Exposure to intrauterine inflammation leads to impaired function and altered structure in the preterm heart of fetal sheep

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 left (LV) and right ventricles (RV). Responsiveness to isoprenaline and stop-flow/reperfusion was assessed. In other experiments, hearts were perfusion-fixed and cardiomyocyte nuclearity, volume and number determined. beta-Adrenoceptor mRNA levels were determined in unfixed tissue. In hearts of LPS-exposed fetuses, contractility in LV and RV was suppressed by 40 and cardiomyocyte numbers were reduced by 25 . Immature mono-nucleated cardiomyocytes had lower volumes ( 18 ), while mature bi-nucleated cardiomyocyte volume was 77 greater. While basal coronary flow was significantly increased by 21+/-7 in LPS-exposed hearts, following ischemia-reperfusion, end diastolic pressure was increased 2.4+/-0.3-fold and infarct area 3.2+/-0.6-fold versus in controls. Maximum responsiveness to isoprenaline was enhanced by LPS, without an increase in b-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 likely contribute to the increased vulnerability of organ perfusion in preterm neonates.