Background Myocarditis is an important cause of acute and chronic heart failure. Men with myocarditis have worse recovery and an increased need for transplantation compared with women, but the reason for the sex difference remains unclear. Elevated sera soluble (s) ST2 predicts mortality from acute and chronic heart failure, but has not been studied in myocarditis patients. Methods and Results Adults with a diagnosis of clinically suspected myocarditis (n=303, 78% male) were identified according to the 2013 European Society of Cardiology position statement. Sera sST2 levels were examined by ELISA in humans and mice and correlated with heart function according to sex and age. Sera sST2 levels were higher in healthy men ( P=8×10-6) and men with myocarditis ( P=0.004) compared with women. sST2 levels were elevated in patients with myocarditis and New York Heart Association class III - IV heart failure ( P=0.002), predominantly in men ( P=0.0003). Sera sST2 levels were associated with New York Heart Association class in men with myocarditis who were ≤50 years old ( r=0.231, P=0.0006), but not in women ( r=0.172, P=0.57). Sera sST2 levels were also significantly higher in male mice with myocarditis ( P=0.005) where levels were associated with cardiac inflammation. Gonadectomy with hormone replacement showed that testosterone ( P<0.001), but not estradiol ( P=0.32), increased sera sST2 levels in male mice with myocarditis. Conclusions We show in a well-characterized subset of heart failure patients with clinically suspected and biopsy-confirmed myocarditis that elevated sera sST2 is associated with an increased risk of heart failure based on New York Heart Association class in men ≤50 years old.

Department of Cardiology and Berlin Brandenburg Center for Regenerative Medicine Campus Virchow Klinikum Charite Universitaetsmedizin Berlin Berlin Germany

Department of Cardiovascular Diseases Mayo Clinic Rochester MN

Department of Cardiovascular Diseases St Anne's University Hospital and Masaryk University Brno Czech Republic

Department of Cardiovascular Medicine Mayo Clinic Jacksonville FL

Department of Environmental Health Sciences Johns Hopkins Bloomberg School of Public Health Baltimore MD

Department of Internal Medicine and Cardiology University Hospital Giessen and Marburg Marburg Germany

Department of Microbiology and Immunology University of Oklahoma Health Sciences Center Oklahoma City OK

Department of Pathological Physiology and the Research Center for the Toxic Compounds in the Environment Faculty of Sciences Masaryk University Brno Czech Republic

Heart and Vascular Institute University of Pittsburgh PA

Institute for Cardiac Diagnostics and Therapy Berlin Germany

Medicine Samsung Medical Center Seoul Korea

Zobrazit více v PubMed

Bui AL, Horwich TB, Fonarow GC. Epidemiology and risk profile of heart failure. Nat Rev Cardiol. 2011;8:30–41. PubMed PMC

Braunwald E. The war against heart failure: the Lancet lecture. Lancet. 2015;385:812–824. PubMed

Cooper LT Jr. Myocarditis. N Engl J Med. 2009;360:1526–1538. PubMed PMC

Cooper LT Jr, Keren A, Sliwa K, Matsumori A, Mensah GA. The global burden of myocarditis: part 1: a systematic literature review for the Global Burden of Diseases, Injuries, and Risk Factors 2010 study. Glob Heart. 2014;9:121–129. PubMed

Felker GM, Hu W, Hare JM, Hruban RH, Baughman KL, Kasper EK. The spectrum of dilated cardiomyopathy. The Johns Hopkins experience with 1,278 patients. Medicine (Baltimore). 1999;78:270–283. PubMed

McNamara DM, Starling RC, Cooper LT, Boehmer JP, Mather PJ, Janosko KM, Gorcsan J III, Kip KE, Dec GW; IMAC Investigators . Clinical and demographic predictors of outcomes in recent onset dilated cardiomyopathy: results of the IMAC (Intervention in Myocarditis and Acute Cardiomyopathy)‐2 study. J Am Coll Cardiol. 2011;58:1112–1118. PubMed PMC

Frisancho‐Kiss S, Davis SE, Nyland JF, Frisancho JA, Cihakova D, Barrett MA, Rose NR, Fairweather D. Cutting edge: cross‐regulation by TLR4 and T cell Ig mucin‐3 determines sex differences in inflammatory heart disease. J Immunol. 2007;178:6710–6714. PubMed

Coronado MJ, Brandt JE, Kim E, Bucek A, Bedja D, Abston ED, Shin J, Gabrielson KL, Mitzner W, Fairweather D. Testosterone and interleukin‐1beta increase cardiac remodeling during coxsackievirus B3 myocarditis via serpin A 3n. Am J Physiol Heart Circ Physiol. 2012;302:H1726–H1736. PubMed PMC

Villacorta H, Maisel AS. Soluble ST2 testing: a promising biomarker in the management of heart failure. Arq Bras Cardiol. 2016;106:145–152. PubMed PMC

Pascual‐Figal DA, Ordonez‐Llanos J, Tornel PL, Vazquez R, Puig T, Valdes M, Cinca J, de Luna AB, Bayes‐Genis A; MUSIC Investigators . Soluble ST2 for predicting sudden cardiac death in patients with chronic heart failure and left ventricular systolic dysfunction. J Am Coll Cardiol. 2009;54:2174–2179. PubMed

Emdin M, Aimo A, Vergaro G, Bayes‐Genis A, Lupon J, Latini R, Meessen J, Anand IS, Cohn JN, Gravning J, Gullestad L, Broch K, Ueland T, Nymo SH, Brunner‐La Rocca HP, de Boer RA, Gaggin HK, Ripoli A, Passino C, Januzzi JL Jr. sST2 predicts outcome in chronic heart failure beyond NT‐proBNP and high‐sensitivity troponin T. J Am Coll Cardiol. 2018;72:2309–2320. PubMed

Weinberg EO, Shimpo M, Hurwitz S, Tominaga S, Rouleau JL, Lee RT. Identification of serum soluble ST2 receptor as a novel heart failure biomarker. Circulation. 2003;107:721–726. PubMed

Rehman SU, Mueller T, Januzzi JL Jr. Characteristics of the novel interleukin family biomarker ST2 in patients with acute heart failure. J Am Coll Cardiol. 2008;52:1458–1465. PubMed

Pascual‐Figal DA, Januzzi JL. The biology of ST2: the international ST2 consensus panel. Am J Cardiol. 2015;115:3B–7B. PubMed

Griesenauer B, Paczesny S. The ST2/IL‐33 axis in immune cells during inflammatory diseases. Front Immunol. 2017;8:475. PubMed PMC

Weinberg EO, Shimpo M, De Keulenaer GW, MacGillivray C, Tominaga S, Solomon SD, Rouleau JL, Lee RT. Expression and regulation of ST2, an interleukin‐1 receptor family member, in cardiomyocytes and myocardial infarction. Circulation. 2002;106:2961–2966. PubMed PMC

Lu J, Kang J, Zhang C, Zhang X. The role of IL‐33/ST2L signals in the immune cells. Immunol Lett. 2015;164:11–17. PubMed

Rostan O, Arshad MI, Piquet‐Pellorce C, Robert‐Gangneux F, Gangneux JP, Samson M. Crucial and diverse role of the interleukin‐33/ST2 axis in infectious diseases. Infect Immun. 2015;83:1738–1748. PubMed PMC

Frisancho‐Kiss S, Coronado MJ, Frisancho JA, Lau VM, Rose NR, Klein SL, Fairweather D. Gonadectomy of male BALB/c mice increases Tim‐3(+) alternatively activated M2 macrophages, Tim‐3(+) T cells, Th2 cells and Treg in the heart during acute coxsackievirus‐induced myocarditis. Brain Behav Immun. 2009;23:649–657. PubMed PMC

Fairweather D, Coronado MJ, Garton AE, Dziedzic JL, Bucek A, Cooper LT Jr, Brandt JE, Alikhan FS, Wang H, Endres CJ, Choi J, Pomper MG, Guilarte TR. Sex differences in translocator protein 18 kDa (TSPO) in the heart: implications for imaging myocardial inflammation. J Cardiovasc Transl Res. 2014;7:192–202. PubMed PMC

Caforio AL, Pankuweit S, Arbustini E, Basso C, Gimeno‐Blanes J, Felix SB, Fu M, Helio T, Heymans S, Jahns R, Klingel K, Linhart A, Maisch B, McKenna W, Mogensen J, Pinto YM, Ristic A, Schultheiss HP, Seggewiss H, Tavazzi L, Thiene G, Yilmaz A, Charron P, Elliott PM; European Society of Cardiology Working Group on Myocardial and Pericardial Diseases . Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2013;34:2636–2648, 2648a‐2648d. PubMed

Jacobsen BK, Heuch I, Kvale G. Age at natural menopause and all‐cause mortality: a 37‐year follow‐up of 19,731 Norwegian women. Am J Epidemiol. 2003;157:923–929. PubMed

Fairweather D. Autoimmune skin diseases: role of sex hormones, vitamin D and menopause In: Farage MA, Miller KW, Fugate‐Woods N, Maibach HI, eds. Skin, Mucosa and Menopause: Management of Clinical Issues. Heidelberg: Springer; 2015:359–381.

Kato I, Toniolo P, Akhmedkhanov A, Koenig KL, Shore R, Zeleniuch‐Jacquotte A. Prospective study of factors influencing the onset of natural menopause. J Clin Epidemiol. 1998;51:1271–1276. PubMed

Regitz‐Zagrosek V, Becher E, Mahmoodzadeh S, Schubert C. Sex steroid hormones In: Bader M, ed. Cardiovascular Hormone Systems. Weinheim: Wiley‐Blackwell; 2008:39–64.

Wu C, Singh A, Collins B, Fatima A, Qamar A, Gupta A, Hainer J, Klein J, Jarolim P, Di Carli M, Nasir K, Bhatt DL, Blankstein R. Causes of troponin elevation and associated mortality in young patients. Am J Med. 2018;131:284–292. e281. PubMed PMC

Myers JM, Fairweather D, Huber SA, Cunningham MW. Autoimmune myocarditis, valvulitis, and cardiomyopathy. Curr Protoc Immunol. 2013;Chapter 15:Unit 15 14 11‐51. PubMed PMC

Robinson DP, Hall OJ, Nilles TL, Bream JH, Klein SL. 17beta‐estradiol protects females against influenza by recruiting neutrophils and increasing virus‐specific CD8 T cell responses in the lungs. J Virol. 2014;88:4711–4720. PubMed PMC

O'Brien JE, Peterson TJ, Tong MH, Lee EJ, Pfaff LE, Hewitt SC, Korach KS, Weiss J, Jameson JL. Estrogen‐induced proliferation of uterine epithelial cells is independent of estrogen receptor alpha binding to classical estrogen response elements. J Biol Chem. 2006;281:26683–26692. PubMed

Georgakopoulos D, Kass DA. Protocols for hemodynamic assessment of transgenic mice in vivo. Methods Mol Biol. 2003;219:233–243. PubMed

Abston ED, Barin JG, Cihakova D, Bucek A, Coronado MJ, Brandt JE, Bedja D, Kim JB, Georgakopoulos D, Gabrielson KL, Mitzner W, Fairweather D. IL‐33 independently induces eosinophilic pericarditis and cardiac dilation: ST2 improves cardiac function. Circ Heart Fail. 2012;5:366–375. PubMed PMC

de Boer RA, Daniels LB, Maisel AS, Januzzi JL Jr. State of the art: newer biomarkers in heart failure. Eur J Heart Fail. 2015;17:559–569. PubMed

Shimpo M, Morrow DA, Weinberg EO, Sabatine MS, Murphy SA, Antman EM, Lee RT. Serum levels of the interleukin‐1 receptor family member ST2 predict mortality and clinical outcome in acute myocardial infarction. Circulation. 2004;109:2186–2190. PubMed

Januzzi JL Jr, Peacock WF, Maisel AS, Chae CU, Jesse RL, Baggish AL, O'Donoghue M, Sakhuja R, Chen AA, van Kimmenade RR, Lewandrowski KB, Lloyd‐Jones DM, Wu AH. Measurement of the interleukin family member ST2 in patients with acute dyspnea: results from the PRIDE (Pro‐Brain Natriuretic Peptide Investigation of Dyspnea in the Emergency Department) study. J Am Coll Cardiol. 2007;50:607–613. PubMed

Whellan DJ, O'Connor CM, Lee KL, Keteyian SJ, Cooper LS, Ellis SJ, Leifer ES, Kraus WE, Kitzman DW, Blumenthal JA, Rendall DS, Houston‐Miller N, Fleg JL, Schulman KA, Pina IL; HF‐ACTION Trial Investigators . Heart failure and a controlled trial investigating outcomes of exercise training (HF‐ACTION): design and rationale. Am Heart J. 2007;153:201–211. PubMed

Ky B, French B, McCloskey K, Rame JE, McIntosh E, Shahi P, Dries DL, Tang WH, Wu AH, Fang JC, Boxer R, Sweitzer NK, Levy WC, Goldberg LR, Jessup M, Cappola TP. High‐sensitivity ST2 for prediction of adverse outcomes in chronic heart failure. Circ Heart Fail. 2011;4:180–187. PubMed PMC

Daniels LB, Maisel AS. Cardiovascular biomarkers and sex: the case for women. Nat Rev Cardiol. 2015;12:588–596. PubMed

Kyto V, Sipila J, Rautava P. The effects of gender and age on occurrence of clinically suspected myocarditis in adulthood. Heart. 2013;99:1681–1684. PubMed

Bohm P, Scharhag J, Meyer T. Data from a nationwide registry on sports‐related sudden cardiac deaths in Germany. Eur J Prev Cardiol. 2016;23:649–656. PubMed PMC

Dieplinger B, Egger M, Poelz W, Gabriel C, Haltmayer M, Mueller T. Soluble ST2 is not independently associated with androgen and estrogen status in healthy males and females. Clin Chem Lab Med. 2011;49:1515–1518. PubMed

Coglianese EE, Larson MG, Vasan RS, Ho JE, Ghorbani A, McCabe EL, Cheng S, Fradley MG, Kretschman D, Gao W, O'Connor G, Wang TJ, Januzzi JL. Distribution and clinical correlates of the interleukin receptor family member soluble ST2 in the Framingham Heart Study. Clin Chem. 2012;58:1673–1681. PubMed PMC

Fairweather D, Cooper LT Jr, Blauwet LA. Sex and gender differences in myocarditis and dilated cardiomyopathy. Curr Probl Cardiol. 2013;38:7–46. PubMed PMC

Krejci J, Mlejnek D, Sochorova D, Nemec P. Inflammatory cardiomyopathy: a current view on the pathophysiology, diagnosis, and treatment. Biomed Res Int. 2016;2016:4087632. PubMed PMC

Myers JM, Cooper LT, Kem DC, Stavrakis S, Kosanke SD, Shevach EM, Fairweather D, Stoner JA, Cox CJ, Cunningham MW. Cardiac myosin‐Th17 responses promote heart failure in human myocarditis. JCI Insight. 2016;1:e85851. PubMed PMC

Suzukawa M, Koketsu R, Iikura M, Nakae S, Matsumoto K, Nagase H, Saito H, Matsushima K, Ohta K, Yamamoto K, Yamaguchi M. Interleukin‐33 enhances adhesion, CD11b expression and survival in human eosinophils. Lab Invest. 2008;88:1245–1253. PubMed

Jovanovic IP, Pejnovic NN, Radosavljevic GD, Pantic JM, Milovanovic MZ, Arsenijevic NN, Lukic ML. Interleukin‐33/ST2 axis promotes breast cancer growth and metastases by facilitating intratumoral accumulation of immunosuppressive and innate lymphoid cells. Int J Cancer. 2014;134:1669–1682. PubMed

Satoh M, Nakamura M, Akatsu T, Iwasaka J, Shimoda Y, Segawa I, Hiramori K. Expression of Toll‐like receptor 4 is associated with enteroviral replication in human myocarditis. Clin Sci (Lond). 2003;104:577–584. PubMed

Fairweather D, Yusung S, Frisancho S, Barrett M, Gatewood S, Steele R, Rose NR. IL‐12 receptor beta 1 and Toll‐like receptor 4 increase IL‐1 beta‐ and IL‐18‐associated myocarditis and coxsackievirus replication. J Immunol. 2003;170:4731–4737. PubMed

Cain BS, Meldrum DR, Dinarello CA, Meng X, Joo KS, Banerjee A, Harken AH. Tumor necrosis factor‐alpha and interleukin‐1beta synergistically depress human myocardial function. Crit Care Med. 1999;27:1309–1318. PubMed

Vasan RS, Sullivan LM, Roubenoff R, Dinarello CA, Harris T, Benjamin EJ, Sawyer DB, Levy D, Wilson PW, D'Agostino RB; Framingham Heart S . Inflammatory markers and risk of heart failure in elderly subjects without prior myocardial infarction: the Framingham Heart Study. Circulation. 2003;107:1486–1491. PubMed

Kindermann I, Kindermann M, Kandolf R, Klingel K, Bultmann B, Muller T, Lindinger A, Bohm M. Predictors of outcome in patients with suspected myocarditis. Circulation. 2008;118:639–648. PubMed

Bartunek J, Delrue L, Van Durme F, Muller O, Casselman F, De Wiest B, Croes R, Verstreken S, Goethals M, de Raedt H, Sarma J, Joseph L, Vanderheyden M, Weinberg EO. Nonmyocardial production of ST2 protein in human hypertrophy and failure is related to diastolic load. J Am Coll Cardiol. 2008;52:2166–2174. PubMed PMC

Boisot S, Beede J, Isakson S, Chiu A, Clopton P, Januzzi J, Maisel AS, Fitzgerald RL. Serial sampling of ST2 predicts 90‐day mortality following destabilized heart failure. J Card Fail. 2008;14:732–738. PubMed

Maisel AS, Richards AM, Pascual‐Figal D, Mueller C. Serial ST2 testing in hospitalized patients with acute heart failure. Am J Cardiol. 2015;115:32B–37B. PubMed

Follistatin-like 1 and its paralogs in heart development and cardiovascular disease

Sex and age differences in sST2 in cardiovascular disease

Innate Lymphoid Cells Play a Pathogenic Role in Pericarditis