Oral Presentation ESA-SRB-ANZBMS 2024 in conjunction with ENSA

Fetal glucose infusion increases cardiac thyroxine and progesterone concentrations in the left ventricle of the sheep fetus exposed to maternal undernutrition in late gestation (#93)

Melanie R Bertossa 1 , Jack R.T Darby 1 , Stacey L Holman 1 , Steven K.S Cho 2 , Jordan A Minns 1 , Ashley S Meakin 1 , Christopher K Macgowan 2 , Mike Seed 2 , Michael D Wiese 1 , Janna L Morrison 1 2
  1. University Of South Australia, Adelaide, SA, Australia
  2. Sick Kids Research Institute, University of Toronto , Toronto, Ontario , Canada

Aims: Late gestation undernutrition (LGUN) during pregnancy reduces fetal nutrient supply, culminating in fetal growth restriction (FGR) and an increased risk for cardiovascular disease (CVD) in later life. Preclinical models of FGR link reduced fetal progesterone concentrations to reduced placental size and perturbed fetal endocrine and immune responses. Similarly, thyroid hormones are critical in regulating cardiac growth, metabolism, and contractility and are also reduced in FGR. We hypothesized that in a clinically relevant sheep model, reduced fetal glucose concentrations in LGUN are a significant mechanism behind cardiac alterations in fetal life, and restoring this would improve markers of cardiac metabolism and contractility.

Methods: At 111 days gestational age (dGA; term, 150d), pregnant ewes were assigned to a Control diet (n=10, 100% metabolizable energy requirement (MER)), LGUN (n=11, 50% MER) or LGUN+intra-fetal glucose infusion (LGUN+G, n=6, 50% MER + 0.6±0.01mmol/h dextrose). At ~141dGA, ewes were humanely killed, and fetal left ventricle samples were collected. Mass spectrometry quantified tissue hormones and proteins involved in contractility/metabolism were measured via western blot. All data was analysed with one-way ANOVA (P<0.05) with a post-hoc Bonferroni correction for multiple comparisons.

Results: LGUN reduced fetal plasma glucose concentrations compared to Controls (P=0.0095). Cortisol, cortisone, or triiodothyronine (T3) concentrations remained unchanged. While LGUN did not impact thyroxine (T4) or progesterone, LGUN+G increased cardiac T4 concentrations compared to Control and LGUN (P=0.0121, 0.0103) and progesterone compared to Control only (P=0.0051). Contractility/hypertrophy marker p-CAMKII was increased in LGUN vs. Control and LGUN+G (P=0.0005, 0.0490) but not LGUN+G vs. Control (P=0.5568). LGUN reduced mitochondrial complex 3 (P= 0.0149, 0.0034) and was restored to control levels by LGUN+G (P=0.7488).

Conclusions: Fetal glucose availability alters cardiac hormones responsible for regulating cardiac contractility and metabolism, providing evidence for a hormonal mechanism linking LGUN with a risk for CVD in FGR-born adults.