Nkx2-5 Loss of Function in the His-Purkinje System Hampers Its Maturation and Leads to Mechanical Dysfunction.

The ventricular conduction or His-Purkinje system (VCS) mediates the rapid propagation and precise delivery of electrical activity essential for the synchronization of heartbeats. Mutations in the transcription factor Nkx2-5 have been implicated in a high prevalence of developing ventricular conduction defects or arrhythmias with age. Nkx2-5 heterozygous mutant mice reproduce human phenotypes associated with a hypoplastic His-Purkinje system resulting from defective patterning of the Purkinje fiber network during development. Here, we investigated the role of Nkx2-5 in the mature VCS and the consequences of its loss on cardiac function. Neonatal deletion of Nkx2-5 in the VCS using a Cx40-CreERT2 mouse line provoked apical hypoplasia and maturation defects of the Purkinje fiber network. Genetic tracing analysis demonstrated that neonatal Cx40-positive cells fail to maintain a conductive phenotype after Nkx2-5 deletion. Moreover, we observed a progressive loss of expression of fast-conduction markers in persistent Purkinje fibers. Consequently, Nkx2-5-deleted mice developed conduction defects with progressively reduced QRS amplitude and RSR' complex associated with higher duration. Cardiac function recorded by MRI revealed a reduction in the ejection fraction in the absence of morphological changes. With age, these mice develop a ventricular diastolic dysfunction associated with dyssynchrony and wall-motion abnormalities without indication of fibrosis. These results highlight the requirement of postnatal expression of Nkx2-5 in the maturation and maintenance of a functional Purkinje fiber network to preserve contraction synchrony and cardiac function.

Adenosine and Adenosine Receptors: Advances in Atrial Fibrillation.

Atrial fibrillation (AF) is the most common arrhythmia in the world. Because the key to developing innovative therapies that limit the onset and the progression of AF is to fully understand the underlying molecular mechanisms of AF, the aim of the present narrative review is to report the most recent advances in the potential role of the adenosinergic system in the pathophysiology of AF. After a comprehensive approach describing adenosinergic system signaling and the mechanisms of the initiation and maintenance of AF, we address the interactions of the adenosinergic system's signaling with AF. Indeed, adenosine release can activate four G-coupled membrane receptors, named A1, A2A, A2B and A3. Activation of the A2A receptors can promote the occurrence of delayed depolarization, while activation of the A1 receptors can shorten the action potential's duration and induce the resting membrane's potential hyperpolarization, which promote pulmonary vein firing, stabilize the AF rotors and allow for functional reentry. Moreover, the A2B receptors have been associated with atrial fibrosis homeostasis. Finally, the adenosinergic system can modulate the autonomous nervous system and is associated with AF risk factors. A question remains regarding adenosine release and the adenosine receptors' activation and whether this would be a cause or consequence of AF.