Objective: Pain and inflammation during acute myocardial infarction (AMI) have been associated with the development of posttraumatic stress disorder and may also impact negatively on somatic outcome. We investigated the relationship between pain during AMI and levels of circulating proinflammatory (tumor necrosis factor [TNF]-α, interleukin [IL]-6) and anti-inflammatory (IL-33 and tissue growth factor [TGF]-β1) cytokines. Methods: Data were collected as part of the Myocardial Infarction - Stress Prevention Intervention (MI-SPRINT) study. We included 140 patients (mean age 59.6 years, 82.1% male) with high acute psychological distress within 48 h after MI. Fasting blood samples were drawn thereafter to measure cytokine levels. Sociodemographic factors, psychological and medical data, as well as cardiometabolic markers were assessed with questionnaires and patient interviews. Results: Linear regression models showed a significant positive correlation of pain with TGF-β1 (b = 770.91, p = 0.031) and a significant inverse correlation of pain with IL-33 (b = -0.11, p = 0.015) after controlling for age, gender, body mass index, lifetime depression, acute stress disorder symptoms, and the prognostic Global Registry of Acute Coronary Events (GRACE) score. Pain was not associated with IL-6 but with the GRACE score (b = 0.01, p = 0.003). Pain showed no significant association with TNF-α. Conclusion: Pain during MI was associated with anti- but not proinflammatory cytokines. As IL-33 has been shown to be cardioprotective, lower IL-33 levels with more intense pain may suggest a pathway through which increased pain during MI may have an impact on the medical prognosis.

Keywords:
Acute myocardial infarction, Cardiovascular disease, Pain, Cytokines, Inflammation, Posttraumatic stress, Psychological stress
1.
Whitehead DL, Strike P, Perkins-Porras L, Steptoe A: Frequency of distress and fear of dying during acute coronary syndromes and consequences for adaptation. Am J Cardiol 2005;96:1512-1516.
2.
Ginzburg K, Solomon Z, Koifman B, Keren G, Roth A, Kriwisky M, et al: Trajectories of posttraumatic stress disorder following myocardial infarction: a prospective study. J Clin Psychiatry 2003;64:1217-1223.
3.
Hari R, Begré S, Schmid J-P, Saner H, Gander M-L, von Känel R: Change over time in posttraumatic stress caused by myocardial infarction and predicting variables. J Psychosom Res 2010;69:143-150.
4.
Whitehead DL, Perkins-Porras L, Strike PC, Steptoe A: Post-traumatic stress disorder in patients with cardiac disease: predicting vulnerability from emotional responses during admission for acute coronary syndromes. Heart 2006;92:1225-1229.
5.
Wiedemar L, Schmid J-P, Müller J, Wittmann L, Schnyder U, Saner H, et al: Prevalence and predictors of posttraumatic stress disorder in patients with acute myocardial infarction. Heart Lung 2008;37:113-121.
6.
von Känel R, Hari R, Schmid J-P, Saner H, Begré S: Distress related to myocardial infarction and cardiovascular outcome: a retrospective observational study. BMC Psychiatry 2011;11:98.
7.
Frangogiannis NG: Regulation of the inflammatory response in cardiac repair. Circ Res 2012;110:159-173.
8.
Prabhu SD, Frangogiannis NG: The biological basis for cardiac repair after myocardial infarction: from inflammation to fibrosis. Circ Res 2016;119:91-112.
9.
Dobaczewski M, Chen W, Frangogiannis NG: Transforming growth factor (TGF)-β signaling in cardiac remodeling. J Mol Cell Cardiol 2011;51:600-606.
10.
Seki K, Sanada S, Kudinova AY, Steinhauser ML, Handa V, Gannon J, et al: Interleukin- 33 prevents apoptosis and improves survival after experimental myocardial infarction through ST2 signaling. Circ Heart Fail 2009;2:684-691.
11.
Kunes P, Mandak J, Holubcova Z, Kolackova M, Krejsek J: Actual position of interleukin (IL)-33 in atherosclerosis and heart failure: great expectations or en attendant Godot? Perfusion 2015;30:356-374.
12.
Kuebler U, Zuccarella-Hackl C, Arpagaus A, Wolf JM, Farahmand F, von Känel R, et al: Stress-induced modulation of NF-κB activation, inflammation-associated gene expression, and cytokine levels in blood of healthy men. Brain Behav Immun 2015;46:87-95.
13.
Marsland AL, Walsh C, Lockwood K, John-Henderson NA: The effects of acute psychological stress on circulating and stimulated inflammatory markers: a systematic review and meta-analysis. Brain Behav Immun 2017;64:208-219.
14.
Steptoe A, Hamer M, Chida Y: The effects of acute psychological stress on circulating inflammatory factors in humans: a review and meta-analysis. Brain Behav Immun 2007;21:901-912.
15.
von Känel R, Mills PJ, Mausbach BT, Dimsdale JE, Patterson TL, Ziegler MG, et al: Effect of Alzheimer caregiving on circulating levels of C-reactive protein and other biomarkers relevant to cardiovascular disease risk: a longitudinal study. Gerontology 2012;58:354-365.
16.
Pace TWW, Heim CM: A short review on the psychoneuroimmunology of posttraumatic stress disorder: from risk factors to medical comorbidities. Brain Behav Immun 2011;25:6-13.
17.
Passos IC, Vasconcelos-Moreno MP, Costa LG, Kunz M, Brietzke E, Quevedo J, et al: Inflammatory markers in post-traumatic stress disorder: a systematic review, meta-analysis, and meta-regression. Lancet Psychiatry 2015;2:1002-1012.
18.
von Känel R, Begré S, Abbas CC, Saner H, Gander M-L, Schmid J-P: Inflammatory biomarkers in patients with posttraumatic stress disorder caused by myocardial infarction and the role of depressive symptoms. Neuroimmunomodulation 2010;17:39-46.
19.
von Känel R, Hepp U, Kraemer B, Traber R, Keel M, Mica L, et al: Evidence for low-grade systemic proinflammatory activity in patients with posttraumatic stress disorder. J Psychiatr Res 2007;41:744-752.
20.
Reuben DB, Cheh AI, Harris TB, Ferrucci L, Rowe JW, Tracy RP, et al: Peripheral blood markers of inflammation predict mortality and functional decline in high-functioning community-dwelling older persons. J Am Geriatr Soc 2002;50:638-644.
21.
Tuomisto K, Jousilahti P, Sundvall J, Pajunen P, Salomaa V: C-reactive protein, interleukin-6 and tumor necrosis factor alpha as predictors of incident coronary and cardiovascular events and total mortality. A population-based, prospective study. Thromb Haemost 2006;95:511-518.
22.
Wassel CL, Barrett-Connor E, Laughlin GA: Association of circulating C-reactive protein and interleukin-6 with longevity into the 80s and 90s: the Rancho Bernardo Study. J Clin Endocrinol Metab 2010;95:4748-4755.
23.
Ridker PM, Rifai N, Pfeffer M, Sacks F, Lepage S, Braunwald E: Elevation of tumor necrosis factor-alpha and increased risk of recurrent coronary events after myocardial infarction. Circulation 2000;101:2149-2153.
24.
Hartford M, Wiklund O, Mattsson Hultén L, Persson A, Karlsson T, Herlitz J, et al: C-reactive protein, interleukin-6, secretory phospholipase A2 group IIA and intercellular adhesion molecule-1 in the prediction of late outcome events after acute coronary syndromes. J Intern Med 2007;262:526-536.
25.
Kavsak PA, Ko DT, Newman AM, Palomaki GE, Lustig V, MacRae AR, et al: Risk stratification for heart failure and death in an acute coronary syndrome population using inflammatory cytokines and N-terminal pro-brain natriuretic peptide. Clin Chem 2007;53:2112-2118.
26.
Zamani P, Schwartz GG, Olsson AG, Rifai N, Bao W, Libby P, et al: Inflammatory biomarkers, death, and recurrent nonfatal coronary events after an acute coronary syndrome in the MIRACL study. J Am Heart Assoc 2013;2:e003103.
27.
Demyanets S, Speidl WS, Tentzeris I, Jarai R, Katsaros KM, Farhan S, et al: Soluble ST2 and interleukin-33 levels in coronary artery disease: relation to disease activity and adverse outcome. PLoS One 2014;9:e95055.
28.
Dhillon OS, Narayan HK, Khan SQ, Kelly D, Quinn PA, Squire IB, et al: Pre-discharge risk stratification in unselected STEMI: is there a role for ST2 or its natural ligand IL-33 when compared with contemporary risk markers? Int J Cardiol 2013;167:2182-2188.
29.
Tashiro H, Shimokawa H, Sadamatu K, Yamamoto K: Prognostic significance of plasma concentrations of transforming growth factor-beta in patients with coronary artery disease. Coron Artery Dis 2002;13:139-143.
30.
Meister R, Princip M, Schmid J-P, Schnyder U, Barth J, Znoj H, et al: Myocardial Infarction - Stress PRevention INTervention (MI-SPRINT) to reduce the incidence of posttraumatic stress after acute myocardial infarction through trauma-focused psychological counseling: study protocol for a randomized controlled trial. Trials 2013;14:329.
31.
Fox KAA, Dabbous OH, Goldberg RJ, Pieper KS, Eagle KA, Werf FV de, et al: Prediction of risk of death and myocardial infarction in the six months after presentation with acute coronary syndrome: prospective multinational observational study (GRACE). BMJ 2006;333:1091.
32.
Killip T, Kimball JT: Treatment of myocardial infarction in a coronary care unit. A two year experience with 250 patients. Am J Cardiol 1967;20:457-464.
33.
Price DD, McGrath PA, Rafii A, Buckingham B: The validation of visual analogue scales as ratio scale measures for chronic and experimental pain. Pain 1983;17:45-56.
34.
Bryant RA, Moulds ML, Guthrie RM: Acute stress disorder scale: a self-report measure of acute stress disorder. Psychol Assess 2000;12:61-68.
35.
Helfricht S, Landolt MA, Moergeli H, Hepp U, Wegener D, Schnyder U: Psychometric evaluation and validation of the German version of the Acute Stress Disorder Scale across two distinct trauma populations. J Trauma Stress 2009;22:476-480.
36.
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, ed 4. Washington, American Psychiatric Association, 1994.
37.
Do CB, Batzoglou S: What is the expectation maximization algorithm? Nat Biotechnol 2008;26:897-899.
38.
Dhillon OS, Narayan HK, Quinn PA, Squire IB, Davies JE, Ng LL: Interleukin 33 and ST2 in non-ST-elevation myocardial infarction: comparison with Global Registry of Acute Coronary Events Risk Scoring and NT-proBNP. Am Heart J 2011;161:1163-1170.
39.
Zhang K, Zhang X, Mi Y, Liu J: Predicting value of serum soluble ST2 and interleukin-33 for risk stratification and prognosis in patients with acute myocardial infarction. Chin Med J (Engl) 2013;126:3628-3631.
40.
Rath D, Chatterjee M, Müller I, Müller K, Böckmann C, Droppa M, et al: Platelet expression of transforming growth factor beta 1 is enhanced and associated with cardiovascular prognosis in patients with acute coronary syndrome. Atherosclerosis 2014;237:754-759.
41.
Lantero A, Tramullas M, Díaz A, Hurlé MA: Transforming growth factor-β in normal nociceptive processing and pathological pain models. Mol Neurobiol 2012;45:76-86.
42.
Pervanidou P, Kolaitis G, Charitaki S, Margeli A, Ferentinos S, Bakoula C, et al: Elevated morning serum interleukin (IL)-6 or evening salivary cortisol concentrations predict posttraumatic stress disorder in children and adolescents six months after a motor vehicle accident. Psychoneuroendocrinology 2007;32:991-999.
43.
Marques-Vidal P, Bochud M, Bastardot F, Lüscher T, Ferrero F, Gaspoz J-M, et al: Levels and determinants of inflammatory biomarkers in a Swiss population-based sample (CoLaus study). PLoS One 2011;6:e21002.
44.
Liu Y, Ho RC-M, Mak A: Interleukin (IL)-6, tumour necrosis factor alpha (TNF-α) and soluble interleukin-2 receptors (sIL-2R) are elevated in patients with major depressive disorder: a meta-analysis and meta-regression. J Affect Disord 2012;139:230-239.
45.
Tuglu C, Kara SH, Caliyurt O, Vardar E, Abay E: Increased serum tumor necrosis factor-alpha levels and treatment response in major depressive disorder. Psychopharmacology (Berl) 2003;170:429-433.
46.
Sheps DS, Creed F, Clouse RE: Chest pain in patients with cardiac and noncardiac disease. Psychosom Med 2004;66:861-867.
47.
Kronfol Z, Remick DG: Cytokines and the brain: implications for clinical psychiatry. Am J Psychiatry 2000;157:683-694.
48.
Maier SF, Watkins LR: Cytokines for psychologists: implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition. Psychol Rev 1998;105:83-107.
© 2017 S. Karger AG, Basel
2017
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.