This thesis of Guido Bossers aimed to study the effects of chronic abnormal overload on the right ventricle (RV) in the context of severe congenital heart defects (CHD).
First, we systematically reviewed the current knowledge on chronic RV pressure load as well as chronic RV volume load and showed that a more standardized approach is needed to better investigate the response of the RV to chronic abnormal loading conditions.
This approach was used to study a novel animal model of chronic pressure overload during childhood, which showed, similar to that observed in patients with CHD, a growth delay and other RV failure symptoms in juvenile rats with chronic pressure overload. RNA sequencing analysis of right ventricular heart tissue revealed a profile of delayed maturation and increased cell-cycle activity in the strained animals. This finding suggests that proliferation could play a cardioprotective role in RV pressure overload during childhood. Therefore, we tested the effects of Neuregulin-1, a growth factor known to stimulate cell-cycle activity in the heart. Administration of Neuregulin-1 in this model improved heart function and increased cardiomyocyte cell-cycle activity. However, we could not definitively demonstrate that this was indeed proliferation.
Lastly, the newly developed model was used to examine sex differences in response to chronic pressure overload during childhood. Fewer female rats developed clinical heart failure compared with male rats with chronic RV pressure overload. Female rats showed better diastolic function after puberty. However, increased RV contractility before puberty in female rats indicates that adaptation mechanisms may involve factors beyond hormonal influences.
