

Myocardial ischemia with nonobstructive coronary arteries (INOCA). Part I. The current state of INOCA problem
https://doi.org/10.33667/2078-5631-2025-18-12-19
Abstract
INOCA (ischemia with nonobstructive coronary arteries) is a general term for different types of coronary artery disease which excludes an obstruction of the coronary arteries: vasospastic angina, microvascular angina and muscular myocardial bridge. According to coronary angiography data, 37–39% of patients don’t have hemodynamically significant stenoses of the coronary arteries. INOCA is assigned with significant quality of life limitations, decreased working capacity, the risk of major cardiovascular events is higher and survival rate is lower than in a healthy population. Two main pathogenetic mechanisms were studied and differentiated based on scientific data: microcirculatory dysfunction and vasospasm. Myocardial bridge is classified as structural vasospasm endotype. Coronary blood flow examination and an acetylcholine provocation test are the main diagnostical procedures, which can help to determine the leading pathophysiological mechanism of INOCA. Microvascular disease treatment is pretty similar to an obstructive coronary disease therapy with the possible addition of metabolic therapy. In vasospastic angina front-line drugs are calcium antagonists.
About the Authors
D. M. MovsisyanRussian Federation
Movsisyan David M., junior researcher at Dept of Emergency Clinical Cardiology with Non-invasive Functional Diagnostics
Moscow
E. A. Komissarov
Russian Federation
Komissarov Evgeny A., clinical resident
Moscow
Kh. G. Alidzhanova
Russian Federation
Alidzhanova Khafiza G., DM Sci (habil.), senior lecturer at Training Center, senior researcher at Dept of Emergency Cardiology with Non-invasive Diagnostics
Moscow
References
1. Vijay Kunadian, Alaide Chieffo, Paolo G Camici, Colin Berry, Javier Escaned, Angela H E M Maas, Eva Prescott, Nicole Karam, Yolande Appelman, Chiara Fraccaro, Gill Louise Buchanan, Stephane Manzo-Silberman, Rasha Al-Lamee, Evelyn Regar, Alexandra Lansky, J Dawn Abbott, Lina Badimon, Dirk J Duncker, Roxana Mehran, Davide Capodanno, Andreas Baumbach, An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries in Collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group, European Heart Journal, Volume 41, Issue 37, 1 October 2020, Pages 3504–3520, https://doi.org/10.1093/eurheartj/ehaa503
2. Carl J. Pepine, ANOCA/INOCA/MINOCA: Open artery ischemia, American Heart Journal Plus: Cardiology Research and Practice, Volume 26, 2023, 100260, ISSN2666–6022, https://doi.org/10.1016/j.ahjo.2023.100260.
3. C.N. Bairey Merz, C.J. Pepine, M.N. Walsh, J.L. Fleg Ischemia and No Obstructive Coronary Artery Disease (INOCA): Developing Evidence-Based Therapies and Research Agenda for the Next Decade Circulation, 135 (2017), pp. 1075–1092. https://doi.org/10.1161/CIRCULATIONAHA.116.024534
4. W.E. Boden, M. Marzilli, F. Crea, G.B.J. Mancini, W.S. Weintraub, V.R. Taqueti, C.J. Pepine, J. Escaned, R. Al-Lamee, L.H.W. Gowdak, C. Berry, J.C. Kaski and on behalf of the Chronic Myocardial Ischemic Syndromes Task Force, Evolving management paradigm for stable ischemic heart disease patients: JACC Review Topic of the Week J. Am. Coll. Cardiol., 81 (2023), pp. 505–514, 10.1016/j.jacc.2022.08.814
5. Ford, T, Stanley, B, Good, R. et al. Stratified Medical Therapy Using Invasive Coronary Function Testing in Angina: The CorMicA Trial. J Am Coll Cardiol. 2018 Dec, 72 (23_Part_A) 2841–2855. https://doi.org/10.1016/j.jacc.2018.09.006
6. Breanna Hansen, Jessica N Holtzman, Caroline Juszczynski, Najah Khan, Gurleen Kaur, Bhavya Varma, Martha Gulati, Ischemia with No Obstructive Arteries (INOCA): A Review of the Prevalence, Diagnosis and Management, Current Problems in Cardiology, Volume 48, Issue 1, 2023, 101420, ISSN0146–2806, https://doi.org/10.1016/j.cpcardiol.2022.101420.
7. Reynolds H.R. et al. Natural history of patients with ischemia and no obstructive coronary artery disease: the CIAO-ISCHEMIA study //Circulation. 2021. Т. 144. № . 13. С. 1008–1023.
8. Johnston N., Schenck-Gustafsson K., Lagerqvist B. Are we using cardiovascular medications and coronary angiography appropriately in men and women with chest pain? //European heart journal. 2011. Т. 32. № . 11. С. 1331–1336.
9. Soh RY, Low TT, Sia CH, Kong WK, Yeo TC, Loh PH, Poh KK. Ischaemia with no obstructive coronary arteries: a review with focus on the Asian population. Singapore Med J. 2024 Jul 1; 65 (7): 380–388. DOI: 10.4103/singaporemedj.SMJ 2023–116. Epub 2024 Jul 8. PMID: 38973187; PMCID: PMC11321541
10. Luu JM, Malhotra P, Cook-Wiens G, Pepine CJ, Handberg EM, Reis SE, Reichek N, Bittner V, Wei J, Kelsey SF, Sailaja Marpuri R, Sopko G, Bairey Merz CN. Long-Term Adverse Outcomes in Black Women With Ischemia and No Obstructive Coronary Artery Disease: A Study of the WISE (Women’s Ischemia Syndrome Evaluation) Cohort. Circulation. 2023 Feb 14; 147 (7): 617–619. DOI: 10.1161/CIRCULATIONAHA.122.063466. Epub 2023 Feb 13. PMID: 36780383; PMCID: PMC10290895
11. Functional and Economic Impact of INOCA and Influence of Coronary Microvascular Dysfunction Christopher L Schumann, Roshin C Mathew, John-Henry L Dean, Yang Yang, Pelbreton C Balfour Jr, Peter W Shaw, Austin A Robinson, Michael Salerno, Christopher M Kramer, Jamieson M Bourque. DOI: 10.1016/j.jcmg.2021.01.041
12. Martha Gulati, Najah Khan, Maria George, Colin Berry, Alaide Chieffo, Paolo G. Camici, Filippo Crea, Juan-Carlos Kaski, Mario Marzilli, C. Noel Bairey Merz, Ischemia with no obstructive coronary artery disease (INOCA): A patient self-report quality of life survey from INOCA international, International Journal of Cardiology, Volume 371, 2023, Pages 28–39, ISSN0167–5273, https://doi.org/10.1016/j.ijcard.2022.09.047.
13. Jespersen L, Hvelplund A, Abildstrøm SZ, Pedersen F, Galatius S, Madsen JK, Jørgensen E, Kelbæk H, Prescott E. Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events. Eur Heart J. 2012 Mar;33(6):734–44. DOI: 10.1093/eurheartj/ehr331. Epub 2011 Sep 11. PMID: 21911339
14. Gulati M, Cooper-DeHoff RM, McClure C, Johnson BD, Shaw LJ, Handberg EM, Zineh I, Kelsey SF, Arnsdorf MF, Black HR, Pepine CJ, Merz CN. Adverse cardiovascular outcomes in women with nonobstructive coronary artery disease: a report from the Women’s Ischemia Syndrome Evaluation Study and the St James Women Take Heart Project. Arch Intern Med. 2009 May 11; 169 (9): 843–50. DOI: 10.1001/archinternmed.2009.50. PMID: 19433695; PMCID: PMC2782882
15. Johnson B.D. et al. Prognosis in women with myocardial ischemia in the absence of obstructive coronary disease: results from the National Institutes of Health–National Heart, Lung, and Blood Institute–Sponsored Women’s Ischemia Syndrome Evaluation (WISE). Circulation. 2004. Т. 109. № . 24. С. 2993–2999.
16. Kenkre TS, Malhotra P, Johnson BD, Handberg EM, Thompson DV, Marroquin OC, Rogers WJ, Pepine CJ, Bairey Merz CN, Kelsey SF. Ten-Year Mortality in the WISE Study (Women’s Ischemia Syndrome Evaluation). Circ Cardiovasc Qual Outcomes. 2017 Dec; 10 (12): e003863. doi:10.1161/CIRCOUTCOMES.116.003863. PMID: 29217675; PMCID: PMC5728666.
17. Jun Takahashi, Akira Suda, Kensuke Nishimiya, Shigeo Godo, Satoshi Yasuda, Hiroaki Shimokawa, Pathophysiology and Diagnosis of Coronary Functional Abnormalities, European Cardiology Review 2021; 16: e30. https://doi.org/10.15420/ecr.2021.23
18. S.P. Solovey. Angina pectoris without obstructive lesion of the coronary arteries (part 1). Pathophysiological basis of development. Emergency cardiology and cardiovascular risks, 2021, Vol. 5, No. 2, pp. 1274–1283. (In Russ.).
19. Micic-Labudovic J, Atanasijevic T, Popovic V, et al. Myocardial bridges: a prospective forensic autopsy study. Srp Arh Celok Lek 2015; 143 (3–4): 153–157. https://doi.org/10.2298/SARH1504153M
20. Přemysl Poláček, Relation of myocardial bridges and loops on the coronary arteries to coronary occlusions, American Heart Journal, Volume 61, Issue 1, 1961, Pages 44–52, ISSN0002–8703, https://doi.org/10.1016/0002–8703 (61) 90515 4
21. Kodama K., Morioka N., Hara Y., Shigematsu Y., Hamada M., Hiwada K. Coronary vasospasm at the site of myocardial bridge – Report of two cases. Angiology. 1998; 49: 659–663. DOI: 10.1177/000331979804900812
22. Suda A. et al. Coronary functional abnormalities in patients with angina and nonobstructive coronary artery disease //Journal of the American College of Cardiology. 2019. Т. 74. № . 19. С. 2350–2360.
23. Fedolov V.K., Samko A.N., Levitsky I.V., Rogoza A.N., Balakhonova T.V., Karpov Yu.A. Prognostic value of dysfunction of the endothelium of the coronary and brachial arteries, traditional risk factors in the development of cardiovascular complications in patients with microvascular angina. Russian Journal of Cardiology. 2017; (3): 54-58. (In Russ.).https://doi.org/10.15829/1560-4071-2017-3-54-58
24. Zhang H, Che W, Shi K, Huang Y, Xu C, Fei M, Fan X, Zhang J, Hu X, Hu F, Qin S, Zhang X, Huang Q and Yu F (2022) FT4/FT3 ratio: A novel biomarker predicts coronary microvascular dysfunction (CMD) in euthyroid INOCA patients. Front. Endocrinol. 13:1021326. DOI: 10.3389/fendo.2022.1021326
25. Almeida AG. MINOCA and INOCA: Role in Heart Failure. Curr Heart Fail Rep. 2023 Jun;20(3):139– 150. DOI: 10.1007/s11897 023 00605 1. Epub 2023 May 18. PMID: 37198520; PMCID: PMC10256635
26. Lanza GA, De Vita A, Kaski JC. ‘Primary’ Microvascular Angina: Clinical Characteristics, Pathogenesis and Management. Interv Cardiol. 2018 Sep; 13 (3): 108–111. DOI: 10.15420/icr.2018.15.2. PMID: 30443265; PMCID: PMC6234490
27. Bakir M, Nelson MD, Jones E, et al. Heart failure hospitalization in women with signs and symptoms of ischemia: a report from the women’s ischemia syndrome evaluation study. Int J Cardiol. 2016; 223: 936–9. https://doi.org/10.1016/j.ijcard.2016.07.301
28. Figura E, Zaremba M, Rogula S, Rolek B, Gasecka A, Kołtowski Ł. Coronary slow flow and microvascular spasm as an underrecognized cause of chest pain. Postepy Kardiol Interwencyjnej. 2023 Sep; 19 (3): 289–291. DOI: 10.5114/aic.2023.131484. Epub 2023 Sep 27. PMID: 37854967; PMCID: PMC10580844
29. Doyeon Hwang, Sang-Hyeon Park, Bon-Kwon Koo Ischemia With Nonobstructive Coronary Artery Disease: Concept, Assessment, and Management, JACC: Asia, Volume 3, Issue 2, 2023, Pages 169–184, ISSN2772–3747, https://doi.org/10.1016/j.jacasi.2023.01.004
30. Pasupathy, Sivabaskari & Tavella, Rosanna & Zeitz, Christopher & Edwards, Suzanne & Worthley, Matthew & Arstall, Margaret & Beltrame, John. (2024). Anti-Anginal Efficacy of Zibotentan in the Coronary Slow-Flow Phenomenon. Journal of Clinical Medicine. 13. 1337. 10.3390/jcm13051337
31. Estrada A., Sousa A.S., Mesquita C.T., Villacorta H. Coronary Tortuosity as a New Phenotype for Ischemia without Coronary Artery Disease. Arq. Bras. Cardiol. 2022; 119: 883–890. DOI: 10.36660/abc.20210787
32. Li Y, Shi Z, Cai Y, Feng Y, Ma G, Shen C, et al. (2012) Impact of Coronary Tortuosity on Coronary Pressure: Numerical Simulation Study. PLoS ONE7 (8): e42558. https://doi.org/10.1371/journal.pone.0042558
33. Hostiuc S., Rusu M. C., Hostiuc M., Negoi R. I., Negoi I. Cardiovascular consequences of myocardial bridging: A meta-analysis and meta-regression. Sci. Rep. 2017; 7: 14644. DOI: 10.1038/s41598-017- 13958-0
34. Teragawa H., Fukuda Y., Matsuda K., Hirao H., Higashi Y., Yamagata T., Oshima T., Matsuura H., Chayama K. Myocardial bridging increases the risk of coronary spasm. Clin. Cardiol. 2003; 26: 377–383. DOI: 10.1002/clc.4950260806
35. M. Zaya, P.K. Mehta, C.N. Merz. Provocative testing for coronary reactivity and spasm J Am Coll Cardiol, 63 (2) (2014), pp. 103–109
36. M.E. Bertrand, J.M. LaBlanche, P.Y. Tilmant, et al. Frequency of provoked coronary arterial spasm in 1089 consecutive patients undergoing coronary arteriography. Circulation, 65 (7) (1982), pp. 1299–1306
37. Takahashi T, Samuels BA, Li W, Parikh MA, Wei J, Moses JW, Fearon WF, Henry TD, Tremmel JA, Kobayashi Y; Microvascular Network. Safety of Provocative Testing With Intracoronary Acetylcholine and Implications for Standard Protocols. J Am Coll Cardiol. 2022 Jun 21; 79 (24): 2367–2378. DOI: 10.1016/j.jacc.2022.03.385. PMID: 35710187; PMCID: PMC8972358
38. Determining the Cause of Coronary Vasomotor Disorders in Patients With Ischemia and Nonobstructive Coronary Arteries: Design and Rationale of the DISCOVER INOCA Prospective, Multicenter Registry Shah, Samit M. et al. Journal of the Society for Cardiovascular Angiography & Interventions, Volume 3, Issue 6, 102046
39. С.П. Соловей. Стенокардия без обструктивного поражения коронарных артерий (часть 2). Методы диагностики в клинической практике. Неотложная кардиология и кардиоваскулярные риски, 2022, Т. 6, № 1, С. 1424–1441.
40. Leonova IA, Boldeuva S, Zakharova O, Gaykovaya L.. Trimetazidine improves symptoms and reduces microvascular dysfunction in patients with microvascular angina. Eur Heart J 2017; 38 (Suppl. 1): ehx501P887.
41. Hasenfuss G, Maier LS.. Mechanism of action of the new anti-ischemia drug ranolazine. Clin Res Cardiol 2008; 97: 222–226.
42. Mehta PK, Goykhman P, Thomson LE, Shufelt C, Wei J, Yang Y, Gill E, Minissian M, Shaw LJ, Slomka PJ, Slivka M, Berman DS, Bairey Merz CN. Ranolazine improves angina in women with evidence of myocardial ischemia but no obstructive coronary artery disease. JACC Cardiovasc Imaging. 2011 May; 4 (5): 514–22. DOI: 10.1016/j.jcmg.2011.03.007. PMID: 21565740; PMCID: PMC6364688
43. Bairey Merz CN, Handberg EM, Shufelt CL, Mehta PK, Minissian MB, Wei J, Thomson LEJ, Berman DS, Shaw LJ, Petersen JW, Brown GH, Anderson RD, Shuster JJ, Cook-Wiens G, Rogatko A, Pepine CJ.. A randomized, placebo-controlled trial of late Na current inhibition (ranolazine) in coronary microvascular dysfunction (CMD): impact on angina and myocardial perfusion reserve. Eur Heart J 2016; 37: 1504–1513. artery disease. JACC Cardiovasc Imaging 2011; 4: 514–522.
44. Patel DJ, Purcell HJ, Fox KM. Cardioprotection by opening of the K(ATP) channel in unstable angina. Is this a clinical manifestation of myocardial preconditioning? Results of a randomized study with nicorandil. CESAR2 investigation. Clinical European studies in angina and revascularization. Eur Heart J. 1999 Jan; 20 (1): 51–7. DOI: 10.1053/euhj.1998.1354. PMID: 10075141
45. Morrow A, Young R, Abraham GR, Hoole S, Greenwood JP, Arnold JR, El Shibly M, Shanmuganathan M, Ferreira V, Rakhit R, Galasko G, Sinha A, Perera D, Al-Lamee R, Spyridopoulos I, Kotecha A, Clesham G, Ford TJ, Davenport A, Padmanabhan S, Jolly L, Kellman P, Kaski JC, Weir RA, Sattar N, Kennedy J, Macfarlane PW, Welsh P, McConnachie A, Berry C; PRIZE Study Group. Zibotentan in Microvascular Angina: A Randomized, Placebo-Controlled, Crossover Trial. Circulation. 2024 Nov 19; 150 (21): 1671–1683. DOI: 10.1161/CIRCULATIONAHA.124.069901. Epub 2024 Sep 1. PMID: 39217504; PMCID: PMC11573082.
46. Jadhav S, Ferrell W, Greer IA, Petrie JR, Cobbe SM, Sattar N.. Effects of metformin on microvascular function and exercise tolerance in women with angina and normal coronary arteries: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol 2006; 48: 956–963.
47. S. P. Solovey. Angina without obstructive coronary artery disease (Part 3). Treatment tactics at the present stage. Emergency cardiology and cardiovascular risks, 2023, Vol. 7, No. 1, Pp. 1742–1757. (In Russ.).
48.
Review
For citations:
Movsisyan D.M., Komissarov E.A., Alidzhanova Kh.G. Myocardial ischemia with nonobstructive coronary arteries (INOCA). Part I. The current state of INOCA problem. Medical alphabet. 2025;(18):12-19. (In Russ.) https://doi.org/10.33667/2078-5631-2025-18-12-19