Fetal programming in right ventricular adaptation to pressure overload

PAH is a progressive disease characterized by vasoconstriction, remodeling of the pulmonary vasculature and in situ thrombosis, leading to an increased vascular resistance and an increase in right ventricular (RV) pressure. Clinical outcome is determined by the adaptive response of the right ventricle (RV), which encompasses hypertrophy and increased contractility and is in part mediated by reactivation of a fetal gene program. As part of fetal gene reactivation, the pressure overloaded adult RV shows similar expressions of natriuretic peptides, insulin like growth factor 1 and myosin heavy chain isotypes as the fetal RV. Inhibition of fetal gene reactivation by HDAC inhibition was shown to impair normal RV adaptation in experimental models. Endothelin receptor antagonists, which are widely used in the treatment of PAH patients, may similarly repress fetal gene re-expression in the adapting RV. More research is needed to determine whether some of the beneficial effects of ERAs in the pulmonary circulation, are offset by negative effects on the RV.