predictors of cardiovascular risk. Anti-vascular endothelial growth factor agents (anti-VEGF), injected intravitreally, can reverse the course of exudate age-related macular degeneration (AMD). We sought to investigate the association of changes in aortic stiffness and systemic inflammation with response to anti-VEGF therapy. 54 patients (mean age: 76 ± 10 years) with AMD received two consecutive monthly intravitreal injections of ranibizumab (0.5 mg). The primary outcome measure was change in carotid-femoral pulse wave velocity (PWV) from baseline to 1 month after the second injection. Secondary endpoint was the change in serum high sensitivity interleukin-6 (hsIL-6) levels. Ranibizumab caused a decrease of PWV after the first (by 0.36 ± 1.4 m/s) and the second injection (by 0.31 ± 1.4 m/s) and remained decreased 1 month after the second injection (overall P < 0.05). PWV decreased significantly in good responders (according to clinical criteria and fundus findings, P = 0.004), whereas it increased numerically in poor responders (P = 0.21) over the study period. In responders, hsIL-6 decreased after the first injection and remained decreased 1 month after the second injection (by 0.63 ± 0.35 pg/ml, overall P = 0.02). PWV (P = 0.005) and hsIL-6 (P = 0.042) were independent predictors of improvement after adjusting for age and presence of hypertension and diabetes. The decrease in PWV through the whole study period was positively correlated with the reduction in hsIL-6 (r = 0.36, P < 0.01). Intravitreal ranibizumab injections lead to a decrease in PWV and hsIL-6. Both parameters predict clinical improvement and may aid to improving treatment targeting and hence therapeutic outcome in patients with AMD.

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Fig. 1: Acute and mid-term systematic effect of intravitreal ranibizumab injections on aortic stiffness and inflammation.
Fig. 2: Positive association between changes in aortic stiffness and changes in systemic inflammation with response to intravitreal administration of ranibizumab.


  1. Hernández-Zimbrón LF, Zamora-Alvarado R, Ochoa-De la Paz L, Velez-Montoya R, Zenteno E, Gulias-Canizo R, et al. Age-related macular degeneration: new paradigms for treatment and management of AMD. Oxid Med Cell Longev. 2018;2018:8374647.

    Article  Google Scholar 

  2. Mitchell P, Liew G, Gopinath B, Wong T. Age-related macular degeneration. Lancet. 2018;392:1147–59.

    Article  Google Scholar 

  3. Vlachopoulos C, Xaplanteris P, Aboyans V, Brodmann M, Cifkova R, Cosentino F, et al. The role of vascular biomarkers for primary and secondary prevention. A position paper from the European Society of Cardiology Working Group on peripheral circulation: Endorsed by the Association for Research into Arterial Structure and Physiology (ARTERY) Society. Atherosclerosis. 2015;241:507–32.

    CAS  Article  Google Scholar 

  4. Vlachopoulos C, Terentes-Printzios D, Laurent S, Nilsson PM, Protogerou AD, Aznaouridis C, et al. Association of estimated pulse wave velocity with survival: a secondary analysis of SPRINT. JAMA Netw Open. 2019;2:e1912831.

    Article  Google Scholar 

  5. Fernandez AB, Wong TY, Klein R, Collins D, Burke G, Cotch MF, et al. Age-related macular degeneration and incident cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis. Ophthalmology. 2012;119:765–70.

    Article  Google Scholar 

  6. McCarty CA, Dowrick A, Cameron J, McGrath B, Robman LD, Dimitrov P, et al. Novel measures of cardiovascular health and its association with prevalence and progression of age-related macular degeneration: the CHARM Study. BMC Ophthalmol. 2008;8:25.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Klein R, Myers CE, Cruickshanks KJ, Gangnon RE, Danforth LG, Sivakumaran TA, et al. Markers of inflammation, oxidative stress, and endothelial dysfunction and the 20-year cumulative incidence of early age-related macular degeneration: the Beaver Dam Eye Study. JAMA Ophthalmol. 2014;132:446–55.

    CAS  Article  Google Scholar 

  8. Pennington KL, DeAngelis MM. Epidemiology of age-related macular degeneration (AMD): associations with cardiovascular disease phenotypes and lipid factors. Eye Vis. 2016;3:34.

    Article  Google Scholar 

  9. McGuinness MB, Karahalios A, Finger RP, Guymer RH, Simpson JA. Age-Related Macular Degeneration and Mortality: A Systematic Review and Meta-Analysis. Ophthalmic Epidemiol. 2017;24:141–52.

    Article  Google Scholar 

  10. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9:669–76.

    CAS  Article  Google Scholar 

  11. Fogli S, Del ReM, Rofi E, Posarelli C, Figus M, Danesi R. Clinical pharmacology of intravitreal anti-VEGF drugs. Eye. 2018;32:1010–20.

    CAS  Article  Google Scholar 

  12. Stewart MW. The expanding role of vascular endothelial growth factor inhibitors in ophthalmology. Mayo Clin Proc. 2012;87:77–88.

    CAS  Article  Google Scholar 

  13. Schmidt-Erfurth U, Chong V, Loewenstein A, Larsen M, Souied E, Schlingemann R, et al. European Society of Retina Specialists. Guidelines for the management of neovascular age-related macular degeneration by the European Society of Retina Specialists (EURETINA). Br J Ophthalmol. 2014;98:1144–6.

    Article  Google Scholar 

  14. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, et al. MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419–31.

    CAS  Article  Google Scholar 

  15. Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T. ANCHOR Study Group. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR study. Ophthalmology. 2009;116:57–65.

    Article  Google Scholar 

  16. Nichols WW, O’Rourke MF, Vlachopoulos C. McDonald’s blood flow in arteries. 6th ed. London: Arnold Hodder; 2011.

  17. Vlachopoulos C, Georgakopoulos C, Pietri P, Ioakeimidis N, Koutouzis M, Vaina S, et al. Effect of ticagrelor versus clopidogrel on aortic stiffness in patients with coronary artery disease. J Am Heart Assoc. 2019;8:e012521.

    CAS  Article  Google Scholar 

  18. Abdel-Qadir H, Ethier JL, Lee DS, Thavendiranathan P, Amir E. Cardiovascular toxicity of angiogenesis inhibitors in treatment of malignancy: A systematic review and meta-analysis. Cancer Treat Rev. 2017;53:120–7.

    CAS  Article  Google Scholar 

  19. Chakravarthy U, Wong TY, Fletcher A, Piault E, Evans C, Zlateva G, et al. Clinical risk factors for age-related macular degeneration: a systematic review and meta-analysis. BMC Ophthalmol. 2010;10:31.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Thulliez M, Angoulvant D, Le Lez ML, Jonville-Bera AP, Pisella PJ, Gueyffier F, et al. Cardiovascular events and bleeding risk associated with intravitreal antivascular endothelial growth factor monoclonal antibodies: systematic review and meta-analysis. JAMA Ophthalmol. 2014;132:1317–26.

    Article  Google Scholar 

  21. Dalvin LA, Starr MR, AbouChehade JE, Damento GM, Garcia M, Shah SM, et al. Association of intravitreal anti-vascular endothelial growth factor therapy with risk of stroke, myocardial infarction, and death in patients with exudative age-related macular degeneration. JAMA Ophthalmol. 2019;137:483–90.

    Article  Google Scholar 

  22. Vlachopoulos C, Gravos A, Georgiopoulos G, Terentes-Printzios D, Ioakeimidis N, Vassilopoulos D, et al. The effect of TNF-a antagonists on aortic stiffness and wave reflections: a meta-analysis. Clin Rheumatol. 2018;37:515–26.

    CAS  Article  Google Scholar 

  23. Lorés-Motta L, de Jong EK, den Hollander AI. Exploring the use of molecular biomarkers for precision medicine in age-related macular degeneration. Mol Diagn Ther. 2018;22:315–43.

    Article  Google Scholar 

  24. Avery RL, Castellarin AA, Steinle NC, Dhoot DS, Pieramici DJ, See R, et al. Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD. Br J Ophthalmol. 2014;98:1636–41.

    Article  Google Scholar 

  25. Wells JA, Glassman AR, Ayala AR, Jampol LM, Bressler NM, Brucker AJ, et al. Diabetic retinopathy clinical research network. aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology. 2016;123:1351–9.

    Article  Google Scholar 

  26. Enseleit F, Michels S, Sudano I, Stahel M, Zweifer S, Schlager O, et al. SAVE-AMD: safety of VEGF inhibitors in age-related macular degeneration. Ophthalmologica. 2017;238:205–16.

    CAS  Article  Google Scholar 

  27. Vlachopoulos C, Dima I, Aznaouridis K, Vasiliadou C, Ioakeimidis N, Aggeli C, et al. Acute systemic inflammation increases arterial stiffness and decreases wave reflections in healthy individuals. Circulation. 2005;112:2193–200.

    Article  Google Scholar 

  28. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation. 2000;101:1767–72.

    CAS  Article  Google Scholar 

  29. Sakamoto S, Takahashi H, Tan X, Inoue Y, Nomura Y, Arai Y, et al. Changes in multiple cytokine concentrations in the aqueous humour of neovascular age-related macular degeneration after 2 months of ranibizumab therapy. Br J Ophthalmol. 2018;102:448–54.

    Article  Google Scholar 

  30. Song Y, Song Q, Li L, Xu J, Liu X. Effect of ranibizumab on levels of IL-6 and VEGF in peripheral blood and aqueous humor of glaucoma rat model and association of IL-6 and VEGF with optic nerve damage. Exp Ther Med. 2018;16:2506–10.

    PubMed  PubMed Central  Google Scholar 

  31. Oakley CL, Allen PL, Vote BJ. Effect of intravitreal anti-vascular endothelial growth factor agents on blood pressure - a cross-sectional analysis. J Hypertens. 2016;34:2099–100.

    CAS  Article  Google Scholar 

  32. Zhong P, He M, Yu H, Wu Q, Peng Q, Huang M, et al. A meta-analysis of cardiovascular events associated with intravitreal anti-VEGF treatment in patients with retinal vein occlusion. Curr Eye Res. 2020;45:615–22.

    CAS  Article  Google Scholar 

  33. Kepez Yildiz B, Ozdek S, Ergun MA, Ergun S, Yaylacioglu Tuncay F, Elbeg S. CFH Y402H and VEGF polymorphisms and anti-VEGF treatment response in exudative age-related macular degeneration. Ophthalmic Res. 2016;56:132–8.

    CAS  Article  Google Scholar 

  34. Shiba T, Takahashi M, Yoshida I, Taniguchi H, Matsumoto T, Hori Y. Arteriosclerotic changes after intravitreal injections of anti-vascular endothelial growth factor drugs in patients with exudative age-related macular degeneration. Ophthalmologica. 2016;235:225–32.

    CAS  Article  Google Scholar 

  35. Chalam KV, Grover S, Sambhav K, Balaiya S, Murthy RK. Aqueous interleukin-6 levels are superior to vascular endothelial growth factor in predicting therapeutic response to bevacizumab in age-related macular degeneration. J Ophthalmol. 2014;2014:502174.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations



NI: conceived, designed, analyzed data, and revised the paper, IG: analyzed data, performed the work, and revised the paper, DG: performed the work, DT-P, CG, KA, SP, DT, CT: analyzed data and revised the paper, CV: conceived, designed, analyzed data, and revised the paper.

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Correspondence to Charalambos Vlachopoulos.

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Ioakeimidis, N., Gourgouli, I., Terentes-Printzios, D. et al. Aortic stiffness and systemic inflammation changes predict clinical response to intravitreal anti-vascular endothelial growth factor therapy in patients with age-related macular degeneration. J Hum Hypertens (2022).

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