Authors
Glazkova P.A.2, Kulikov D.A.2, 3, Glazkov A.A.2, Rogatkin D.A.2, Kulikov A.B.4, Kozlova K.A.2, Terpigorev S.A.2, SHekhyan G.G.2, Kovaleva Yu.A.2, Shestakova T.P.2, Nechaeva O.A.2, Dreval A.V.2, Paleev F.N.1
1 Federal State budget organization National medical research center of cardiology of the Ministry of healthcare of the Russian Federation, Moscow
2 Moscow Regional Research and Clinical Institute («MONIKI»), Moscow
3 Federal Scientific State Budgetary Institution «N.A. Semashko National Research Institute of Health», Moscow
4 Institute of Theoretical and Experimental Biophysics of Russian Academy of Sciences, Moscow
Abstract
Background: It is suggested that microcirculation disorders play an important role in the pathogenesis of cardiovascular diseases, including in patients with diabetes mellitus.
Aims: The purpose of this research is to study the relationship between skin microcirculation disorders and the risk of cardiovascular diseases in diabetic patients.
Materials and methods: Study subjects included patients with diabetes mellitus aged 30 to 74 years without established cardiovascular diseases (angina pectoris, chronic heart failure, history of myocardial infarction, history of stroke, peripheral artery diseases). The reactivity of skin microcirculation was assessed by laser Doppler flowmetry during a heating test. Based on the median of a microcirculation growth, the subjects were divided into two subgroups: the subgroup of patients with “high” and the subgroup of patients with “low” reactivity of microcirculation. The 10-year cardiovascular risk was assessed using the Framingham Score (modification of 2008).
Results: The subgroup of patients with “high” reactivity of microcirculation (n=21; median age 55 [40; 59]; 18 females; 3 males) and the subgroup of patients with “low” reactivity (n = 21; median age 60 [54; 64]; 14 females; 7 males) were comparable in sex, body mass index, smoking status, type of diabetes, microcirculatory complications of diabetes, diabetes duration, glycated hemoglobin level, total cholesterol level, high-density lipoprotein level (p>0.05 for all comparisons). Patients with “high” microcirculation reactivity had significantly lower 10-year risk of the first cardiovascular disease, estimated according to Framingham score, than the subgroup of patients with “low” microcirculation reactivity (13.9 [8.8; 22.9] % and 27.4 [18.7; 35.1] %, respectively; p = 0.012).
Conclusions: Reduced reactivity of skin microcirculation during heating is associated with increased risk of cardiovascular diseases in patients with diabetes mellitus. Evaluation of skin microcirculation in prospect may improve the accuracy of cardiovascular disease prediction in diabetic patients and may be considered as an additional cardiovascular risk factor.
Keywords: diabetes mellitus; cardiovascular diseases; risk; microcirculation; laser-Doppler flowmetry.
References
1. Strain WD, Adingupu DD, Shore AC. Microcirculation on a large scale: techniques, tactics and relevance of studying the microcirculation in larger population samples. Microcirculation. 2012;19(1):37–46. Doi: 10.1111/j.1549-8719.2011.00140.x.
2. Fundamental'naya i klinicheskaya fiziologiya. Ed by Kamkin A.G., Kamenskii A.A. Moscow: Academia; 2004.
3. Feihl F, Liaudet L, Waeber B, Levy BI. Hypertension: a disease of the microcirculation? Hypertension. 2006;48(6):1012–1017. Doi: 10.1161/01.HYP.0000249510.20326.72.
4. Strain WD, Paldánius PM. Diabetes, cardiovascular disease and the microcirculation. Cardiovasc Diabetol. 2018;17(1):57. Doi: 10.1186/s12933-018-0703-2.
5. Holowatz LA, Thompson-Torgerson CS, Kenney WL. The human cutaneous circulation as a model of generalized microvascular function. J Appl Physiol. 2008;105(1):370–372. Doi: 10.1152/japplphysiol.00858.2007.
6. Fuchs D, Dupon PP, Schaap LA, Draijer R. The association between diabetes and dermal microvascular dysfunction non-invasively assessed by laser Doppler with local thermal hyperemia: a systematic review with meta-analysis. Cardiovasc Diabetol. 2017;16(1):11. Doi: 10.1186/s12933-016-0487-1.
7. Kulikov DA, Glazkov AA, Kovaleva YA, et al. Prospects of Laser Doppler flowmetry application in assessment of skin microcirculation in diabetes. Diabetes mellitus. 2017;20(4):279–285. Doi: 10.14341/DM8014.
8. Triantafyllou A, Anyfanti P, Pyrpasopoulou A, et al. Capillary rarefaction as an index for the microvascular assessment of hypertensive patients. Curr Hypertens Rep. 2015;17(5):33. Doi: 10.1007/s11906-015-0543-3.
9. Strain WD, Hughes AD, Mayet J, et al. Attenuation of microvascular function in those with cardiovascular disease is similar in patients of Indian Asian and European descent. BMC Cardiovasc Disord. 2010;10:3. Doi: 10.1186/1471-2261-10-3.
10. Çekiç EG, Başaran Ö, Filiz Başaran N, et al. Cutaneous microvascular reactivity and aortic elasticity in coronary artery disease: comparison of the laser Doppler flowmetry and echocardiography. Microvasc Res. 2017;109:19–25. Doi: 10.1016/j.mvr.2016.09.003.
11. Tikhomirova I, Petrochenko E, Muravyov A, et al. Microcirculation and blood rheology abnormalities in chronic heart failure. Clin Hemorheol Microcirc. 2017;65(4):383–391. Doi: 10.3233/CH-16206.
12. Edvinsson ML, Uddman E, Andersson SE. Deteriorated function of cutaneous microcirculation in chronic congestive heart failure. J Geriatr Cardiol. 2011;8(2):82–87. Doi: 10.3724/SP.J.1263.2011.00082.
13. Antonios TF, Singer DR, Markandu ND, et al. Rarefaction of skin capillaries in borderline essential hypertension suggests an early structural abnormality. Hypertension. 1999;34(4):655–658. Doi: 10.1161/01.hyp.34.4.655.
14. Antonios TF, Rattray FM, Singer DR, et al. Rarefaction of skin capillaries in normotensive offspring of individuals with essential hypertension. Heart. 2003;89(2):175–178. Doi: 10.1136/heart.89.2.175.
15. Ijzerman RG, Serne EH, Van Weissenbruch MH, et al. Cigarette smoking is associated with an acute impairment of microvascular function in humans. Clin Sci. 2003;104(3):247–252. Doi: 10.1042/CS20020318.
16. Altintas AA, Aust MC, Krämer R, et al. In vivo reflectance-mode confocal microscopy assessments: impact of overweight on human skin microcirculation and histomorphology. J Biomed Opt. 2016;21(3):036009. Doi: 10.1117/1.JBO.21.3.036009.
17. Grinevich A, Tankanag A, Tikhonova I, Chemeris N. A new approach to the analysis of skin blood flow oscillations in human. Microvasc Res. 2019;126:103889. Doi: 10.1016/j.mvr.2019.103889.
18. Hsiu H, Hu HF, Tsai HC. Differences in laser-Doppler indices between skin-surface measurement sites in subjects with diabetes. Microvasc Res. 2018;115:1–7. Doi: 10.1016/j.mvr.2017.07.004.
19. Nguyen TT, Shaw JE, Robinson C, et al. Diabetic retinopathy is related to both endothelium-dependent and -independent responses of skin microvascular flow. Diabetes Care. 2011;34(6):1389–1393. Doi: 10.2337/dc10-1985.
20. Brooks BA, McLennan SV, Twigg SM, Yue DK. Detection and characterisation of microcirculatory abnormalities in the skin of diabetic patients with microvascular complications. Diabetes Vasc Dis Res. 2008;5(1):30–35. Doi: 10.3132/dvdr.2008.006.
21. Tomešová J, Gruberova J, Lacigova S, et al. Differences in skin microcirculation on the upper and lower extremities in patients with diabetes mellitus: Relationship of diabetic neuropathy and skin microcirculation. Diabetes Technol Ther. 2013;15(11):968–975. Doi: 10.1089/dia.2013.0083.
22. Hu HF, Hsiu H, Sung CJ, Lee CH. Combining laser-Doppler flowmetry measurements with spectral analysis to study different microcirculatory effects in human prediabetic and diabetic subjects. Lasers Med Sci. 2017;32(2):327–334. Doi: 10.1007/s10103-016-2117-2.
23. Sarwar N, Gao P, Kondapally Seshasai SR, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375(9733):2215–2222. Doi: 10.1016/S0140-6736(10)60484-9.
24. Dedov II, Shestakova MV, Mayorov AYu, et al. Standards of specialized diabetes care. Edited by Dedov I.I., Shestakova M.V., Mayorov A.Yu. 9th edition. Diabetes mellitus. 2019;22(1S1):1–144. Doi: 10.14341/DM221S1.
25. Houben AJ, Eringa EC, Jonk AM, et al. Perivascular fat and the microcirculation: relevance to insulin resistance, diabetes, and cardiovascular disease. Curr Cardiovasc Risk Rep. 2012;6(1):80–90. Doi: 10.1007/s12170-011-0214-0.
26. D’Agostino RB, Vasan RS, Pencina MJ, et al. General cardiovascular risk profile for use in primary care: the Framingham heart study. Circulation. 2008;117(6):743–753. Doi: 10.1161/CIRCULATIONAHA.107.699579.
27. Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH Guidelines for themanagement of arterial hypertension. Eur Heart J. 2018;39(33):3021–3104. Doi: 10.1093/eurheartj/ehy339.
28. Andersson C, Johnson AD, Benjamin EJ, et al. 70-year legacy of the Framingham Heart Study. Nat Rev Cardiol. 2019;16(11):687–698. Doi: 10.1038/s41569-019-0202-5.
29. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41(1):111–188. Doi: 10.1093/eurheartj/ehz455.
30. Binggeli C, Spieker LE, Corti R, et al. Statins enhance postischemic hyperemia in the skin circulation of hypercholesterolemic patients: a monitoring test of endothelial dysfunction for clinical practice? J Am Coll Cardiol. 2003;42(1):71–77. Doi: 10.1016/s0735-1097(03)00505-9.
31. Kenney WL, Cannon JG, Alexander LM. Cutaneous microvascular dysfunction correlates with serum LDL and sLOX-1 receptor concentrations. Microvasc Res. 2013;85(1):112–117. Doi: 10.1016/j.mvr.2012.10.010.
32. Boĭtsov SA, Shal'nova SA, Deev AD, Kalinina AM. Simulation of a risk for cardiovascular diseases and their events at individual and group levels. Ter Arkh. 2013;85(9):4–10.
33. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and other societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts) developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation. Eur Heart J. 2016;37(29):2315–2381. Doi: 10.1093/eurheartj/ehw106.
34. Genest J, McPherson R, Frohlich J, et al. 2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult - 2009 recommendations. Can J Cardiol. 2009;25(10):567–579. Doi: 10.1016/s0828-282x(09)70715-9.
35. Minson CT, Berry LT, Joyner MJ. Nitric oxide and neurally mediated regulation of skin blood flow during local heating. J Appl Physiol. 2001;91(4):1619–1626. Doi: 10.1152/jappl.2001.91.4.1619.
36. Glazkova PA, Terpigorev SA, Kulikov DA, et al. Increasing the diagnostic significance of the laser Doppler flowmetry in assessing skin microcirculation in hypertension. Arterial’naya gipertenziya (Arterial Hypertension). 2019;25(1):74–83. Doi: 10.18705/1607-419X-2019-25-1-74-83.
37. Rogatkin DA, Glazkova PA, Kulikov DA, et al. Is the microvasculature tone increasing with arterial hypertension? Almanac of Clinical Medicine. 2019;47(7):662–668. Doi: 10.18786/2072-0505-2019-47-073.
38. Kruger A, Stewart J, Sahityani R, et al. Laser Doppler flowmetry detection of endothelial dysfunction in end-stage renal disease patients: correlation with cardiovascular risk. Kidney Int. 2006;70(1):157–164. Doi: 10.1038/sj.ki.5001511.
39. IJzerman RG, De Jongh RT, Beijk MA, et al. Individuals at increased coronary heart disease risk are characterized by an impaired microvascular function in skin. Eur J Clin Invest. 2003;33(7):536–542. Doi: 10.1046/j.1365-2362.2003.01179.x.
