0177 : Deciphering multiple roles of Nkx2-5 during ventricular non-compaction

Left ventricular non-compaction (LVNC), characterized by prominent trabeculations and deep trabecular recesses in the ventricles, is the most common cardiomyopathy with a spectrum ranging from extreme normal variants to a pathological phenotype. In all forms, heart failure and sudden cardiac death represent the most severe complications related with noncompaction and arrhythmias. The presence of ventricular trabeculae is a normal component of ventricular myocardium during embryonic development. Trabeculae are also progenitors of the ventricular conduction system (VCS), which is composed of a complex network of Purkinje fibers controlling the rapid propagation of electrical activity in the ventricles. The transcription factor Nkx2.5 is a key regulator of cardiac development. Conduction disturbances and ventricular non-compaction are traits that have been observed in patients and mutant mice carrying NKX2-5 mutations. However, the relationship between Purkinje fiber differentiation and trabecular compaction is unknown, despite recent evidence that abnormal conduction system morphology underlies conduction defects and arrhythmias. In order to dissect the role of this gene in the apparition of the pathological outcomes of LVNC, we specifically inactivate Nkx2-5 in a time and tissue specific manner. Nkx2-5 floxed mice were crossed with Cx40-creERT2 mice and tamoxifen injections, to induce gene deletion, were performed at different time of trabecular development to detect the impact of this gene in ventricular trabeculation, compaction and in the VCS. Morphological and functional cardiac phenotypes in these different mutant mice were analysed by oupling non-invasive imaging techniques and immunofluorescent studies. Preliminary results showed that the degree of non-compaction and the VCS morphology differ according to the timing of Nkx2-5 inactivation, suggesting multiple roles for this transcription factor during ventricular trabeculae development. The author hereby declares no conflict of interest