Abstract 2165: Notch Signaling Contributes to Specification of the AV Node
The cardiac conduction system is a specialized network of cells within the heart that is specified from cardiomyocytes during development, and functions to both generate and propagate electrical impulses. The AV node delays electrical impulses originating in the atrium from propagating into the ventricles, thereby allowing coordinated contraction of the heart. Recently there has been substantial emphasis placed on developing a “biological pacemaker”, either through manipulating embryonic stem cells or induced pluripotent stem cells to become “nodal-like” cells. However, little is known regarding the molecular signals that regulate formation of cells that compose the AV node. Notch regulates cell fate specification and differentiation in many cell types. We utilized a Cre-mediated dominant negative approach in vivo to selectively inhibit the activity of all Notch receptors within murine cardiomyocytes. These mice are viable and fertile, with normal morphogenesis and normal contractility as assessed by echocardiography. However, the mutant mice have a significantly shorter PR interval than control littermates, indicative of accelerated AV conduction. Electrophysiology studies reveal that the AH interval is significantly shorter in the mutants versus controls (28.1 versus 35.6 msec, p=0.004) without evidence of a bypass tract, while the HV interval is unchanged. Together with a shorter AV node effective refractory period in the mutants versus controls, these data suggest a defect within the AV node. Morphometry indicates that the mutant AV node area is approximately half the size of control, and there is a loss of connexin 30.2 slow-conducting cells. Reciprocal experiments involving gain-of-function for Notch signaling are underway and also produce conduction defects. These studies define a role for Notch in development of the specialized cardiac conduction system.