title: Exposure to intrauterine inflammation leads to impaired function and altered structure in the preterm heart of fetal sheep.
abstract: Intrauterine inflammation is a major contributor to preterm birth and has adverse effects on preterm neonatal cardiovascular physiology. Cardiomyocyte maturation occurs in late gestation in species such as humans and sheep. We tested the hypothesis that intrauterine inflammation has deleterious effects on cardiac function in preterm sheep which might be explained by altered cardiomyocyte proliferation and maturation. Pregnant ewes received an ultrasound-guided intra-amniotic injection of lipopolysaccharide (LPS) or saline 7 days prior to delivery at day 127 of pregnancy (term 147 days). Cardiac contractility was recorded in spontaneously beating hearts of the offspring, perfused in a Langendorff apparatus. Saline-filled latex balloons were inserted into the left ventricle (LV) and right ventricle (RV). Responsiveness to isoprenaline and stop-flow/reperfusion was assessed. In other experiments, hearts were perfusion-fixed, and cardiomyocyte nuclearity, volume and number were determined. β-Adrenoceptor mRNA levels were determined in unfixed tissue. In hearts of LPS-exposed fetuses, contractility in the LV and RV was suppressed by ~40% and cardiomyocyte numbers were reduced by ~25%. Immature mono-nucleated cardiomyocytes had lower volumes (~18%), whereas mature bi-nucleated cardiomyocyte volume was ~77% greater. Although basal coronary flow was significantly increased by 21±7% in LPS-exposed hearts, following ischaemia/reperfusion (IR), end-diastolic pressure was increased 2.4±0.3-fold and infarct area was increased 3.2±0.6-fold compared with those in controls. Maximum responsiveness to isoprenaline was enhanced by LPS, without an increase in β-adrenoceptor mRNA, suggesting altered second messenger signalling. Intrauterine inflammation altered cardiac growth, suppressed contractile function and enhanced responsiveness to stress. Although these effects may ensure immediate survival, they probably contribute to the increased vulnerability of organ perfusion in preterm neonates.
authors.affiliation: *Department of Physiology, Monash University, Clayton, Australia.
authors.forename: Marianne
authors.initials: M
authors.lastname: Tare
authors.affiliation: †Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia.
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Bensley
authors.forename: Timothy J M
authors.initials: TJ
authors.lastname: Moss
authors.affiliation: ∥University of Queensland Centre for Clinical Research, University of Queensland, Brisbane, Australia.
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Lingwood
authors.affiliation: ∥University of Queensland Centre for Clinical Research, University of Queensland, Brisbane, Australia.
authors.forename: Min Y
authors.initials: MY
authors.lastname: Kim
authors.forename: Samantha K
authors.initials: SK
authors.lastname: Barton
authors.affiliation: ¶Department of Neonatal Medicine, Royal North Shore Hospital and University of Sydney, Sydney, Australia.
authors.forename: Martin
authors.initials: M
authors.lastname: Kluckow
authors.affiliation: **Centre for Neonatal Research and Education, University of Western Australia, Crawley, Australia.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Gill
authors.affiliation: †Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia.
authors.forename: Robert
authors.initials: R
authors.lastname: De Matteo
authors.affiliation: †Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Harding
authors.affiliation: †Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia.
authors.forename: M Jane
authors.initials: MJ
authors.lastname: Black
authors.affiliation: *Department of Physiology, Monash University, Clayton, Australia.
authors.forename: Helena C
authors.initials: HC
authors.lastname: Parkington
authors.forename: Graeme R
authors.initials: GR
authors.lastname: Polglase
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D005260:Female; D005318:Fetal Heart / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000139:chemically induced / Q000196:embryology / Q000503:physiopathology*; D007545:Isoproterenol / Q000494:pharmacology; D008070:Lipopolysaccharides; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D015428:Myocardial Reperfusion Injury / Q000196:embryology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D020033:Protein Isoforms / Q000235:genetics; D011943:Receptors, Adrenergic, beta / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012756:Sheep
chemical_list: D000318:Adrenergic beta-Agonists; D008070:Lipopolysaccharides; D020033:Protein Isoforms; D011943:Receptors, Adrenergic, beta; D007545:Isoproterenol