Prenatal Glucocorticoid Exposure Programs Long-Term Left Ventricular Metabolism, Function, and Remodeling in Baboons

Women threatening premature delivery receive synthetic glucocorticoids (sGC) to reduce offspring neonatal respiratory distress. Evidence linking prenatal sGC exposures to adverse cardiovascular outcomes is accumulating. We studied adult baboons, which had been exposed in utero to sGC equivalent to a human therapeutic dose, and compared to age-matched saline-exposed controls (CTR). Magnetic resonance imaging was performed in middle-aged male offspring (~10.5 y.) and in both sexes at old age (~16.5 y.) to assess heart structure, function, and paracardial adipose thickness (PAT). Postmortem left ventricular (LV) tissues were analyzed for mitochondrial electron transport chain complex activities and protein expression. In sGC vs CTR males, LV end-systolic (ESSI) and end-diastolic (EDSI) sphericity indexes increased with age (ESSI: p=0.0001, EDSI: p=0.002) being greater in elderly sGC group (ESSI: p=0.03, EDSI: p=0.0001 two-way ANOVA). In sGC-exposed males, global longitudinal strain (GLS) decreased with age versus CTR (p=0.03) and PAT was greater (p=0.03) than CTR males. In elderly sGC-exposed baboons, ejection fraction (p=0.04), ESSI (p=0.002), and PAT (p=0.002) were greater in males than females, while global radial strain (p=0.032) and GLS (p=0.014) were lower. EDSI was higher in both male and female sGC than in CTR (M: p=0.014, F: p=0.009). Mitochondrial analyses revealed reduced Complex I-linked respirations (p<0.05) with a negative correlation between PAT and MTCO1 mitochondrial protein in males (p=0.02), but not females. These results indicate that fetal sGC exposure impairs heart function and metabolism. Enhanced lifelong monitoring could improve understanding of the sex-specific mechanisms impacted by antenatal sGC.