0212 : Characterization of ventricular trabeculae and conduction system development in a mouse model of left ventricular non-compaction cardiomyopathy

Abstract

Left ventricular non-compaction (LVNC) is a rare cardiomyopathy characterized by prominent ventricular trabeculations and deep trabecular recesses in the left ventricular cavity. The degree of severity is heterogeneous, and the most severe complications are associated with conduction defects including arrhythmias, heart failure or sudden death. Ventricular trabeculation is a normal, but transient, step during embryonic development. In fact, compaction of trabeculae at fetal stages is necessary to form a competent myocardial wall. Trabeculae are also progenitors of the ventricular conduction system (VCS), composed of a complex network of Purkinje fibers controlling the rapid propagation of the electrical activity in the ventricles. Defects in trabecular development may result in incorrect development of the VCS, causing conduction defects. Indeed, ventricular non-compaction and conduction defects have been observed in patients and mutant mice carrying mutations in NKX2-5 , encoding a key transcriptional regulator of heart development. Deciphering the relationship between trabeculae morphogenesis and VCS differentiation during embryonic development is thus essential to understand the origin of conduction defects in LVNC. In order to analyze the link between trabecular fate and differentiation of the VCS, we perform a genetic lineage tracing of trabeculae using Cx40-CreERT2 mice expressing a tamoxifen-inducible Cre recombinase in ventricular trabeculae and in the definitive ventricular conduction system. These mice were crossed with Rosa26-YFP reporter mice to define the progeny of Cx40 expressing trabeculae during development or with Rosa26- confetti mice for a prospective clonal analysis of trabeculae. With the aim of dissecting the role of Nkx2-5 in the apparition of the pathological outcomes of LVNC, we performed the same lineage tracing experiments with Nkx2-5 conditional mutant mice where deletion was performed at different stages of trabecular development. The author hereby declares no conflict of interest