Endothelial dysfunction and inflammation in patients with non-obstructive coronary arteries
https://doi.org/10.18087/cardio.2021.1.n1423
Abstract
Aim To determine levels of markers for endothelial dysfunction and inflammation, endothelin-1, E-selectin, and tumor necrosis factor α (TNF-α) in patients with ischemic heart disease (IHD) and non-obstructive and obstructive coronary artery (CA) disease.
Material and methods This study included 32 patients with verified IHD and non-obstructive (main group, n=19) and obstructive (comparison group, n=13) CA disease. Endothelial dysfunction was diagnosed by photoplethysmography and videocapillaroscopy. Serum concentrations of endothelin-1, E-selectin, and TNF- α were measured in all patients.
Results Patients with non-obstructive CA disease showed a tendency towards more pronounced endothelial dysfunction (alternative stiffness index, 7.8 m /s [6.35; 9.08]; reflection index, 36.95 % [23.4; 52.65]; capillary density following reactive hyperemia, 54.33 cap /mm2 [48.92; 75.83]; capillary density following venous occlusion, 74.33 cap /mm2 [67.83; 93.00]) compared to the comparison group (alternative stiffness index, 9.05 m/s [7.08; 10.58]; reflection index, 28.25 % [23.35; 53.75]; capillary density following reactive hyperemia, 66.83 cap /mm2 [50.83; 78.67]; capillary density following venous occlusion, 87.0 cap /mm2 [77.58; 78.67]), although statistically significant differences were not found. Concentration of endothelin-1 was significantly higher in the IHD group with non-obstructive CA disease (0.45 ng/ml [0.28;0.65]) compared to patients with CA atherosclerotic stenosis (0.35 ng/ml [0.25; 0.38], p=0.035). Concentrations of E-selectin did not significantly differ between the groups (main group, 21.1 ng/ml [18.45; 35.03]; comparison group, 28.55 ng/ml [19.08; 35.01], p=0.29). In both groups, concentrations of TNF-α did not exceed the lower threshold of sensitivity (<2.3 pg/ml).
Conclusion Endothelial dysfunction and increased endothelin-1 in patients with non-obstructive CA disease along with inflammation may additionally contribute to the pathogenesis of IHD in the absence of hemodynamically significant CA stenoses. Too low level of TNFα in both groups prevented us from using it as a diagnostic marker. Further study is needed that would include a greater number of patients and a search for alternative markers.
Keywords
About the Authors
N. N. PakhtusovRussian Federation
postgraduate student
A. O. Iusupova
Russian Federation
MD, PhD, assistant professor
E. V. Privalova
Russian Federation
MD, PhD, professor
N. V. Khabarova
Russian Federation
MD, PhD, Assistant
Yu. N. Belenkov
Russian Federation
MD, PhD, Professor, Academician of the Russian Academy of Sciences
References
1.
2. World Health Organisation. The top 10 causes of death. [Internet] Available at: https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death
3. Genders TSS, Steyerberg EW, Alkadhi H, Leschka S, Desbiolles L, Nieman K et al. A clinical prediction rule for the diagnosis of coronary artery disease: validation, updating, and extension. European Heart Journal. 2011;32(11):1316–30. DOI: 10.1093/eurheartj/ehr014
4. Reeh J, Therming CB, Heitmann M, Højberg S, Sørum C, Bech J et al. Prediction of obstructive coronary artery disease and prognosis in patients with suspected stable angina. European Heart Journal. 2019;40(18):1426–35. DOI: 10.1093/eurheartj/ehy806
5. Knuuti J, Wijns W, Saraste A, Capodanno D, Barbato E, FunckBrentano C et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. European Heart Journal. 2020;41(3):407–77. DOI: 10.1093/eurheartj/ehz425
6. Federal State Statistics Service. Health in Russia. 2019. Statistical book. -M.: Rosstat;2019. - 170 p. [Russian: Федеральная служба государственной статистики. Здравоохранение в России. 2019. Статистический сборник. - М.: Росстат, 2019. - 170с. Доступно на: https://www.gks.ru/storage/mediabank/Zdravoohran-2019.pdf]. ISBN 978-5-89476-470-2
7. Jespersen L, Hvelplund A, Abildstrom SZ, Pedersen F, Galatius S, Madsen JK et al. Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events. European Heart Journal. 2012;33(6):734–44. DOI: 10.1093/eurheartj/ehr331
8. Safdar B, Spatz ES, Dreyer RP, Beltrame JF, Lichtman JH, Spertus JA et al. Presentation, Clinical Profile, and Prognosis of Young Patients with Myocardial Infarction With Nonobstructive Coronary Arteries (MINOCA): Results From the VIRGO Study. Journal of the American Heart Association. 2018;7(13): e009174. DOI: 10.1161/JAHA.118.009174
9. Agewall S, Beltrame JF, Reynolds HR, Niessner A, Rosano G, Caforio ALP et al. ESC working group position paper on myocardial infarction with non-obstructive coronary arteries. European Heart Journal. 2016;38(3):143–53. DOI: 10.1093/eurheartj/ehw149
10. Ford TJ, Rocchiccioli P, Good R, McEntegart M, Eteiba H, Watkins S et al. Systemic microvascular dysfunction in microvascular and vasospastic angina. European Heart Journal. 2018;39(46):4086–97. DOI: 10.1093/eurheartj/ehy529
11. Bender SB, de Beer VJ, Tharp DL, Bowles DK, Laughlin MH, Merkus D et al. Severe familial hypercholesterolemia impairs the regulation of coronary blood flow and oxygen supply during exercise. Basic Research in Cardiology. 2016;111(6):61. DOI: 10.1007/s00395- 016-0579-9
12. Bagi Z, Feher A, Cassuto J. Microvascular responsiveness in obesity: implications for therapeutic intervention. British Journal of Pharmacology. 2012;165(3):544–60. DOI: 10.1111/j.1476-5381.2011.01606.x
13. Jager J, Grémeaux T, Cormont M, Le Marchand-Brustel Y, Tanti J-F. Interleukin-1beta-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression. Endocrinology. 2007;148(1):241–51. DOI: 10.1210/en.2006-0692
14. Borst SE. The Role of TNF-α in Insulin Resistance. Endocrine. 2004;23(2–3):177–82. DOI: 10.1385/ENDO:23:2-3:177
15. Di Pino A, DeFronzo RA. Insulin Resistance and Atherosclerosis: Implications for Insulin-Sensitizing Agents. Endocrine Reviews. 2019;40(6):1447–67. DOI: 10.1210/er.2018-00141
16. Gast KB, Tjeerdema N, Stijnen T, Smit JWA, Dekkers OM. Insulin resistance and risk of incident cardiovascular events in adults without diabetes: meta-analysis. PloS One. 2012;7(12): e52036. DOI: 10.1371/journal.pone.0052036
17. Paolisso P, Foà A, Bergamaschi L, Donati F, Fabrizio M, Chiti C et al. Hyperglycemia, Inflammatory Response and Infarct Size in Obstructive Acute Myocardial Infarction and MINOCA. 2020. Av. at: https:// www.preprints.org/manuscript/202010.0350/v1.
18. Kuvin JT, Patel AR, Sliney KA, Pandian NG, Sheffy J, Schnall RP et al. Assessment of peripheral vascular endothelial function with finger arterial pulse wave amplitude. American Heart Journal. 2003;146(1):168–74. DOI: 10.1016/S0002-8703(03)00094-2
19. Bonetti PO, Pumper GM, Higano ST, Holmes DR, Kuvin JT, Lerman A. Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. Journal of the American College of Cardiology. 2004;44(11):2137–41. DOI: 10.1016/j.jacc.2004.08.062
20. Yusupova A.O., Shendrygina A.A., Privalova E.V., Belenkov Yu.N. Microvascular angina. Modern aspects of pathogenesis, diagnostics and treatment. Clinical Medicine. 2016;94(10):736–45. DOI: 10.18821/0023-2149- 2016-94-10-736-745
21. Cheng C, Daskalakis C, Falkner B. Original Research: Capillary rarefaction in treated and untreated hypertensive subjects. Therapeutic Advances in Cardiovascular Disease. 2008;2(2):79–88. DOI: 10.1177/1753944708089696
22. Belenkov Yu.N., Privalova E.V., Shchendrygina A.A., Chekneva I.S., Emelyanova T.V. Microcirculatory disorders in patients with coronary heart disease and type 2 diabetes. Sechenov Medical Journal. 2014;4(18):27–33.
23. Halcox JPJ, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA et al. Prognostic Value of Coronary Vascular Endothelial Dysfunction. Circulation. 2002;106(6):653–8. DOI: 10.1161/01.CIR.0000025404.78001.D8
24. Bugiardini R, Manfrini O, Pizzi C, Fontana F, Morgagni G. Endothelial Function Predicts Future Development of Coronary Artery Disease: A Study of Women with Chest Pain and Normal Coronary Angiograms. Circulation. 2004; 109(21): 2518–23. DOI: 10.1161/01.CIR.0000128208.22378.E3
25. Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR, Lerman A. Long-Term Follow-Up of Patients with Mild Coronary Artery Disease and Endothelial Dysfunction. Circulation. 2000;101(9):948– 54. DOI: 10.1161/01.CIR.101.9.948
26. Ong P, Athanasiadis A, Sechtem U. Intracoronary Acetylcholine Provocation Testing for Assessment of Coronary Vasomotor Disorders. Journal of Visualized Experiments. 2016; 114:54295. DOI: 10.3791/54295
27. Ong P, Athanasiadis A, Borgulya G, Mahrholdt H, Kaski JC, Sechtem U. High prevalence of a pathological response to acetylcholine testing in patients with stable angina pectoris and unobstructed coronary arteries. The ACOVA Study (Abnormal COronary VAsomotion in patients with stable angina and unobstructed coronary arteries). Journal of the American College of Cardiology. 2012;59(7):655–62. DOI: 10.1016/j.jacc.2011.11.015
28. Matsuzawa Y, Sugiyama S, Sugamura K, Nozaki T, Ohba K, Konishi M et al. Digital Assessment of Endothelial Function and Ischemic Heart Disease in Women. Journal of the American College of Cardiology. 2010;55(16):1688–96. DOI: 10.1016/j.jacc.2009.10.073
29. Shaw J, Anderson T. Coronary endothelial dysfunction in nonobstructive coronary artery disease: Risk, pathogenesis, diagnosis and therapy. Vascular Medicine. 2016;21(2):146–55. DOI: 10.1177/1358863X15618268
30. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332(6163):411–5. DOI: 10.1038/332411a0
31. Anggrahini DW, Emoto N, Nakayama K, Widyantoro B, Adiarto S, Iwasa N et al. Vascular endothelial cell-derived endothelin-1 mediates vascular inflammation and neointima formation following blood flow cessation. Cardiovascular Research. 2009;82(1):143–51. DOI: 10.1093/cvr/cvp026
32. Ali M, Girgis S, Hassan A, Rudick S, Becker RC. Inflammation and coronary artery disease: from pathophysiology to Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS). Coronary Artery Disease. 2018;29(5):429–37. DOI: 10.1097/MCA.0000000000000625
33. Nidorf SM, Fiolet ATL, Eikelboom JW, Schut A, Opstal TSJ, Bax WA et al. The effect of low-dose colchicine in patients with stable coronary artery disease: The LoDoCo2 trial rationale, design, and baseline characteristics. American Heart Journal. 2019;218: 46–56. DOI: 10.1016/j.ahj.2019.09.011
34. Farhat N, Matouk CC, Mamarbachi AM, Marsden PA, Allen BG, Thorin E. Activation of ET B receptors regulates the abundance of ET-1 mRNA in vascular endothelial cells: ET-1 regulates ET-1 mRNA levels. British Journal of Pharmacology. 2008;153(7):1420–31. DOI: 10.1038/bjp.2008.25
35. Dancu MB, Tarbell JM. Coronary endothelium expresses a pathologic gene pattern compared to aortic endothelium: Correlation of asynchronous hemodynamics and pathology in vivo. Atherosclerosis. 2007;192(1):9–14. DOI: 10.1016/j.atherosclerosis.2006.05.042
36. Urbich C, Kuehbacher A, Dimmeler S. Role of microRNAs in vascular diseases, inflammation, and angiogenesis. Cardiovascular Research. 2008;79(4):581–8. DOI: 10.1093/cvr/cvn156
37. Matkovich SJ, Hu Y, Dorn GW. Regulation of Cardiac MicroRNAs by Cardiac MicroRNAs. Circulation Research. 2013;113(1):62–71. DOI: 10.1161/CIRCRESAHA.113.300975
38. Yang J, Zeng P, Yang J, Liu X, Ding J, Wang H et al. MicroRNA-24 regulates vascular remodeling via inhibiting PDGF-BB pathway in diabetic rat model. Gene. 2018; 659:67–76. DOI: 10.1016/j.gene.2018.03.056
Review
For citations:
Pakhtusov N.N., Iusupova A.O., Privalova E.V., Khabarova N.V., Belenkov Yu.N. Endothelial dysfunction and inflammation in patients with non-obstructive coronary arteries. Kardiologiia. 2021;61(1):52-58. https://doi.org/10.18087/cardio.2021.1.n1423