Тhe Role of Retinal Vascular Reactions in the Development and Regression of Diabetic Retinopathy

Objective: to study retinal vascular reactions (RVR) with a glycemic gradient, vitrectomy (VE) without panretinal photocoagulation (PRP) and after IVI aflibercept in patients with diabetes mellitus (DM).

Methods. In three independent groups, variations in retinal vessel (RV) caliber were studied with a glycemic gradient (DR progression factor), after VE without PRP and after IVI (DR/PDR regression factors). Retinal images were obtained using Heidelberg Retinal tomograph HRT II (Germany).

Results. With an increase in the level of glycemia, the tendency to increase the diameter of the RV in DM1 and DM2 was revealed both in eyes without DR and in the presence of DR. However, only in DR were the changes significant. After VE without PRP in the eyes with PDR, the diameter of the veins decreased by 7 % 2 months after VE and by 14 % after 18 months (p < 0.01); the arteries had persistent and significant changes in caliber after 2 months. After IVI aflibercept, the caliber of retinal vessels in DMO significantly decreased from the first to the third injection.

Conclusion. Patients with DM initially represent a heterogeneous group in terms of the severity of RVR, depending on the presence or absence of ДР. After treatment, BCVA indicators improved against the background of retinal vasoconstriction in all study groups. After VE without PRP there was a persistent and significant reduction of PV diameters. Thus, the dynamics of retinal vessel caliber may reflect the phases of DR/PDR evolution: progression or regression. Persistent PDR remission can be achieved without lasercoagulation of the retinal “avascular zones”.

1. Root H, Mirsky S, Ditzel J. Proliferative retinopathy in diabetes mellitus; review of eight hundred fortyseven cases. J Am Med Assoc. 1959;169(9):903–909. doi: 10.1001/jama.1959.03000260001001.

2. Dobree JH. Proliferative diabetic retinopathy: evolution of the retinal lesions. Br J Ophthalmol. 1964;48(12):637–649. doi: 10.1136/bjo.48.12.637.

3. Shao Q, Heussen FM, Ouyang Y, HagerA. Retinal vessel diameter changesin different severities of diabetic retinopathy by SDOCT. Eur J Ophthalmol. 2016;10;26(4):342– 346. doi: 10.5301/ejo.5000694.

4. Genes. SG. Diabetic capillaropathy and its pathogenesis. Annals of Ophthalmology. 1972;4:83–87 (In Russ.).

5. Klein R, Myers CE, Lee KE, Gangnon R, Klein BE. Changes in retinal vessel diameter and incidence and progression of diabetic retinopathy. Arch Ophthalmol. 2012;130(6):749–755. doi: 10.1001/archophthalmol.2011.2560.

6. Kohner EM, Hamilton AM, Saunders SJ, Sutcliffe BA, Bulpitt CJ. The retinal blood flow in diabetes. Diabetologia. 1975;11(1):27–33. doi: 10.1007/BF00422814.

7. BurganskyEliash Z, Barak A, Barash H, Nelson DA, Pupko O, Lowenstein A, Grinvald A, Rubinstein A. Increased retinal blood flow velocity in patients with early diabetes mellitus. Retina. 2012;32(1):112–119. doi: 10.1097/IAE.0b013e31821ba2c4.

8. Grunwald JE, Riva CE, Petrig BL, Sinclair SH, Brucker AJ. Effect of pure O2breathing on retinal blood flow in normals and in patients with background diabetic retinopathy. Curr Eye Res. 1984;3(1):239–241. doi: 10.3109/02713688408997205.

9. Gardiner TA, Archer DB, Curtis TM, Stitt AW. Arteriolar involvement in the microvascular lesions of diabetic retinopathy: implications for pathogenesis. Microcirculation. 2007;14(1):25–38. doi: 10.1080/10739680601072123.

10. Arai T, Numata K, Tanaka K, Kiba T, Kawasaki S, Saito T, Satoh S, Sekihara H. Ocular arterial flow hemodynamics in patients with diabetes mellitus. J Ultrasound Med. 1998;17(11):675–681. doi: 10.7863/jum.1998.17.11.675.

11. Patel V, Rassam S, Newsom R, Wiek J, Kohner E. Retinal blood flow in diabetic retinopathy. BMJ. 1992;305(6855):678–683. doi: 10.1136/bmj.305.6855.678.

12. MacKinnon JR, O’Brien C, Swa K, Aspinall P, Butt Z, Cameron D. Pulsatile ocular blood flow in untreated diabetic retinopathy. Acta Ophthalmol Scand. 1997;75(6):661–664. doi: 10.1111/j.1600-0420.1997.tb00626.x.

13. Sdobnikova SV. Regularities of the Natural Evolution of the Proliferative Process in Diabetic Retinopathy. The Concept of Remission of Proliferative Diabetic Retinopathy. Ophthalmology in Russia. 2021;18(4):763–768 (In Russ.). doi: 10.18008/1816-5095-2021-4-763-768.

14. Ditzel J, Sargeant L, Hadley WB. The relationship of abnormal vascular responses to retinopathy and nephropathy in diabetics. AMA Arch Intern Med. 1958;101(5):912–920. doi: 10.1001/archinte.1958.00260170068009.

15. Grunwald JE, Riva CE, Brucker AJ, Sinclair SH, Petrig BL. Altered retinal vascular response to 100% oxygen breathing in diabetes mellitus. Ophthalmology. 1984;91(12):1447–1452. doi: 10.1016/s0161-6420(84)34124-0.

16. Evans DW, Harris A, Danis RP, Arend O, Martin BJ. Altered retrobulbar vascular reactivity in early diabetic retinopathy. Br J Ophthalmol. 1997;81(4):279–282. doi: 10.1136/bjo.81.4.279.

17. CunhaVaz JG. Diabetic retinopathy. World Scientific Publishing Co Pte Ltd; 2011:386.

18. Дедов ИИ, Шестакова МВ, Миленькая ТМ. Сахарный диабет: ретинопатия, нефропатия. M.: Медицина, 2001:176. Dedov II, Shestakova MV, Milenkaya TM. Diabetes mellitus: retinopathy, nephropathy. Moscow: Medicine. 2001:176 (In Russ.).

19. Kohner EM, Patel V, Rassam SM. Role of blood flow and impaired autoregulation in the pathogenesis of diabetic retinopathy. Diabetes. 1995;44:603–607. doi: 10.2337/diab.44.6.603.

20. Mendivil A, Cuartero V. Ocular blood flow velocities in patients with proliferative diabetic retinopathy after scatter photocoagulation. Two years of followup. Retina. 1996;16(3):222–227. doi: 10.1097/00006982-199616030-00007.

21. Mendrinos E, Mangioris G, Papadopoulou DN, Dosso AA, Pournaras CJ. Retinal vessel analyzer measurements of the effect of panretinal photocoagulation on the retinal arteriolar diameter in diabetic retinopathy. Retina. 2010;30(4):555–561. doi: 10.1097/IAE.0b013e3181bd2f79.

22. Feke GT, Green GJ, Goger DG, McMeel JW. Laser Doppler measurements of the effect of panretinal photocoagulation on retinal blood flow. Ophthalmology. 1982;89(7):757–762. doi: 10.1016/s0161-6420(82)34726-0.

23. Krepler K, Polska E, Wedrich A, Schmetterer L. Ocular blood flow parameters after pars plana vitrectomy in patients with diabetic retinopathy. Retina. 2003;Apr;23(2):192–196. doi: 10.1097/00006982-200304000-00009.

24. Lee SU, Nam KY, Lee SJ. Surgically induced changes in retinal vessel diameter, retinal nerve fibre layer thickness, and the optic disc after 23gauge pars plana vitrectomy. Int Ophthalmol. 2017;Jun;37(3):575–581. doi: 10.1007/s10792-016-0302-8.

25. Sullu Y, Hamidova R, Beden U, Yakupov K, Canbaz S, Danaci M. Effects of pars plana vitrectomy on retrobulbar haemodynamics in diabetic retinopathy. Clin Exp Ophthalmol. 2005;Jun;33(3):246–251. doi: 10.1111/j.1442-9071.2005.01013.x

26. Li D, Chen H, Huang S, Jia B, Lu L, Fu J. Microstructural and hemodynamic changes in the fundus after pars plana vitrectomy for different vitreoretinal diseases. Graefes Arch Clin Exp Ophthalmol. 2024;Jul;262(7):1977–1992. doi: 10.1007/s00417-023-06303-x.

27. Nitta F, Kunikata H, Aizawa N, Omodaka K, Shiga Y, Yasuda M, Nakazawa T. The effect of intravitreal bevacizumab on ocular blood flow in diabetic retinopathy and branch retinal vein occlusion as measured by laser speckle flowgraphy. Clin Ophthalmol. 2014;8:1119–1127. doi: 10.2147/OPTH.S62022.

28. MurschEdlmayr AS, Luft N, Podkowinski D, Ring M, Schmetterer L, Bolz M. Effects of three intravitreal injections of aflibercept on the ocular circulation in eyes with agerelated maculopathy. Br J Ophthalmol. 2020;104(1):53–57. doi: 10.1136/bjophthalmol-2019-313919.

29. Okamoto M, Yamashita M, Ogata N. Effects of intravitreal injection of ranibizumab on choroidal structure and blood flow in eyes with diabetic macular edema. Graefes Arch Clin Exp Ophthalmol. 2018;256(5):885–892. doi: 10.1007/s00417-018-3939-3.

30. Pivovarov NN, Glukhoded SV, Simonova KK, Smolova LG, Mostovoi EN. Possibility of surgical treatment of proliferative diabetic retinopathy using circular compressive surgery of the coats of the eye. Annals of Ophthalmology 1984;2:15–22 (In Russ.).

31. Nagahara M, Tamaki Y, Araie M, Eguchi S. Effects of scleral buckling and encircling procedures on human optic nerve head and retinochoroidal circulation. Br J Ophthalmol. 2000;84(1):31–36. doi: 10.1136/bjo.84.1.31.

32. Sdobnikova CV. The role of posterior thyroid membrane removal in transvitreal surgery of proliferative diabetic retinopathy: dis. … cand. med. sci. Moscow, 1997:121.

33. Davis MD. Vitreous contraction in proliferative diabetic retinopathy. Arch Ophthalmol. 1965;74(6):741–751. doi: 10.1001/archopht.1965.00970040743003.

34. Bandello F, Gass JD, Lattanzio R, Brancato R. Spontaneous regression of neovascularization at the disk and elsewhere in diabetic retinopathy. Am J Ophthalmol. 1996;122(4):494–501. doi: 10.1016/s0002-9394(14)72108-7.

35. Yamana Y, Oka Y, Ohnishi Y, Ishibashi T, Inoguchi T. Reflow of obstructed capillaries in the maculae of humans with diabetic retinopathy, observed by fluorescein angiography. Br. J. Ophth. 1988;72(9):660–665. doi: 10.1136/bjo.72.9.660.

36. Stulova AN, Semenova NS, Zheleznyakova AV, Akopyan VS, Lipatov DV, Shestakova MV. Early functional and microcirculatory changes in patients with type 1 diabetes mellitus and no apparent diabetic retinopathy. Diabetes mellitus. 2021;24(3):243–250 (In Russ.). doi: 10.14341/DM12532.

37. Rimmer T, Fallon TJ, Kohner EM. Longterm followup of retinal blood flow in diabetes using the blue light entoptic phenomenon. Br J Ophthalmol. 1989;73:1–5. doi: 10.1136/bjo.73.1.1.

38. Cheung N, Rogers SL, Donaghue KC, Jenkins AJ, Tikellis G, Wong TY. Retinal arteriolar dilation predicts retinopathy in adolescents with type 1 diabetes. Diabetes Care. 2008;31(9):1842–1846. doi: 10.2337/dc08-0189.

39. Popova TV. Biull Eksp Biol Med. 1953;(12) (In Russ.). Cite by Genes S.G. Nervous system and internal secretion. Moscow: Medgiz, 1955:72–95 (In Russ.).

40. Rassam SM, Patel V, Kohner EM. The effect of experimental hypertension on retinal vascular autoregulation in humans: a mechanism for the progression of diabetic retinopathy. Exp Physiol. 1995;80(1):53–68. doi: 10.1113/expphysiol.1995.sp003834.

41. Mazurina NK, Sdobnikova SV. [The role of hyperglycemia in hemodynamic disorders of the retina]. Annals of Ophthalmology. 2004;6:46–49 (In Russ.).

42. Tooke JE. Microvascular function in human diabetes. A physiological perspective. Diabetes. 1995;44(7):721–726. doi: 10.2337/diab.44.7.721.

43. Shimizu K, Kobayashi Y, Muraoka K. Midperipheral fundus involvement in diabetic retinopathy. Ophthalmology. 1981;88(7):601–612. doi: 10.1016/s0161-6420(81)34983-5.