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. 2014 Apr;35(15):999-1006.
doi: 10.1093/eurheartj/eht392. Epub 2013 Sep 17.

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

Milosz Jaguszewski  1 , 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
Affiliations

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

Milosz Jaguszewski et al. Eur Heart J. 2014 Apr.

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.

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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.
See this image and copyright information in PMC

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