The development of the sympathetic system of the heart

Development of the sympathetic nervous system begins at about embryonic day 9 in mice with the migration of the neural crest cells to the dorsal aorta and the development of neurons and the sympathetic ganglia. This is followed by the axonal elongation towards the developing cardiac tissue. This process is directed by a series of signal ligands including ephrin-B1, semaphorin 3a (Sema3a), F-Spondin, bone morphogenetic proteins (BMPs), Wnt-1 protein, neurotrophin-3 (NT-3), nerve growth factor (NGF) and artemin (ARTN). Once at the developing heart, the nerve fibres follow the coronary veins in the subepicardium using NGF and the chemorepellent Sema3a as signals. Here they interact with the cardiac conduction system. Although these cardiac neural cells are part of the autonomic system, they are developed later, mainly on the epicardial surface. Bilateral innervation of the heart comes from the middle cervical stellate (MC-S) ganglion. Although the left ventricle and atrium receive noradrenaline from the MC-S on both sides, the right ventricle receives more from the MC-S from the left rather than from the right side. The development of the great vessels also contributes towards the pattern of development of cardiac innervation. The afferent fibres leaving the heart are also described. Their development relates to the sympathetic innervation of the heart and therefore to cardiac sensations. We hypothesise about how this reflects on the patterns of ischaemic cardiac pain.peer-reviewe