Left right asymmetry, the pulmonary vein, and a-fib.

Atrial Fibrillation: General Considerations Atrial fibrillation (AF), a common adult cardiac arrhythmia, involves abnormal atrial contractions. As every medical student is taught, it is easily diagnosed as an irregularly irregular pulse and loss of organized atrial activity on an ECG. Clinical interest in AF is considerable because AF is the most common adult arrhythmia that increases in prevalence with age, with 5% of the over 65 population having AF. Moreover, patients with AF have a significantly increased risk of stroke.1 Electrical impulses, critical for a coordinated and physiologic heartbeat, are normally initiated in the sinoatrial (SA) node. However, in AF the disorganized atrial activity overrides normal SA node function resulting in irregular conduction of impulses to the ventricles. In the majority of cases, ectopic electrical activity originates in the pulmonary veins.1 In this issue of Circulation Research, Mommersteeg and colleagues2 make a significant advance in our understanding of pulmonary vein development by making a strong connection between AF and embryonic axis determination. Moreover, their work fits nicely with exciting new data from human genetic studies implicating the same genetic pathways in familial AF.3 Mommersteeg and colleagues make a number of fundamental observations regarding pulmonary vein development. Previous work suggested that pulmonary myocardium derives from atrial myocardium.4 Using lineage tracing, the authors convincingly rule out this possibility. Moreover, they show other data revealing that pulmonary myocardium is derived from Isl1-positive second heart field and has a distinct origin from the systemic venous circulation.5 Together, these findings suggest that the pulmonary vein myocardium forms by differentiation of mesenchyme around the pulmonary vein. To address this hypothesis, the authors use a Pitx2 mutant mouse model that had been shown to have defects in pulmonary vein development.6 The Pitx (Pituitary homeobox) family of homeobox genes, containing 3 genes, Pitx1, Pitx2, and Pitx3, is a Bicoid-related subfamily within the larger Paired-related superfamily of homeobox genes.7,8 The Pitx group, a remarkably important gene subfamily, has been implicated in human development, disease, and evolution.9–11 The most extensively studied of the 3 genes, Pitx2, was identified as the gene mutated in Rieger Syndrome I that includes ocular, tooth, and anterior body wall defects as cardinal features.10 Subsequent work on Pitx2 revealed an important function for the Pitx2c isoform of Pitx2 in left right asymmetry (LRA), a fundamental component of organ morphogenesis in vertebrates.