Programming fetal cardiometabolic pathways: the double-edged role of glucocorticoids in heart development

In a normal pregnancy, glucocorticoids (GC), such as cortisol, play an essential role in early heart development. GC concentrations surge in late gestation to facilitate the maturation of fetal systems in preparation for birth. However, pregnancy complications related to stress, lifestyle factors, disease, and commonly used antenatal care treatments (GC therapy and artificial reproductive technology) can lead to prematurely increased GC concentrations that are detrimental to the heart before it is mature enough to benefit. These findings underpin the hypothesis that GC play a double-edged role that benefits normal heart development but is potentially harmful when dysregulated. However, the mechanisms by which both physiological and pathological elevations in GC concentrations influence the fetal cardiometabolic pathways that lead to detrimental long-term cardiovascular outcomes remain unclear. This review will, firstly, describe how cortisol regulates different aspects of cardiac development and, secondly, compare findings from different animal models that have provided mechanistic insight into how excess cortisol/GC during pregnancy impacts cardiac health across the life course.