Normal and abnormal development of pulmonary veins: state of the art and correlation with clinical entities

Interest for the pulmonary veins has increased in the past decade after the potential arrhythmogenicity of the myocardial sleeve surrounding these structures has been recognized. Furthermore, there are several clinical entities, such as anomalous connection pattern and pulmonary vein stenosis, that are related to abnormal pulmonary vein development. In this review, we will describe current literature and aim to elucidate and reorganize current opinions on normal and abnormal pulmonary vein development in relation to clinical (management of) diseases. Several unresolved questions will be addressed, as well as current conceptual controversies. First, a general overview of development of structures at the venous pole of the heart, including normal development of the pulmonary vein from a primitive Anlage, will be provided. Recent insights indicate an important contributory role of the mesoderm behind the heart, the so-called second heart field, to this area. Subsequently, the formation of a myocardial and smooth muscle vascular wall of the pulmonary veins and the left atrium is described, as well as current insights in the mechanisms involved in the differentiation of these different cell types in this area. Next, developmental concepts of normal pulmonary venous drainage patterns are reviewed, and an overview is provided of clinical entities related to abnormal development at several anatomical levels. Lastly, attention is paid to arrhythmogenesis in relation to pulmonary vein development, as well the consequences for clinical management.