Early functional and transcriptomic changes in the myocardium predict outcome in a long-term rat model of sepsis

被引:50
作者
Rudiger, Alain [1 ]
Dyson, Alex [1 ]
Felsmann, Karen [2 ]
Carre, Jane E. [1 ]
Taylor, Valerie [1 ]
Hughes, Sian [3 ]
Clatworthy, Innes [4 ]
Protti, Alessandro [1 ]
Pellerin, Denis [5 ]
Lemm, Jana [6 ]
Claus, Ralf A. [6 ]
Bauer, Michael [6 ]
Singer, Mervyn [1 ]
机构
[1] UCL, Div Med, Bloomsbury Inst Intens Care Med, London WC1E 6BT, England
[2] SIRS Lab GmbH, D-07745 Jena, Germany
[3] UCL, Royal Free & Univ Coll Med Sch, Dept Histopathol, London WC1E 6JJ, England
[4] UCL Inst Opthalmol, Imaging Facil, London EC1V 9EL, England
[5] UCL Hosp NHS Fdn Trust, Heart Hosp, London W1G 8PH, England
[6] Jena Univ Hosp, Integrated Res & Treatment Ctr, Ctr Sepsis Control & Care, D-07747 Jena, Germany
基金
瑞士国家科学基金会; 英国医学研究理事会;
关键词
animal model; echocardiography; faecal peritonitis; gene transcript; heart failure; sepsis; BRAIN NATRIURETIC PEPTIDE; SEPTIC SHOCK; CARDIAC-OUTPUT; MURINE MODEL; DEPRESSION; PERFORMANCE; DYSFUNCTION; MYOCYTES;
D O I
10.1042/CS20120334
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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, beta-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.
引用
收藏
页码:391 / 401
页数:11
相关论文
共 29 条
[1]   Outcome in elderly patients with severe infection is influenced by sex hormones but not gender [J].
Angstwurm, MWA ;
Gaertner, R ;
Schopohl, J .
CRITICAL CARE MEDICINE, 2005, 33 (12) :2786-2793
[2]   ULTIMATE SURVIVAL FROM SEPTIC SHOCK [J].
AZIMI, G ;
VINCENT, JL .
RESUSCITATION, 1986, 14 (04) :245-253
[3]   Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure [J].
Brealey, D ;
Karyampudi, S ;
Jacques, TS ;
Novelli, M ;
Stidwill, R ;
Taylor, V ;
Smolenski, RT ;
Singer, M .
AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, 2004, 286 (03) :R491-R497
[4]   Prognostic value of plasma N-terminal pro-brain natriuretic peptide in patients with severe sepsis [J].
Brueckmann, M ;
Huhle, G ;
Lang, S ;
Haase, KK ;
Bertsch, T ;
Weiss, C ;
Kaden, JJ ;
Putensen, C ;
Borggrefe, M ;
Hoffmann, U .
CIRCULATION, 2005, 112 (04) :527-534
[5]   Brain natriuretic peptide: A marker of myocardial dysfunction and prognosis during severe sepsis [J].
Charpentier, J ;
Luyt, CE ;
Fulla, Y ;
Vinsonneau, C ;
Cariou, A ;
Grabar, S ;
Dhainaut, JF ;
Mira, JP ;
Chiche, JD .
CRITICAL CARE MEDICINE, 2004, 32 (03) :660-665
[6]   Sepsis-induced myocardial depression is associated with transcriptional changes in energy metabolism and contractile related genes: A physiological and gene expression-based approach [J].
dos Santos, Claudia C. ;
Gattas, David J. ;
Tsoporis, James N. ;
Smeding, Lonneke ;
Kabir, Golam ;
Masoom, Hussain ;
Akram, Ali ;
Plotz, Frans ;
Slutsky, Arthur S. ;
Husain, Mansoor ;
Sibbald, William J. ;
Parker, Thomas G. .
CRITICAL CARE MEDICINE, 2010, 38 (03) :894-902
[7]   Protein phosphatase 1 and an opposing protein kinase regulate steady-state L-type Ca2+ current in mouse cardiac myocytes [J].
duBell, WH ;
Rogers, TB .
JOURNAL OF PHYSIOLOGY-LONDON, 2004, 556 (01) :79-93
[8]   TNF-α and IL-1β increase Ca2+ leak from the sarcoplasmic reticulum and susceptibility to arrhythmia in rat ventricular myocytes [J].
Duncan, David J. ;
Yang, Zhaokang ;
Hopkins, Philip M. ;
Steele, Derek S. ;
Harrison, Simon M. .
CELL CALCIUM, 2010, 47 (04) :378-386
[9]   Time course of endothelial damage in septic shock: Prediction of outcome [J].
Hein, OV ;
Misterek, K ;
Tessmann, JP ;
van Dossow, V ;
Krimphove, M ;
Spies, C .
CRITICAL CARE, 2005, 9 (04) :R323-R330
[10]   Proteome and Metabolome Alterations in Heart and Liver Indicate Compromised Energy Production During Sepsis [J].
Hinkelbein, Jochen ;
Kalenka, Armin ;
Schubert, Charlotte ;
Peterka, Anna ;
Feldmann, Robert E., Jr. .
PROTEIN AND PEPTIDE LETTERS, 2010, 17 (01) :18-31