The mammalian heart can regenerate only during the first week of life. This window coincides with maturation of the myocardial wall through compaction of ventricular trabeculae, transient invaginations at the inner surface of the developing heart. Trabeculae give rise both to contractile cardiomyocytes (CM) and to Purkinje fibers composing the ventricular conductive system (VCS). Given the regenerative capacities of the uncompacted neonatal mammalian heart, we hypothesized that ventricular trabeculae possess superior regenerative capacities than compact myocardium. We also questioned the capacity of the VCS to undergo repair during the regenerative window.

Investigate the contribution of ventricular trabeculae to the regeneration of contractile and conductive cardiac tissue after neonatal myocardial infarction (MI).

Neonatal MI was performed by permanent ligation of the left coronary artery on one-day-old mice. Trabecular derivatives were genetically traced using Connexin40 driven inducible Cre recombinase together with a fluorescent conditional reporter gene (Cx40-CreERT2, Rosa26-YFP). VCS structure and function were respectively assessed by histology or electrocardiogram (ECG) analysis in a longitudinal study.

Trabecular derivatives were found in an extended number in the regenerated myocardium after neonatal MI, compared to the same area in sham or remote regions of MI-operated hearts. Moreover, trabecular derivatives in the border zone show reactivation of Cx40 indicating a switch of these CM towards an immature phenotype.

In contrast to regeneration of contractile myocardium, damage to the VCS after MI was not repaired, despite being spatially restricted. Moreover, maturation defects, characterized by a global hyperplasia of the VCS, was observed after regeneration and persists over time. The abnormal structure of the Purkinje fiber network in regenerated hearts is accompanied by a slowed ventricular conduction as shown by a prolonged QRS on ECG recording (Fig. 1).

Trabeculae show an increased participation in the regeneration of the contractile compartment relative to that of the compact layer. Contrary to contractile myocardium, VCS is not repaired and its maturation is perturbed in the regenerative context, which permanently perturbed conduction. Together our data identify cellular mechanisms involved in cardiac repair and reveal limits to cardiac regeneration during the postnatal window.