J.ophthalmol.(Ukraine).2022;1:3-10.

Fulltext  Pdf

http://doi.org/10.31288/oftalmolzh20221310

Received: 12 November 2021; Published on-line: 15 March 2022


Angiopoietins and prediction of vitreous hemorrhage in type 2 diabetes patients with diabetic retinopathy

S. O. Rykov, S. Iu. Mogilevskyy, S. S. Lytvynenko, S. V. Ziablitsev 

1 Shupyk National Healthcare University of Ukraine; Kyiv (Ukraine)

2 Bogomolets National Medical University; Kyiv (Ukraine)

E-mail:  sergey.mogilevskyy@gmail.com

TO CITE THIS ARTICLE: Rykov S. O., Mogilevskyy S. Iu., Lytvynenko S. S., Ziablitsev S. V. Angiopoietins and prediction of vitreous hemorrhage in type 2 diabetes patients with diabetic retinopathy. J.ophthalmol.(Ukraine).2022;1:3-10.    http://doi.org/10.31288/oftalmolzh20221310


Background: Various types of vitreoretinal surgery are used for the treatment of severe diabetic retinopathy (DR), with vitreous hemorrhage being a common postoperative complication. Impaired angiopoietin system function in type 2 diabetes mellitus (T2DM) patients with DR plays a role in retinal vascular damage and may determine the development of vitreous hemorrhage, e.g., after vitrectomy.

Purpose: To identify the effects of angiopoietins on and their prognostic value in the development of vitreous hemorrhage after advanced vitreoretinal surgery in T2DM patients with DR.

Material and Methods: The study included 118 T2DM patients (118 eyes) with DR. These included patients with mild nonproliferative DR (NPDR; Group 1; n = 28), moderate or severe NPDR (Group 2; n = 49), and proliferative DR (PDR; Group 3; n = 41). They underwent a 25-G closed subtotal vitrectomy (CSTV) with panretinal laser photocoagulation. Either a mixture of perfluoropropane (18% C3F8) and air was used to perform tamponade of the vitreous cavity or balance salt solution (BSS plus) was left in the vitreous cavity. Vitreous samples were obtained during vitrectomy, and Ang1 and Ang2 concentrations and their ratio for these samples were measured by enzyme-linked immunosorbent assay. Models were developed using the EZR version 1.54 software (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing; Vienna, Austria).

Results: Vitreous hemorrhage developed in 33.1% of patients with T2DM by three months after vitrectomy for DR, and was directly associated with increased levels of Ang1 and Ang2 in the vitreous (p < 0.005). After adjustment for DR severity stage, the risk of postoperative vitreous hemorrhage in patients with mild NPDR was associated with an increased level of Ang2 in the vitreous (OR, 1.95; 95% CI, 1.06-3.59 per 100 pg/ml), with an optimal cut-off point of 1246 pg/ml (р = 0.003). The risk of postoperative vitreous hemorrhage in patients with severe NPDR and PDR was associated with the level of Ang2 as well as the Ang2/ Ang1 ratio in the vitreous. The study identified cut-off vitreous levels of Ang2 of (a) 2806 pg/mL for moderate or severe NPDR (AUC=0.84; 95% CI, 0.71-0.93; p < 0.001) and (b) 4610 pg/mL for PDR (AUC=0.71; 95% CI, 0.55-0.84; p = 0.013).

Conclusion: The results obtained demonstrated that Ang2 accumulation in the vitreous resulted in an increased risk of postoperative vitreous hemorrhage, and was of high prognostic significance.

Keywords: closed subtotal vitrectomy, postoperative vitreous hemorrhage, angiopoietins, diabetic retinopathy, type 2 diabetes mellitus

 

References

1.World Health Organization. Global Report on Diabetes . Geneva, Switzerland: World Health Organization; 2016. apps.who.int/iris/bitstream/10665/204871/1/9789241565257_eng.pdf. Accessed January 2, 2022.

2.World Health Organization. Noncommunicable diseases: key facts. 2021. https://www.who.int/news-room/fact-sheets/detail/noncommunicable-diseases. Accessed January 2, 2022.

3.Sun H, Saeedi P, Karuranga S, Pinkepank M, Ogurtsova K, Duncan BB et al. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract. 2021 Nov 24;109119. 

Crossref

4.Thomas RL, Halim S, Gurudas S, Sivaprasad S, Owens DR. IDF Diabetes Atlas: A review of studies utilising retinal photography on the global prevalence of diabetes related retinopathy between 2015 and 2018. Diabetes Res Clin Pract. 2019 Nov;157:107840. 

Crossref 

5.Nentwich MM, Ulbig MW. Diabetic retinopathy - ocular complications of diabetes mellitus. World J Diabetes. 2015 Apr 15;6(3):489-99.

Crossref

6.Wang CY, Cheang WM, Hwang DK, Lin CH. Vitreous haemorrhage: a population-based study of the incidence and risk factors in Taiwan. Int J Ophthalmol. 2017 Mar 18;10(3):461-466.

Crossref

7.Marques RE, Sousa DC, Leal I, Faria MY, Marques-Neves C. Complete ILM peeling versus inverted flap technique for macular hole surgery: a meta-analysis. Ophthalmic Surg Lasers Imaging Retina. 2020;51(3):187-A2.

Crossref

8.Taskintuna I, Elsayed ME, Taskintuna K, Ahmad K, Khandecar R, Schatz P et al. Comparison of outcomes of four different treatment modalities for diabetic vitreous haemorrhage. Sci Rep [Internet]. 2020;10(3674). 

Crossref

9.Ding Y, Yao B, Hang H, Ye Hui. Multiple factors in the prediction of risk of recurrent vitreous haemorrhage after sutureless vitrectomy for non-clearing vitreous haemorrhage in patients with diabetic retinopathy. BMC Ophthalmol. 2020.

Crossref

10.Hayashi SI, Rakugi H, Morishita R. Insight into the role of angiopoietins in ageing-associated diseases. Cells. 2020;9(12):2636.

Crossref

11.Khan M, Aziz AA, Shafi NA, Abbas T, Khanani AM. Targeting angiopoietin in retinal vascular diseases: a literature review and summary of clinical trials involving faricimab. Cells. 2020;9(8):1869.

Crossref

12.Souma T, Thomson BR, Heinen S, Carota IA, Yamaguchi S, Onay T et al. VEPTP determines ANGPT2 activity on TIE2 receptor. Proceedings of the National Academy of Sciences. 2018;115(6);1298-303.

Crossref

13.Saharinen P, Eklund L, Alitalo K. Therapeutic targeting of the angiopoietin–TIE pathway. Nat Rev Drug Discov. 2017;16:635-61.

Crossref

14.Early Treatment Diabetic Retinopathy Study Research Group. Grading Diabetic Retinopathy from Stereoscopic Color Fundus Photographs – An Extension of the Modified Airlie House Classification: ETDRS Report Number 10. Ophthalmology. 2020 Apr;127(4S):S99-S119.

Crossref

15.Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48:452-8.

Crossref

16.Skowerski T, Nabrdalik K, Kwiendacz H, Gumprecht J. Angiopoietin-2 and vascular complications of type 2 diabetes. Clinical diabetology. 2020;9(3):201-204.

Crossref

17.Raj KK. Angiopoietin 2 in type 2 diabetes mellitus patients and those with complications: an observational comparative study. Int J Adv Med. 2020;7(5):733-6.

Crossref

18.Geranmayeh MH, Rahbarghazi R, Farhoudi M. Targeting pericytes for neurovascular regeneration. Cell Commun Signal. 2019 Mar 20;17(1):26.

Crossref

19.Khalaf N, Helmy H, Labib H, Fahmy I, El Hamid MA, Moemen L. Role of Angiopoietins and Tie-2 in Diabetic Retinopathy. Electron Physician. 2017 Aug 25;9(8):5031-5.

Crossref

20.Watanabe D, Suzuma K, Suzuma I, Ohashi H, Ojima T, Kurimoto M, Murakami T, Kimura T, Takagi H. Vitreous levels of angiopoietin 2 and vascular endothelial growth factor in patients with proliferative diabetic retinopathy. Am J Ophthalmol. 2005 Mar;139(3):476-81.

Crossref

21.Keles A, Sonmez K, Erol YO, Ayyıldız SN, Ogus E. Vitreous levels of vascular endothelial growth factor, stromal cell-derived factor-1α, and angiopoietin-like protein 2 in patients with active proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol. 2021 Jan;259(1):53-60.

Crossref

22.Yu Y, Zhang J, Zhu R, Zhao R, Chen J, Jin J, Tian Y, Su SB. The Profile of Angiogenic Factors in Vitreous Humor of the Patients with Proliferative Diabetic Retinopathy. Curr Mol Med. 2017 Dec 7;17(4):280-6.

Crossref

23.Patel JI, Hykin PG, Gregor ZJ, Boulton M, Cree IA. Angiopoietin concentrations in diabetic retinopathy. Br J Ophthalmol. 2005;89(4):480-3.

Crossref

24.Gupta A, Bhatnagar S. Vasoregression: a shared vascular pathology underlying macrovascular and microvascular pathologies? OMICS. 2015;19(12):733-53.

Crossref

25.Akwii RG, Sajib MS, Zahra FT, Mikelis CM. Role of angiopoietin-2 in vascular physiology and pathophysiology. Cells. 2019;8(5):471. doi: 10.3390/cells8050471

26.Yun JH, Park SW, Kim JH, Park YJ, Cho CH, Kim JH. Angiopoietin 2 induces astrocyte apoptosis via αvβ5-integrin signaling in diabetic retinopathy. Cell Death Dis. 2016 Feb 18;7(2):e2101.

Crossref

27.Hakanpaa L, Sipila T, Leppanen VM, Gautam P, Nurmi H, Jacquemet G, Eklund L, Ivaska J, Alitalo K, Saharinen P. Endothelial destabilization by angiopoietin-2 via integrin β1 activation. Nat Commun. 2015 Jan 30;6:5962.

Crossref

28.Cai J, Kehoe O, Smith GM, Hykin P, Boulton ME. The angiopoietin/Tie-2 system regulates pericyte survival and recruitment in diabetic retinopathy. Invest Ophthalmol Vis Sci. 2008 May;49(5):2163-71.

Crossref

29.Pfister F, Feng Y, vom Hagen F, Hoffmann S, Molema G, Hillebrands JL, Shani M, Deutsch U, Hammes HP. Pericyte migration: a novel mechanism of pericyte loss in experimental diabetic retinopathy. Diabetes. 2008 Sep;57(9):2495-502.

Crossref

30.Cabral T, Mello LG, Lima LH, Polido J, Regatieri CV, Belfort R Jr at al. Retinal and choroidal angiogenesis: a review of new targets. Int J Retina Vitreous. 2017;3:31.

Crossref

31.Regula JT, Lundh von Leithner P, Foxton R, Barathi VA, Cheung CM, Bo Tun SB, Wey YS, Iwata D, Dostalek M, Moelleken J, Stubenrauch KG, Nogoceke E, Widmer G, Strassburger P, Koss MJ, Klein C, Shima DT, Hartmann G. Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases. EMBO Mol Med. 2016 Nov 2;8(11):1265-88.

Crossref

32.Khanani AM, Russell MW, Aziz AA, Danzig CJ, Weng CY, Eichenbaum DA, Singh RP. Angiopoietins as Potential Targets in Management of Retinal Disease. Clin Ophthalmol. 2021 Sep 4;15:3747-55.

Crossref

 

Conflict of Interest Statement: The authors declare no conflict of interest. 

Funding Support: There are no external sources of funding.