Pathological changes of the eye retina at cardiovascular disease and diabetes mellitus

Objective. In this work we analyzed the current literature data about the retinal damage in cardiovascular diseases and diabetes mellitus (published from 2005 to 2020). The damage of retinal vascular bed and optic nerve represents a relevant problem in the modern world in view of the significant prevalence, severity of retinal irreversible damage leading to disability, and in relation to comorbidity with cardiovascular diseases (CVD).

Methods. Publications on selected topic were analyzed from 2005 to 2020. The search was carried out using the electronic databases of the Google Academy (https://scholar.google.com/), PubMed (https://www.ncbi.nlm.nih.gov/pubmed/), eLIBRARY.ru (https: //www.elibrary.ru/) and foreign and national journals devoted to cardiology, therapy and ophthalmology.

Results. The analysis of literature showed that atherosclerotic lesion of the microvascular retinal bed is a significant risk factor for acute coronary syndrome myocardial infarction (MI) and stroke. However, the identity of atherosclerotic processes occurring in the retinal vascular bed and in the peripheral arteries remains open. A strong association was shown between hypertensive retinopathy (HR) has with MI, congestive heart failure (CHF) and CHD mortality in large-scale population-based studies such as ARIC and Rotterdam Study. The question of the predictive significance of GR, depending on its degree, remains debatable. There are consistent evidence on the association between HR and CHD and CHF. Diabetic retinopathy (DR) represents a neurovascular complication of diabetes. In predominantly clinical work, there is evidence of the significance of DR as a risk marker for Stroke, diabetics peripheral neuropathy, autonomic cardiac neuropathy, thickness of carotid intima-media, micro albuminuria. A number of other major clinical works has not shown a significant association between DR and stroke. A significant drawback of investigation of the relationship between DR and CVD is a lack of population studies on this topic.

Conclusions. Despite the use of modern diagnostic methods and a fairly large number of studies of the eye vascular bed and retina, the data about their relationship with CVD remain scare and contradictory, which is largely due to the limited size of the studied samples, the variability of the estimates, and a complexity of the pathway of atherosclerosis and CVD. The study of association between CVD and retinal pathology in the Russian population with using of automatic assessment of the microvascular bed provides a unique opportunity to solve some contradictory aspects and obtain new data.

1. World Health Organization. Global diffusion of eHealth: making universal health coverage achievable: report of the third global survey on eHealth. World Health Organization, 2017.

2. Ho H., Cheung C.Y., Sabanayagam C., Yip W., Ikram M.K., Ong P.G., Mitchell P., Chow K.Y., Cheng C.Y., Tai E.S., Wong T.Y. Retinopathy signs improved prediction and reclassification of cardiovascular disease risk in diabetes: a prospective cohort study. Sci. Rep. 2017; 7(1): 1–8. doi:10.1038/srep41492

3. Cheung C.Y.L., Tay W.T., Ikram M.K., Ong Y.T., De Silva D.A., Chow K.Y., Wong T.Y. Retinal microvascular changes and risk of stroke: the Singapore Malay Eye Study. Stroke. 2013; 201344 (9): 2402– 2408. doi: 10.1161/STROKEAHA.113.001738

4. Wagner S.K., Fu D.J., Faes L., Liu X., Huemer J., Khalid H., Ferraz D., Korot E., Kelly C., Balaskas K., Denniston A. K., Keane P. A. Insights into systemic disease through retinal imaging-based oculomics. Translat. Vision Sci. & Technol. 2020; 9 (2): 6–6. doi: 10.1167/tvst.9.2.6

5. Жданов В.С., Дробкова И.П., Галахов И.Е. Эпидемиологические морфологические исследования атеросклероза. Кардиол. вестн. 2015; 10 (1): 52–57. [Zhdanov V.S., Drobkova I.P., Galakhov I.E. Epidemiologicheskie i morphologicheskie issledovaniya aterosclerosa. Cardiologicheskii vestnik. 2015; 10 (1): 52–57 (In Russ.)].

6. Ma Y.H., Leng X.Y., Dong Y. Xu W., Cao X.P., Ji X., Wang H.F., Tan L., Yu J.T. Association of MR-proadrenomedullin with cardiovascular risk factors and subclinical cardiovascular disease. Atherosclerosis. 2013; 228 (2): 451–459. doi: 10.1016/j.atherosclerosis.2018.12.015

7. Chandra A., Seidelmann S.B., Claggett B.L., Klein B.E., Klein R., Shah A.M., Solomon S.D. The association of retinal vessel calibres with heart failure and longterm alterations in cardiac structure and function: the Atherosclerosis Risk in Communities (ARIC) Study. Eur. J. Heart Failure. 2019; 21 (10): 1207–1215. doi: 10.1002/ejhf.1564

8. Crosby-Nwaobi R., Heng L.Z., Sivaprasad S. Retinal vascular calibre, geometry and progression of diabetic retinopathy in type 2 diabetes mellitus. Ophthalmologica. 2012; 228 (2): 84–92. doi: 10.1159/000337252

9. Myers C.E., Klein R., Knudtson M.D., Lee K.E., Gangnon R., Wong T.Y., Klein B.E.K. Determinants of retinal venular diameter: the Beaver Dam Eye Study. Ophthalmology. 2012; 119 (12): 2563–2571. doi: 10.1016/j.ophtha.2012.06.038

10. Klein R., Myers C., Knudtson M. Relationship of blood pressure and other factors to serial retinal arteriolar diameter measurements over time: the Beaver Dam Eye Study. Arch. Ophthalmol. 2012; 130 (8): 1019–1027. doi: 10.1001/archophthalmol.2012.560

11. Sun R., Liu D., Zhou Q., Sun R., Liu D., Zhou Q. A review of the carotid artery stenosis and ocular ischemic disease from the perspective of integrative medicine. In Integrative Ophthalmology. Springer, Singapore, 2020. doi: 10.1007/978-981-13-7896-6

12. Hafner J., Zierfuss B., Schernthaner G.H., SchmidtErfurth U. From the eye into the foot? Atherosclerosis. 2020; 294: 41–43. doi: 10.1016/j.atherosclerosis.2019.12.007

13. Bertelli P.M., Pedrini E., Guduric-Fuchs J., Peixoto E., Pathak V., Stitt A.W., Medina R.J. Vascular regeneration for ischemic retinopathies: Hope from cell therapies. Curr. Eye Res. 2020; 45 (3): 372–384. doi: 10.1080/02713683.2019.1681004

14. Elwood K.F., Taboada J.L., Wong R.W. Ocular ischemic syndrome with congenital absence of internal carotid artery. J. VitreoRetinal Diseases. 2020; 4 (1): 79–83. doi: 10.1177/2474126419866136

15. Sun R., Liu D., Zhou Q. A review of the carotid artery stenosis and ocular ischemic disease from the perspective of integrative medicine. Integrative Ophthalmology. Singapore: Springer, 2020. 133–136. doi: 10.1007/978-981-13-7896-6

16. Kang H.M., Choi J.H., Koh H.J., Lee S.C. Kang H.M., Choi J.H., Koh H.J., Lee S.C. Significant changes of the choroid in patients with ocular ischemic syndrome and symptomatic carotid artery stenosis. PloS One. 2019; 14 (10). doi: 10.1371/journal.pone.0224210

17. Hayreh S.S. Acute retinal arterial occlusive disorders. Prog. in Retinal and Eye Res. 2011; 30 (5): 359–394. doi: 10.1016/j.preteyeres.2011.05.001

18. Olsen T., Pulido J. On behalf of the American Academy of Ophthalmology referred Practice Pattern Retina/Vitreous Panel. Retinal and Ophthalmic Artery Occlusions Preferred Practice Pattern. Ophthalmology. 2016; 124: 120–143. doi: 10.1177/2474126419866136

19. Biousse V., Nahab F., Newman N.J. Management of acute retinal ischemia: follow the guidelines! Ophthalmology. 2018; 125 (10): 1597–1607. doi: 10.1016/j.ophtha.2018.03.054

20. Chang Y.S., Chu C.C., Weng S.F., Chang C., Wang J.J., Jan R.L. The risk of acute coronary syndrome after retinal artery occlusion: a population-based cohort study. Br. J. Ophthalmol. 2015; 99 (2): 227–231. doi: 10.1136/bjophthalmol-2014-305451

21. Park S.J., Choi N.K., Yang B.R., Park K.H., Lee J., Jung S.Y., Woo S.J. Risk and risk periods for stroke and acute myocardial infarction in patients with central retinal artery occlusion. Ophthalmology. 2015; 122 (11): 2336–2343. doi: 10.1016/j.ophtha.2015.07.018

22. Lee J., Kim S.W., Lee S.C., Kwon O.W., Kim Y.D., Byeon S.H. Co-occurrence of acute retinal artery occlusion and acute ischemic stroke: diffusion-weighted magnetic resonance imaging study. Am. J. Ophthalmol. 2014; 157 (6): 1231–1238. doi: 10.1016/j.ajo.2014.01.033

23. Sharma R.A., Newman N.J., Biousse V. New concepts on acute ocular ischemia. Curr. Opinion in Neurol. 2019; 32 (1): 19–24. doi:10.1097/WCO.0000000000000634

24. Katz D.M., Trobe J.D. Is there treatment for nonarteritic anterior ischemic optic neuropathy. Curr. Opinion in Ophthalmol. 2015; 26 (6): 458–463. doi: 10.1097/ICU.0000000000000199

25. Lee M.S., Grossman D., Arnold A.C., Sloan F.A. Incidence of nonarteritic anterior ischemic optic neuropathy: increased risk among diabetic patients. Ophthalmology. 2011; 118 (5): 959–963. doi: 10.1016/j.ophtha.2011.01.054

26. Callizo J., Feltgen N., Pantenburg S., Wolf A., Neubauer A.S., Jurklies B., Wachter R., Schmoor C., Schumacher M., Junker B., Pielen A. Cardiovascular risk factors in central retinal artery occlusion: results of a prospective and standardized medical examination. Ophthalmology. 2015; 122 (9): 1881–1888. doi: 10.1016/j.ophtha.2015.05.044

27. Giambene B., Sodi A., Sofi F., Marcucci R., Fedi S., Abbate R., Prisco D., Menchini U. Evaluation of traditional and emerging cardiovascular risk factors in patients with non-arteritic anterior ischemic optic neuropathy: a case-control study. Graefe's Arch. for Clin. and Exp. Ophthalmol. 2009; 247 (5): 693–697. doi: 10.1007/s00417-008-0981-6

28. Cestari D.M., Gaier E.D., Bouzika P., Blachley T.S., De Lott L.B., Rizzo J.F., Wiggs J.L., Kang J.H., Pasquale L.R., Stein J.D. Demographic, systemic, and ocular factors associated with nonarteritic anterior ischemic optic neuropathy. Ophthalmology. 2016; 123 (12): 2446–2455. doi: 10.1016/j.ophtha.2016.08.017

29. Hayreh S.S., Zimmerman M.B. Non-arteritic anterior ischemic optic neuropathy: role of systemic corticosteroid therapy. Graefe's Arch. for Clin. and Exp. Ophthalmol. 2008; 246 (7): 1029–1046. doi: 10.1007/s00417-008-0805-8

30. Williams B., Mancia G., Spiering W., Rosei E. A., Azizi M., Burnier M., Clement D., Coca A., De Simone G., Dominiczak A., Kahan T., Mahfoud F., Redon J., Ruilope L., Zanchetti A., Kerins M., Kjeldsen S., Kreutz R., Laurent S., Desormais I. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Kardiologia Polska (Polish Heart Journal). 2019; 77 (2): 71–159. doi: 10.1080/08037051.2018.1527177

31. Cuspidi C., Sala C., Grassi G. Updated classification of hypertensive retinopathy: which role for cardiovascular risk stratification? J. Hypertens. 2015; 33 (11): 2204–2206. doi: 10.1097/HJH.0000000000000733

32. Ambresin A., Borruat F.X. Hypertension and the eye. Rev. Med. Suisse. 2015; 11 (499): 2366–2368. PMID: 26852552

33. Ahn S.J., Woo S.J., Park K.H. Retinal and choroidal changes with severe hypertension and their association with visual outcome. Invest. Ophthalmol. & Visual Sci. 2014; 55 (12): 7775–7785. doi: 10.1167/iovs.14-14915

34. Keith N.M. Some different types of essential hypertension: their course and prognosis. Am. J. Med. Sci. 1974; 268: 336–345. doi: 10.1097/00000441-197412000-00004

35. Wong T.Y., Mitchell P. Hypertensive retinopathy. New Engl. J. Med. 2004; 351 (22): 2310–2317. doi: 10.1056/NEJMra032865

36. van den Born B.J.H., Hulsman C.A.A., Hoekstra J.B.L., Schlingemann R.O., van Montfrans G.A. Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial. BMJ. 2014; 348: g366. doi: 10.1136/bmj.331.7508.73

37. Mancia G., Fagard R., Narkiewicz K., Redon J., Zanchetti A., Böhm M., Christiaens T., Cifkova R., de Backer G., Dominiczak A., Galderisi M., Grobbee D.E., Jaarsma T., Kirchhof P., Kjeldsen S.E., Laurent S., Manolis A.J., Nilsson P.M., Ruilope L.M., Wood D.A. 2013 ESH/ESC Practice guidelines for the management of arterial hypertension: ESH-ESC The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Blood Press. 2014; 23 (1): 3–16. doi: 10.1097/01.hjh.0000431740.32696.cc

38. Spence J.D., Fraser J.A. Retinal vasculature: a window on the brain. Hypertension. 2013; 62 (4): 678– 679. doi: 10.1161/HYPERTENSIONAHA.113.01519

39. Heringa S.M., Bouvy W.H., van den Berg E., Moll A.C., Kappelle L.J., Biessels G.J. Associations between retinal microvascular changes and dementia, cognitive functioning, and brain imaging abnormalities: a systematic review. J. Cereb. Blood Flow. Metab. 2013; 33 (7): 983–995. doi: 10.1038/jcbfm.2013.58

40. Hanff T. C., Sharrett A. R., Mosley T. H., Shibata D., Knopman D.S., Klein R., Klein B.E.K., Gottesman R.F. Retinal microvascular abnormalities predict progression of brain microvascular disease: an atherosclerosis risk in communities magnetic resonance imaging study. Stroke. 2014; 45 (4): 1012–1017. doi: 10.1161/strokeaha.113.004166

41. Lindley R.I., Wang J.J., Wong M.C., Mitchell P., Liew G., Hand P., Wardlaw J., de Silva D.A., Baker M., Rochtchina E., Chen C., Hankey G.J., Chang H.M., Fung V.S., Gomes L., Wong T.Y. Retinal microvasculature in acute lacunar stroke: a crosssectional study. Lancet Neurol. 2009; 8 (7): 628–634. doi: 10.1016/S1474-4422(09)70131-0

42. Wieberdink R.G., Ikram M.K., Koudstaal P.J., Hofman A., Vingerling J.R., Breteler M. Retinal vascular calibers and the risk of intracerebral hemorrhage and cerebral infarction: the Rotterdam Study. Stroke. 2010; 41 (12): 2757–2761. doi: 10.1161/STROKEAHA.110.599084

43. Liew G., Wong T.Y., Mitchell P., Cheung N., Wang J.J. Retinopathy predicts coronary heart disease mortality. Heart. 2009; 95 (5): 391–394. doi: 10.1136/hrt.2008.146670

44. Wong T.Y., Rosamond W., Chang P.P., Couper D.J., Sharrett A.R., Hubbard L.D., Folsom A.R., Klein R. Retinopathy and risk of congestive heart failure. JAMA. 2005; 293 (1): 63–69. doi: 10.1001/jama.293.1.63

45. Liu Y., Yang J., Tao L., Lv H., Jiang X., Zhang M., Li X. Risk factors of diabetic retinopathy and sightthreatening diabetic retinopathy: a cross-sectional study of 13 473 patients with type 2 diabetes mellitus in mainland China. BMJ Open. 2017; 7 (9): e016280. doi: 10.1136/bmjopen-2017-016280

46. International Diabetes Federation. IDF Dia-betes Atlas 2019; Available from: http://www.diabetesatlas.org/

47. Antonetti D.A., Klein R., Gardner T.W. Diabetic retinopathy: seeing beyond glucose-induced microvascular disease. Diabetes. 2006; 55 (9): 2401–2411. doi: 10.1056/NEJMra1005073

48. Yau J.W.Y., Rogers S.L., Kawasaki R., Lamoureux E.L., Kowalski J.W., Bek T., Chen S.-J., Dekker J.M., Fletcher A., Grauslund J., Haffner S., Hamman R.F., Kamran Ikram M., Kayama T., Klein B.E.K., Klein R., Krishnaiah S., Mayurasakorn K., O’hare J.P., Wong T.Y. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012; 35 (3): 556– 564. doi: 10.2337/dc11-1909

49. Wong T.Y., Cheung C.M.G., Larsen M., Sharma S., Simó R. Diabetic retinopathy. Nat. Rev. Dis. Primers. 2016; 2: 1–16 doi: 10.1038/nrdp.2016.12

50. Simó R., Hernández C. European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR) Neurodegeneration in the diabetic eye: new insights and therapeutic perspectives. Trends Endocrinol. Metab. 2014; 25 (1): 23–33. doi: 10.1016/j.tem.2013.09.005

51. Simó R., Stitt A.W., Gardner T.W. Neurodegeneration in diabetic retinopathy: does it really matter? Diabetologia. 2018; 0061 (9): 1902–1912. doi: 10.1007/s00125-018-4692-1

52. Solomon S.D., Chew E., Duh E.J., Sobrin L., Sun J.K., VanderBeek B.L., Wykoff C.C., Gardner T.W. Diabetic retinopathy: a position statement by the American Diabetes Association. Diabetes Care. 2017; 40 (3): 412–418. doi: 10.2337/dc16-2641

53. Алгоритмы специализированной медицинской помощи больным сахарным диабетом. Под ред. И.И. Дедова, М.В. Шестаковой, А.Ю. Майорова. 9-й вып. М.: УП ПРИНТ, 2019. [Algoritmy spetsializirovannoi meditsinskoi pomoshchi bol’nym sakharnym diabetom. Pod red. I.I. Dedova, M.V. Shestakovoi, A.Yu. Maiorova. 9-i vypusk. M.: UP PRINT, 2019. (In Russ.).] doi: 10.14341/DM221S1

54. Zhao Q., Zhou F., Zhang Y., Zhou X., Ying C. Fasting plasma glucose variability levels and risk of adverse outcomes among patients with type 2 diabetes: a systematic review and meta-analysis. Diabet. Res. and Clin. Pract. 2019; 148: 23–31. doi: 10.1016/j.diabres.2018.12.010

55. Prospective D.U.K. Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ: British Medical Journal. 1998; 317 (7160): 703. PMCID: PMC28659

56. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. New Engl. J. Med. 1993; 329 (14): 977–986. doi: 10.1056/NEJM199309303291401

57. Nordwall M., Abrahamsson M., Dhir M., Fredrikson M., Ludvigsson J., Arnqvist H.J. Impact of HbA1c, followed from onset of type 1 diabetes, on the development of severe retinopathy and nephropathy: the VISS Study (Vascular Diabetic Complications in Southeast Sweden). Diabetes Care. 2015; 38 (2): 308–315. doi: 10.2337/dc14-1203

58. DCCT Research Group. Early worsening of diabetic retinopathy in the diabetes control and complications trial. Arch. Ophthalmol. 1998; 113: 874–886. doi: 10.1001/archopht.116.7.874

59. Henricsson M., Nilsson A., Janzon L., Groop L. The effect of glycaemic control and the introduction of insulin therapy on retinopathy in non-insulin-dependent diabetes mellitus. Diabetic Med. 1997; 14 (2): 123– 131. doi: 10.1002/(SICI)1096-9136(199708)14:83.0.CO;2-4

60. Roysarkar T.K., Gupta A., Dogra M.R., Dash R.J. Effect of insulin therapy on progression of retinopathy in noninsulin-dependent diabetes mellitus. Am. J. Ophthalmol. 1993; 115 (5): 569–574. doi: 10.1016/s0002-9394(14)71452-7

61. Casson R.J., Wood J.P.M., Osborne N.N. Hypoglycaemia exacerbates ischaemic retinal injury in rats. British J. Ophthalmol. 2004; 88 (6): 816–820. doi: 10.1136/bjo.2003.024661

62. Pearce I., Simó, R., Lövestam-Adrian M., Wong D.T., Evans M. Association between diabetic eye disease and other complications of diabetes: implications for care. A systematic review. Diabetes, Obesity and Metabolism. 2019; 21 (3): 467–478. doi: 10.1111/dom.13550

63. Kostev K., Jockwig A., Hallwachs A., Rathmann W. Prevalence and risk factors of neuropathy in newly diagnosed type 2 diabetes in primary care practices: a retrospective database analysis in Germany and UK. Primary Care Diabetes. 2014; 8 (3): 250–255. doi: 10.1016/j.pcd.2014.01.011

64. Lin I.C., Wang Y.H., Lin C.L., Chang Y.J., Lee S.H., Wang I.J. Diabetic polyneuropathy and the risk of developing diabetic retinopathy: a nationwide, population-based study. Acta Ophthalmol. 2015; 93 (8): 713–718. doi: 10.1111/aos.12746

65. Huang C.C., Lee J.J., Lin T.K., Tsai N.W., Huang C.R., Chen S.F., Lu C.H., Liu R.T. Diabetic retinopathy is strongly predictive of cardiovascular autonomic neuropathy in type 2 diabetes. J. Diabet. Res. 2016. doi: 10.1155/2016/6090749

66. Voulgari C., Psallas M., Kokkinos A., Argiana V., Katsilambros N., Tentolouris N. The association between cardiac autonomic neuropathy with metabolic and other factors in subjects with type 1 and type 2 diabetes. J. Diabet. Complicat. 2011; 25 (3): 159–167. doi: 10.1016/j.jdiacomp.2010.06.001

67. Pemp B., Palkovits S., Howorka K., Pumprla J., Sacu S., Garhöfer G., Bayerle-Eder M., Schmetterer L., Schmidt–Erfurth U. Correlation of retinal neurodegeneration with measures of peripheral autonomic neuropathy in type 1 diabetes. Acta Ophthalmol. 2018; 96 (7): e804–e810. doi: 10.1111/aos.13733

68. Li L.X., Li M.F., Lu J.X., Jia L.L., Zhang R., Zhao C.C., Ren Y., Tu Y.F., Shen Y., Liu F., Bao Y.Q., Jia W.P. Retinal microvascular abnormalities are associated with early carotid atherosclerotic lesions in hospitalized Chinese patients with type 2 diabetes mellitus. J. Diabet. Complicat. 2014; 28 (3): 378–385. doi: 10.1016/j.jdiacomp.2014.02.004

69. Prospective D.U.K. Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ: British Medical Journal. 1998; 317 (7160): 703. PMC28659

70. Liu Y., Yang J., Tao L., Lv H., Jiang X., Zhang M., Li X. Risk factors of diabetic retinopathy and sightthreatening diabetic retinopathy: a cross-sectional study of 13 473 patients with type 2 diabetes mellitus in mainland China. BMJ Open. 2017; 7 (9): e016280. doi: 10.1136/bmjopen-2017-016280

71. Chou A.Y., Liu C.-J., Chao T.-F., Wang K.-L., Tuan T.-C., Chen T.-J., Chen S.-A. Presence of diabetic microvascular complications does not incrementally increase risk of ischemic stroke in diabetic patients with atrial fibrillation: a nationwide cohort study. Medicine. 2016; 95 (27). PMC5058804

72. Hägg S., Thorn L., Forsblom C., Stroke D.G. Different risk factor profiles for ischemic and hemorrhagic stroke in type 1 diabetes mellitus. Stroke. 2014; 45 (9): 2558–2562. doi: 10.1161/STROKEAHA.114.005724

73. Juutilainen A., Lehto S., Ronnemaa T., Pyorala K., Laakso M. Retinopathy predicts cardiovascular mortality in type 2 diabetic men and women. Diabetes Care. 2007; 30 (2): 292–299. doi: 10.2337/dc06-1747

74. Brownrigg J.R.W., Hughes C.O., Burleigh D., Karthikesalingam A., Patterson B.O., Holt P.J., Thompson M.M., de Lusignan S., Ray K.K., Hinchliffe R.J. Microvascular disease and risk of cardiovascular events among individuals with type 2 diabetes: a populationlevel cohort study. The Lancet Diabet. Endocrinol. 2016; 4 (7): 588–597. doi: 10.1016/S2213-8587(16)30057-2

75. Karlberg C., Falk C., Green A., Sjølie A.K., Grauslund J. The role of lean process improvement in implementation of evidence-based practices in behavioral health care. J. Behavior. Health Servic. Res. 2015; 42 (4): 504–518. doi: 10.1007/s00592-011-0304-y