Myocardial function is depressed in sepsis and is an important prognosticator in the human condition. Using echocardiography in a long-term fluid-resuscitated Wistar rat model of faecal peritonitis we investigated whether depressed myocardial function could be detected at an early stage of sepsis and, if so, whether the degree of depression could predict eventual outcome. At 6 h post-insult, a stroke volume <0.17 ml prognosticated 3-day mortality with positive and negative predictive values of 93 and 80%, respectively. Subsequent fluid loading studies demonstrated intrinsic myocardial depression with poor-prognosis animals tolerating less fluid than either good-prognosis or sham-operated animals. Cardiac gene expression analysis at 6 h detected 527 transcripts significantly up- or down-regulated by the septic process, including genes related to inflammatory and cell cycle pathways. Predicted mortality was associated with significant differences in transcripts of genes expressing proteins related to the TLR2/MyD88 (Toll-like receptor 2/myeloid differentiation factor 88) and JAK/STAT (Janus kinase/signal transducer and activator of transcription) inflammatory pathways, β-adrenergic signalling and intracellular calcium cycling. Our findings highlight the presence of myocardial depression in early sepsis and its prognostic significance. Transcriptomic analysis in heart tissue identified changes in signalling pathways that correlated with clinical dysfunction. These pathways merit further study to both better understand and potentially modify the disease process.
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Research Article|
November 27 2012
Early functional and transcriptomic changes in the myocardium predict outcome in a long-term rat model of sepsis
Alain Rudiger;
Alain Rudiger
*Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, Gower Street, London WC1E 6BT, U.K.
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Alex Dyson;
Alex Dyson
*Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, Gower Street, London WC1E 6BT, U.K.
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Karen Felsmann;
Karen Felsmann
†SIRS-Lab GmbH, Otto-Schott-Strasse 15, D-07745 Jena, Germany
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Jane E. Carré;
Jane E. Carré
*Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, Gower Street, London WC1E 6BT, U.K.
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Valerie Taylor;
Valerie Taylor
*Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, Gower Street, London WC1E 6BT, U.K.
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Sian Hughes;
Sian Hughes
‡Department of Histopathology, Royal Free and University College Medical School, University College London, Rockefeller Building, University Street, London WC1E 6JJ, U.K.
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Innes Clatworthy;
Innes Clatworthy
§Imaging Facility, UCL Institute of Opthalmology, 11–43 Bath Street, London EC1V 9EL, U.K.
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Alessandro Protti;
Alessandro Protti
*Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, Gower Street, London WC1E 6BT, U.K.
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Denis Pellerin;
Denis Pellerin
∥The Heart Hospital, UCL Hospitals NHS Foundation Trust, 16-18 Westmoreland Street, London W1G 8PH, U.K.
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Jana Lemm;
Jana Lemm
¶Integrated Research and Treatment Center–Center for Sepsis Control and Care, Jena University Hospital, Allee 101, D-07747 Jena, Germany
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Ralf A. Claus;
Ralf A. Claus
¶Integrated Research and Treatment Center–Center for Sepsis Control and Care, Jena University Hospital, Allee 101, D-07747 Jena, Germany
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Michael Bauer;
Michael Bauer
1
¶Integrated Research and Treatment Center–Center for Sepsis Control and Care, Jena University Hospital, Allee 101, D-07747 Jena, Germany
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Mervyn Singer
*Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, Gower Street, London WC1E 6BT, U.K.
Correspondence: Professor Mervyn Singer (email m.singer@ucl.ac.uk).
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Publisher: Portland Press Ltd
Received:
June 25 2012
Revision Received:
August 31 2012
Accepted:
September 18 2012
Accepted Manuscript online:
September 18 2012
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2013 Biochemical Society
2013
Clin Sci (Lond) (2013) 124 (6): 391–401.
Article history
Received:
June 25 2012
Revision Received:
August 31 2012
Accepted:
September 18 2012
Accepted Manuscript online:
September 18 2012
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The promise and challenge of systems biology in translational medicine
Citation
Alain Rudiger, Alex Dyson, Karen Felsmann, Jane E. Carré, Valerie Taylor, Sian Hughes, Innes Clatworthy, Alessandro Protti, Denis Pellerin, Jana Lemm, Ralf A. Claus, Michael Bauer, Mervyn Singer; Early functional and transcriptomic changes in the myocardium predict outcome in a long-term rat model of sepsis. Clin Sci (Lond) 1 March 2013; 124 (6): 391–401. doi: https://doi.org/10.1042/CS20120334
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