title: Early functional and transcriptomic changes in the myocardium predict outcome in a long-term rat model of sepsis.
abstract: 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.
authors.affiliation: Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Alain
authors.initials: A
authors.lastname: Rudiger
authors.forename: Alex
authors.initials: A
authors.lastname: Dyson
authors.forename: Karen
authors.initials: K
authors.lastname: Felsmann
authors.forename: Jane E
authors.initials: JE
authors.lastname: Carré
authors.forename: Valerie
authors.initials: V
authors.lastname: Taylor
authors.forename: Sian
authors.initials: S
authors.lastname: Hughes
authors.forename: Innes
authors.initials: I
authors.lastname: Clatworthy
authors.forename: Alessandro
authors.initials: A
authors.lastname: Protti
authors.forename: Denis
authors.initials: D
authors.lastname: Pellerin
authors.forename: Jana
authors.initials: J
authors.lastname: Lemm
authors.forename: Ralf A
authors.initials: RA
authors.lastname: Claus
authors.forename: Michael
authors.initials: M
authors.lastname: Bauer
authors.forename: Mervyn
authors.initials: M
authors.lastname: Singer
mesh_terms: D000818:Animals; D053612:Janus Kinases / Q000096:biosynthesis; D008297:Male; D023421:Models, Animal; D053594:Myeloid Differentiation Factor 88 / Q000096:biosynthesis; D009206:Myocardium / Q000378:metabolism*; D010538:Peritonitis / Q000503:physiopathology; D011379:Prognosis; D051381:Rats; D050791:STAT Transcription Factors / Q000096:biosynthesis; D018805:Sepsis / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology; D051195:Toll-Like Receptor 2 / Q000096:biosynthesis; D059467:Transcriptome
chemical_list: D053594:Myeloid Differentiation Factor 88; D050791:STAT Transcription Factors; D051195:Toll-Like Receptor 2; D053612:Janus Kinases