A signature of circulating microRNAs differentiates takotsubo cardiomyopathy from acute myocardial infarction

Milosz Jaguszewski, Julia Osipova, Jelena-Rima Ghadri, Lars Christian Napp, Christian Widera, Jennifer Franke, Marcin Fijalkowski, Radoslaw Nowak, Marta Fijalkowska, Ingo Volkmann, Hugo A Katus, Kai C Wollert, Johann Bauersachs, Paul Erne, Thomas F Lüscher, Thomas Thum, Christian Templin, Milosz Jaguszewski, Julia Osipova, Jelena-Rima Ghadri, Lars Christian Napp, Christian Widera, Jennifer Franke, Marcin Fijalkowski, Radoslaw Nowak, Marta Fijalkowska, Ingo Volkmann, Hugo A Katus, Kai C Wollert, Johann Bauersachs, Paul Erne, Thomas F Lüscher, Thomas Thum, Christian Templin

Abstract

Aims: Takotsubo cardiomyopathy (TTC) remains a potentially life-threatening disease, which is clinically indistinguishable from acute myocardial infarction (MI). Today, no established biomarkers are available for the early diagnosis of TTC and differentiation from MI. MicroRNAs (miRNAs/miRs) emerge as promising sensitive and specific biomarkers for cardiovascular disease. Thus, we sought to identify circulating miRNAs suitable for diagnosis of acute TTC and for distinguishing TTC from acute MI.

Methods and results: After miRNA profiling, eight miRNAs were selected for verification by real-time quantitative reverse transcription polymerase chain reaction in patients with TTC (n = 36), ST-segment elevation acute myocardial infarction (STEMI, n = 27), and healthy controls (n = 28). We quantitatively confirmed up-regulation of miR-16 and miR-26a in patients with TTC compared with healthy subjects (both, P < 0.001), and up-regulation of miR-16, miR-26a, and let-7f compared with STEMI patients (P < 0.0001, P < 0.05, and P < 0.05, respectively). Consistent with previous publications, cardiac specific miR-1 and miR-133a were up-regulated in STEMI patients compared with healthy controls (both, P < 0.0001). Moreover, miR-133a was substantially increased in patients with STEMI compared with TTC (P < 0.05). A unique signature comprising miR-1, miR-16, miR-26a, and miR-133a differentiated TTC from healthy subjects [area under the curve (AUC) 0.835, 95% CI 0.733-0.937, P < 0.0001] and from STEMI patients (AUC 0.881, 95% CI 0.793-0.968, P < 0.0001). This signature yielded a sensitivity of 74.19% and a specificity of 78.57% for TTC vs. healthy subjects, and a sensitivity of 96.77% and a specificity of 70.37% for TTC vs. STEMI patients. Additionally, we noticed a decrease of the endothelin-1 (ET-1)-regulating miRNA-125a-5p in parallel with a robust increase of ET-1 plasma levels in TTC compared with healthy subjects (P < 0.05).

Conclusion: The present study for the first time describes a signature of four circulating miRNAs as a robust biomarker to distinguish TTC from STEMI patients. The significant up-regulation of these stress- and depression-related miRNAs suggests a close connection of TTC with neuropsychiatric disorders. Moreover, decreased levels of miRNA125a-5p as well as increased plasma levels of its target ET-1 are in line with the microvascular spasm hypothesis of the TTC pathomechanism.

Keywords: Biomarker; Endothelin-1; MicroRNA; Takotsubo cardiomyopathy.

Figures

Figure 1
Figure 1
MicroRNA array profiling in patients with takotsubo cardiomyopathy compared with healthy subjects. Red colour indicates microRNA candidates considered for the real-time quantitative reverse transcription polymerase chain reaction validation. miR-1 was not detectable in healthy subjects and, therefore, not presented here.
Figure 2
Figure 2
Comparative analysis of expression levels for selected microRNA candidates for takotsubo cardiomyopathy, ST-segment elevation acute myocardial infarction, and healthy controls; *P < 0.05, **P < 0.001, ***P < 0.0001.
Figure 3
Figure 3
ROC curve analysis for single microRNAs (A: miR-16; B: miR-26a; C: miR-1; D: miR-133a) and combinations (E: miR-16+miR-26a; F: miR-1+miR-133a; G: miR-16+miR-26a+miR-1; H: miR-16+miR-26a+miR-133a) to discriminate takotsubo cardiomyopathy from healthy controls and ST-segment elevation acute myocardial infarction patients.
Figure 4
Figure 4
ROC curve analysis for the combination of four microRNAs resulting in enhanced specificity and sensitivity to distinguish takotsubo cardiomyopathy form healthy subjects (74.2, 78.6%, respectively) and ST-segment elevation acute myocardial infarction controls (96.8, 70.4%, respectively).
Figure 5
Figure 5
Results of the quantitative reverse transcription polymerase chain reaction of the miR-125a-5p expression (A) and endothelin-1 assay (B) in takotsubo cardiomyopathy, ST-segment elevation acute myocardial infarction and healthy subjects; *P < 0.05, ***P < 0.0001.

References

    1. Matsuoka K, Okubo S, Fujii E, Uchida F, Kasai A, Aoki T, Makino K, Omichi C, Fujimoto N, Ohta S, Sawai T, Nakano T. Evaluation of the arrhythmogenecity of stress-induced ‘takotsubo cardiomyopathy’ from the time course of the 12-lead surface electrocardiogram. Am J Cardiol. 2003;92:230–233. .
    1. Bybee KA, Prasad A, Barsness GW, Lerman A, Jaffe AS, Murphy JG, Wright RS, Rihal CS. Clinical characteristics and thrombolysis in myocardial infarction frame counts in women with transient left ventricular apical ballooning syndrome. Am J Cardiol. 2004;94:343–346. .
    1. Eitel I, Behrendt F, Schindler K, Kivelitz D, Gutberlet M, Schuler G, Thiele H. Differential diagnosis of suspected apical ballooning syndrome using contrast-enhanced magnetic resonance imaging. Eur Heart J. 2008;29:2651–2659. .
    1. Eitel I, von Knobelsdorff-Brenkenhoff F, Bernhardt P, Carbone I, Muellerleile K, Aldrovandi A, Francone M, Desch S, Gutberlet M, Strohm O, Schuler G, Schulz-Menger J, Thiele H, Friedrich MG. Clinical characteristics and cardiovascular magnetic resonance findings in stress (takotsubo) cardiomyopathy. JAMA. 2011;306:277–286. .
    1. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, Katus HA, Apple FS, Lindahl B, Morrow DA, Clemmensen PM, Johanson P, Hod H, Underwood R, Bax JJ, Bonow JJ, Pinto F, Gibbons RJ, Fox KA, Atar D, Newby LK, Galvani M, Hamm CW, Uretsky BF, Steg PG, Wijns W, Bassand JP, Menasche P, Ravkilde J, Ohman EM, Antman EM, Wallentin LC, Armstrong PW, Januzzi JL, Nieminen MS, Gheorghiade M, Filippatos G, Luepker RV, Fortmann SP, Rosamond WD, Levy D, Wood D, Smith SC, Hu D, Lopez-Sendon JL, Robertson RM, Weaver D, Tendera M, Bove AA, Parkhomenko AN, Vasilieva EJ, Mendis S, Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Kirchhof P, Knuuti J, Kolh P, McDonagh T, Moulin C, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Torbicki A, Vahanian A, Windecker S, Morais J, Aguiar C, Almahmeed W, Arnar DO, Barili F, Bloch KD, Bolger AF, Botker HE, Bozkurt B, Bugiardini R, Cannon C, de Lemos J, Eberli FR, Escobar E, Hlatky M, James S, Kern KB, Moliterno DJ, Mueller C, Neskovic AN, Pieske BM, Schulman SP, Storey RF, Taubert KA, Vranckx P, Wagner DR. Third universal definition of myocardial infarction. J Am Coll Cardiol. 2012;60:1581–1598. .
    1. Prasad A, Lerman A, Rihal CS. Apical ballooning syndrome (tako-tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J. 2008;155:408–417. .
    1. Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, Moss AJ, Seidman CE, Young JB. Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation. 2006;113:1807–1816. .
    1. Sharkey SW, Windenburg DC, Lesser JR, Maron MS, Hauser RG, Lesser JN, Haas TS, Hodges JS, Maron BJ. Natural history and expansive clinical profile of stress (tako-tsubo) cardiomyopathy. J Am Coll Cardiol. 2010;55:333–341. .
    1. Tsuchihashi K, Ueshima K, Uchida T, Oh-mura N, Kimura K, Owa M, Yoshiyama M, Miyazaki S, Haze K, Ogawa H, Honda T, Hase M, Kai R, Morii I. Transient left ventricular apical ballooning without coronary artery stenosis: a novel heart syndrome mimicking acute myocardial infarction. Angina pectoris-myocardial infarction investigations in Japan. J Am Coll Cardiol. 2001;38:11–18. .
    1. Bybee KA, Kara T, Prasad A, Lerman A, Barsness GW, Wright RS, Rihal CS. Systematic review: transient left ventricular apical ballooning: a syndrome that mimics ST-segment elevation myocardial infarction. Ann Intern Med. 2004;141:858–865. .
    1. Elesber AA, Prasad A, Lennon RJ, Wright RS, Lerman A, Rihal CS. Four-year recurrence rate and prognosis of the apical ballooning syndrome. J Am Coll Cardiol. 2007;50:448–452. .
    1. Jaguszewski M, Fijalkowski M, Nowak R, Czapiewski P, Ghadri JR, Templin C, Rynkiewicz A. Ventricular rupture in takotsubo cardiomyopathy. Eur Heart J. 2012;33:1027. .
    1. Desmet WJ, Adriaenssens BF, Dens JA. Apical ballooning of the left ventricle: first series in white patients. Heart. 2003;89:1027–1031. .
    1. Hertting K, Krause K, Harle T, Boczor S, Reimers J, Kuck KH. Transient left ventricular apical ballooning in a community hospital in Germany. Int J Cardiol. 2006;112:282–288. .
    1. Kurowski V, Kaiser A, von Hof K, Killermann DP, Mayer B, Hartmann F, Schunkert H, Radke PW. Apical and midventricular transient left ventricular dysfunction syndrome (tako-tsubo cardiomyopathy): frequency, mechanisms, and prognosis. Chest. 2007;132:809–816. .
    1. Frohlich GM, Schoch B, Schmid F, Keller P, Sudano I, Luscher TF, Noll G, Ruschitzka F, Enseleit F. Takotsubo cardiomyopathy has a unique cardiac biomarker profile: NT-proBNP/myoglobin and NT-proBNP/troponin T ratios for the differential diagnosis of acute coronary syndromes and stress induced cardiomyopathy. Int J Cardiol. 2012;154:328–332. .
    1. Zampetaki A, Mayr M. MicroRNAs in vascular and metabolic disease. Circ Res. 2012;110:508–522. .
    1. Gupta SK, Bang C, Thum T. Circulating microRNAs as biomarkers and potential paracrine mediators of cardiovascular disease. Circ Cardiovasc Genet. 2010;3:484–488. .
    1. Thum T, Galuppo P, Wolf C, Fiedler J, Kneitz S, van Laake LW, Doevendans PA, Mummery CL, Borlak J, Haverich A, Gross C, Engelhardt S, Ertl G, Bauersachs J. MicroRNAs in the human heart: a clue to fetal gene reprogramming in heart failure. Circulation. 2007;116:258–267. .
    1. Fichtlscherer S, De Rosa S, Fox H, Schwietz T, Fischer A, Liebetrau C, Weber M, Hamm CW, Roxe T, Muller-Ardogan M, Bonauer A, Zeiher AM, Dimmeler S. Circulating microRNAs in patients with coronary artery disease. Circ Res. 2010;107:677–684. .
    1. D'Alessandra Y, Devanna P, Limana F, Straino S, Di Carlo A, Brambilla PG, Rubino M, Carena MC, Spazzafumo L, De Simone M, Micheli B, Biglioli P, Achilli F, Martelli F, Maggiolini S, Marenzi G, Pompilio G, Capogrossi MC. Circulating microRNAs are new and sensitive biomarkers of myocardial infarction. Eur Heart J. 2010;31:2765–2773. .
    1. Wang GK, Zhu JQ, Zhang JT, Li Q, Li Y, He J, Qin YW, Jing Q. Circulating microRNA: a novel potential biomarker for early diagnosis of acute myocardial infarction in humans. Eur Heart J. 2010;31:659–666. .
    1. Steg PG, James SK, Atar D, Badano LP, Blomstrom-Lundqvist C, Borger MA, Di Mario C, Dickstein K, Ducrocq G, Fernandez-Aviles F, Gershlick AH, Giannuzzi P, Halvorsen S, Huber K, Juni P, Kastrati A, Knuuti J, Lenzen MJ, Mahaffey KW, Valgimigli M, van 't Hof A, Widimsky P, Zahger D. Esc Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J. 2012;33:2569–2619. .
    1. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD. Third universal definition of myocardial infarction. Eur Heart J. 2012;33:2551–2567. .
    1. Lorenzen JM, Kielstein JT, Hafer C, Gupta SK, Kumpers P, Faulhaber-Walter R, Haller H, Fliser D, Thum T. Circulating mir-210 predicts survival in critically ill patients with acute kidney injury. Clin J Am Soc Nephrol. 2011;6:1540–1546. .
    1. Martino F, Lorenzen J, Schmidt J, Schmidt M, Broll M, Gorzig Y, Kielstein JT, Thum T. Circulating microRNAs are not eliminated by hemodialysis. PLoS One. 2012;7:e38269. .
    1. Widera C, Gupta SK, Lorenzen JM, Bang C, Bauersachs J, Bethmann K, Kempf T, Wollert KC, Thum T. Diagnostic and prognostic impact of six circulating microRNAs in acute coronary syndrome. J Mol Cell Cardiol. 2011;51:872–875. .
    1. Rinaldi A, Vincenti S, De Vito F, Bozzoni I, Oliverio A, Presutti C, Fragapane P, Mele A. Stress induces region specific alterations in microRNAs expression in mice. Behav Brain Res. 2010;208:265–269. .
    1. Katsuura S, Kuwano Y, Yamagishi N, Kurokawa K, Kajita K, Akaike Y, Nishida K, Masuda K, Tanahashi T, Rokutan K. MicroRNAs mir-144/144* and mir-16 in peripheral blood are potential biomarkers for naturalistic stress in healthy Japanese medical students. Neurosci Lett. 2012;516:79–84. .
    1. Ai J, Zhang R, Li Y, Pu J, Lu Y, Jiao J, Li K, Yu B, Li Z, Wang R, Wang L, Li Q, Wang N, Shan H, Yang B. Circulating microRNA-1 as a potential novel biomarker for acute myocardial infarction. Biochem Biophys Res Commun. 2010;391:73–77. .
    1. De Rosa S, Fichtlscherer S, Lehmann R, Assmus B, Dimmeler S, Zeiher AM. Transcoronary concentration gradients of circulating microRNAs. Circulation. 2011;124:1936–1944. .
    1. Kuwabara Y, Ono K, Horie T, Nishi H, Nagao K, Kinoshita M, Watanabe S, Baba O, Kojima Y, Shizuta S, Imai M, Tamura T, Kita T, Kimura T. Increased microRNA-1 and microRNA-133a levels in serum of patients with cardiovascular disease indicate myocardial damage. Circ Cardiovasc Genet. 2011;4:446–454. .
    1. Dwivedi Y. Evidence demonstrating role of microRNAs in the etiopathology of major depression. J Chem Neuroanat. 2011;42:142–156. .
    1. Mouillet-Richard S, Baudry A, Launay JM, Kellermann O. MicroRNAs and depression. Neurobiol Dis. 2012;46:272–278. .
    1. Baudry A, Mouillet-Richard S, Schneider B, Launay JM, Kellermann O. Mir-16 targets the serotonin transporter: a new facet for adaptive responses to antidepressants. Science. 2010;329:1537–1541. .
    1. Swaab DF, Bao AM, Lucassen PJ. The stress system in the human brain in depression and neurodegeneration. Ageing Res Rev. 2005;4:141–194. .
    1. Neil CJ, Chong CR, Nguyen TH, Horowitz JD. Occurrence of tako-tsubo cardiomyopathy in association with ingestion of serotonin/noradrenaline reuptake inhibitors. Heart Lung Circ. 2012;21:203–205. .
    1. Summers MR, Lennon RJ, Prasad A. Pre-morbid psychiatric and cardiovascular diseases in apical ballooning syndrome (tako-tsubo/stress-induced cardiomyopathy): potential pre-disposing factors? J Am Coll Cardiol. 2010;55:700–701. .
    1. Nef HM, Mollmann H, Akashi YJ, Hamm CW. Mechanisms of stress (takotsubo) cardiomyopathy. Nat Rev Cardiol. 2010;7:187–193. .
    1. Wittstein IS, Thiemann DR, Lima JA, Baughman KL, Schulman SP, Gerstenblith G, Wu KC, Rade JJ, Bivalacqua TJ, Champion HC. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med. 2005;352:539–548. .
    1. Miyauchi T, Tomobe Y, Shiba R, Ishikawa T, Yanagisawa M, Kimura S, Sugishita Y, Ito I, Goto K, Masaki T. Involvement of endothelin in the regulation of human vascular tonus. Potent vasoconstrictor effect and existence in endothelial cells. Circulation. 1990;81:1874–1880. .
    1. Kiowski W, Luscher TF, Linder L, Buhler FR. Endothelin-1-induced vasoconstriction in humans. Reversal by calcium channel blockade but not by nitrovasodilators or endothelium-derived relaxing factor. Circulation. 1991;83:469–475. .
    1. Luscher TF, Barton M. Endothelins and endothelin receptor antagonists: therapeutic considerations for a novel class of cardiovascular drugs. Circulation. 2000;102:2434–2440. .
    1. Freixa X, Heras M, Ortiz JT, Argiro S, Guasch E, Doltra A, Jimenez M, Betriu A, Masotti M. Usefulness of endothelin-1 assessment in acute myocardial infarction. Rev Esp Cardiol. 2011;64:105–110. .
    1. Li D, Yang P, Xiong Q, Song X, Yang X, Liu L, Yuan W, Rui YC. MicroRNA-125a/b-5p inhibits endothelin-1 expression in vascular endothelial cells. J Hypertens. 2010;28:1646–1654. .
    1. Eitel I, Nowak M, Stehl C, Adams V, Fuernau G, Hildebrand L, Desch S, Schuler G, Thiele H. Endothelin-1 release in acute myocardial infarction as a predictor of long-term prognosis and no-reflow assessed by contrast-enhanced magnetic resonance imaging. Am Heart J. 2010;159:882–890. .
    1. Velasco CE, Turner M, Inagami T, Atkinson JB, Virmani R, Jackson EK, Murray JJ, Forman MB. Reperfusion enhances the local release of endothelin after regional myocardial ischemia. Am Heart J. 1994;128:441–451. .

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner