Abstract
Takotsubo syndrome (TTS) is an acute heart failure (AHF) syndrome that mimics the symptoms of acute myocardial infarction and is often preceded by emotional and/or physical stress. There is currently no treatment for TTS. Here we show that injection of 2.5 mg/kg of epinephrine (EPI) into mice recapitulates numerous features of human TTS, including increased myocardial damage and mortality in males. Gene set enrichment analysis of myocardial RNA-sequencing after EPI injection revealed significant enrichment of calcineurin-dependent pro-inflammatory gene networks, which was more pronounced in male vs female mice, in agreement with observed sex discrepancies in the mouse phenotype. An increase in calcineurin activity was detected in TTS patients' circulating cells, suggesting a systemic nature of the syndrome. Preventive and therapeutic treatment of mice injected with EPI by calcineurin inhibitors cyclosporine and tacrolimus improved heart function and reduced myocardial injury. Our work suggests that calcineurin inhibition could be a potential therapy for TTS.
| Original language | English |
|---|---|
| Pages (from-to) | 645-655 |
| Number of pages | 11 |
| Journal | Nature Cardiovascular Research |
| Volume | 2 |
| Issue number | 7 |
| Early online date | 13 Jul 2023 |
| DOIs | |
| Publication status | Published - Jul 2023 |
Bibliographical note
AcknowledgementsWe thank P. Nawroth (Department of Endocrinology, University Hospital Heidelberg, Germany) for the opportunity to conduct RIA (corticosterone), HPLC (catecholamines) and automated Cobas (hs-TnT) analysis in his laboratory. S. Martinache (Department of General Internal Medicine and Psychosomatics, University Hospital Heidelberg, Germany), J. Krebs-Haupenthal, S. Harrack and M. Oestringer (all affiliated with the Institute of Experimental Cardiology, Medical Faculty, Heidelberg University, Germany) provided excellent technical assistance. This work was supported by grants from the Deutsche Forschungsgemeinschaft (BA 2258/9-1 and the CRC 1550, INST 35/1699-1) and the Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK; German Centre for Cardiovascular Research), from the BMBF (German Ministry of Education and Research) to J.B., from the German Cardiac Society (DGK) to B.B., I.B. and M.S., and from the German Heart Foundation (DHS) to M.A. C.D. and N.F. were also supported by the CRC 1550 and DZHK. The funders had no role in study design, data collection and analysis, the decision to publish or preparation of the manuscript.
Data Availability Statement
The authors declare that the data supporting the findings of this study are available within the paper and its supplementary information. RNA sequencing data are available from ENA and BioStudies under accession number E-MTAB-13031. The following publicly available data (or datasets) were used: murine 45 S ribosomal RNA precursor sequence (BK000964.3), mouse genome sequence and annotation (GRCm38_90) together with the splice-aware STAR read aligner (release 2.5.1b) (ref. 44), and the cufflinks package version 2.2.1. GSEA was conducted with the GSEA 4.0.3 software and the Molecular Signatures Database (MSigDB 7.2, Broad Institute)46,47. Gene overlap network design was conducted via the EnrichmentMap plugin for the Cytoscape software (3.8.0) (refs. 49,50) and the collection of annotated drug gene sets from the Drug SIGnatures DataBase (DSigDB 1.0, Tanlab)51.Keywords
- Takotsubo
- stress
- calcineurin
- heart failure
- epinephrine
- sex
Access to Document
- Bruns_etal_NC_Calcineurin_Signaling_Promotes_VOR
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.