His-Purkinje system defects induced by Nkx2-5 deletion leads to progressive conduction defects and heart failure

The synchronization of heartbeats is triggered by electric impulses delivered by specialized cardiomyocytes of the conduction system. In the ventricles, the His-Purkinje system mediates rapid propagation of electrical activity such that contractions propagate from the apex to the base of the heart to increase the efficiency of blood expulsion to the great arteries. Human heterozygous mutations of NKX2-5 are associated with a large spectrum of congenital heart diseases and atrioventricular conduction block. In agreement with these observations, mouse genetics has revealed the complexity of the role of Nkx2-5 during cardiac development. Germline deletion of Nkx2-5 results in cardiac lethality at early stages, while Nkx2-5± embryos and mice appear normal and reproduce the phenotype observed in patients, including atrial septal defects and conduction disturbances. These mice display ventricular conduction defects that can be correlated with hypoplastic development of the His-Purkinje system. To further decipher the role of this transcription factor in the conduction system, we conditionally inactivated Nkx2-5 in the His-Purkinje system using a Cx40-CreERT2 mouse line. Postnatal deletion of Nkx2-5 in the His-Purkinje system induced a progressive loss of expression of conduction markers and hypoplasia of the Purkinje fiber network. These mice develop conduction defects with enlarged QRS intervals and left bundle branch block. Long-term follow-up of cardiac function recorded by MRI and echocardiography shows a progressive reduction of ejection fraction correlated with strain defects. These results highlight the importance of Nkx2-5-dependent maintenance of the His-Purkinje system in preserving cardiac function.