Plasticity of ventricle position after heart looping in heterotaxy with right isomerism

The heart functions in two parallel but asymmetric circulations, driven by the right and left ventricles. In the heterotaxy syndrome, abnormal left-right patterning leads to a spectrum of severe congenital heart defects, including ventricle malposition. A postulate anchored in the clinical nomenclature assumes that the looping direction of the embryonic heart tube determines ventricle position at birth. However, this has not been demonstrated experimentally. Here, we performed a unique longitudinal analysis of heterotaxy with right isomerism, using multimodality imaging of <i>Nodal</i> mouse mutants. Using direct correlations and advanced statistics, we dissected the contribution of heart looping variations to specific structural heart malformations, and uncovered unexpected plasticity of ventricle position after looping in 30% of revertant samples. Genetic tracing and topological associations show that plasticity involves a further step of heart remodeling at E13.5, rather than molecular reprogramming. Human patient scans are consistent with ventricle plasticity and suggest association with poorer prognosis. Our work reveals distinct asymmetric events shaping organs.