Abnormal Conduction and Morphology in the Atrioventricular Node of Mice With Atrioventricular Canal–Targeted Deletion of Alk3/Bmpr1a Receptor

Abstract

Background-The atrioventricular (AV) node is essential for the sequential excitation and optimized contraction of the adult multichambered heart; however, relatively little is known about its formation from the embryonic AV canal. A recent study demonstrated that signaling by Alk3, the type 1a receptor for bone morphogenetic proteins, in the myocardium of the AV canal was required for the development of both the AV valves and annulus fibrosus. To test the hypothesis that bone morphogenetic protein signaling also plays a role in AV node formation, we investigated conduction system function and AV node morphology in adult mice with conditional deletion of Alk3 in the AV canal. Methods and Results-High-resolution optical mapping with correlative histological analysis of 28 mutant hearts revealed 4 basic phenotypic classes based on electrical activation patterns and volume-conducted ECGs. The frequency of AV node conduction and morphological abnormalities increased from no detectable anomalies (class I) to severe defects (class IV), which included the presence of bypass tracts, abnormal ventricular activation patterns, fibrosis of the AV node, and twin AV nodes. Conclusion-The present findings demonstrate that bone morphogenetic protein signaling is required in the myocardium of the AV canal for proper AV junction development, including the AV node.

The formation and function of the cardiac conduction system

“…Bone morphogenetic protein 2 (Bmp2) is expressed specifically in the embryonic AVC and is required for AVC development, acting to control the AVC-restricted expression of Tbx2 and Tbx3 (Ma et al, 2005;Singh et al, 2012). Accordingly, AVC-restricted deficiency of the Bmp receptor Alk3 (Bmpr1a) results in defective AVN morphogenesis (Gaussin et al, 2005;Stroud et al, 2007). Bmp2/Smad signalling activates Tbx2 to drive its expression in the AVC (Ma et al, 2005;Singh et al, 2009); Tbx20, which is required for heart tube formation and chamber development, represses this activation to confine the expression of Tbx2 to the AVC and delimit the AVC boundary (Singh et al, 2009).…”

Cx30.2enhancer analysis identifies Gata4 as a novel regulator of atrioventricular delay

“…In addition to Cx30.2 expression, recent studies have implicated BMP signaling in mice (Gaussin et al, 2005;Stroud et al, 2007) and Neuregulin and Notch signaling in zebrafish (Milan et al, 2006) in establishing normal AV delay, although the downstream targets of these pathways have not been characterized. Here we have focused on Cx30.2, a crucial gene involved in establishing normal AV delay, and worked upstream to identify Gata4 as a potential nodal point for regulating other genes dedicated to slow AV impulse propagation.…”

“…In particular, Tbx3, which has been implicated in the human ulnarmammary syndrome, is required for pacemaker development and AVCS specification (Hoogaars et al, 2007;Bakker et al, 2008). More recently, conditional deletion of Alk3 (Bmpr1a -Mouse Genome Informatics) in the developing AV canal (AVC) using cGATA6-Cre mice demonstrated that BMP signaling impacts AV impulse propagation by regulating the proper formation of the annulus fibrosus and the AVN (Gaussin et al, 2005;Stroud et al, 2007). Although these studies have provided valuable insights into the formation and function of the AVCS, many of the molecular details remain to be completely elucidated.…”

Defective Tbx2-dependent patterning of the atrioventricular canal myocardium causes accessory pathway formation in mice

“…Accessory myocardial connections that can lead to preexcitation are commonly thought to result from malformation of the annulus fibrosus (6)(7)(8)(9). However, during development, the AV canal myocardium causes an adequate AV delay to allow synchronized alternating contraction of the atria and ventricles (10) in the absence of an annulus fibrosus.…”