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Loss of sinoatrial node or atrioventricular node function may lead to severe bradyarrhythmias, requiring the implantation of an electronic pacemaker. These devices come with several short comings such as lack of adequate autonomic responsiveness, recurrent need for battery replacement, suboptimal cardiac output, and an increasing risk for device-related infections. To overcome these shortcomings, biological pacemakers are under development exploring the use of gene and cell therapy to restore cardiac pacing. In this setting, viral vectors may be used to introduce pacemaker function-related genes to augment spontaneous activity. Moreover, overexpression of transcription factors is being explored to transdifferentiate resident cells towards a pacemaker phenotype. Alternatively, several different stem cells are being investigated as a vehicle for pacemaker function-related genes, or as a source for cells that are being differentiated towards a pacemaker phenotype before transplantation. At present, robust proof-of-concept data has accumulated supporting the initiation of first-in-human testing of short-term biological pacemakers using adenoviral gene transfer. Ongoing research efforts focus on the optimization of long-term biological pacing comparing viral vector-mediated gene transfer to stem cell-based approaches.

Publisher Summary This chapter outlines the mechanisms of formation of the building plan of the vertebrate heart, placing emphasis on cardiac growth and chamber development. It attempts to set the scene for understanding the relationships between the building plan and mechanisms of cardiac patterning in the various fields of cardiac precursor cells. The pulmonary circulation is the essential difference between the mammalian heart and that of its vertebrate ancestors, with their purely systemic circulatory function. It also discusses the significance of the development of the cardiac components required for the pulmonary circulation. The local reinitiation of proliferation in the primary myocardial heart tube indicates that the formation of the myocardium of the chambers, in contrast to the initial formation of the primary myocardium, represents a localized process. As the working myocardium of the chambers is formed, the nondifferentiating and nonexpanding flanking components become visible. The subsequent temporal repression by Tbx2, Tbx3, and other factors of the formation of working myocardium in these flanking regions initially permits these regions to function as peristaltic valves prior to the formation of the definitive valvar leaflets. It will be crucially important to unravel the regional function of cardiac transcription factors such as Nkx2-5, which are essential but nonetheless play divergent roles in the first and second heart fields and in distinct regions of the heart.

This chapter focuses on the cellular origin of the conduction system components and the molecular genetic mechanisms that may control their phenotype and position within the developing heart. It discusses the connection between heart cell precursor pools, which in a temporal pattern form the heart, and the genesis of the conduction system components. The distinct components of the cardiac conduction system of the heart are essentially myocardial. They are innervated by cardiac ganglia largely derived from neural crest. In addition, a large fraction of cells in the mature conduction system is noncardiac, and insulating layers of fibrous tissue are found around conduction system components, such as the SAN and AV bundle. These noncardiac cell types are derived from the epicardium (fibroblasts), endocardium, neural crest (neural innervations), and other sources, although their origins have not been defined in detail. Although these nerves and fibrous tissues are important, or even a prerequisite, for conduction system formation and function, the cardiomyocytes are essential for impulse generation and propagation. Furthermore, in the embryo the functional myocardial conduction system is not yet innervated and interstitial fibroblast and fibrous tissues in association with the conduction system are sparse or absent. Studies of the development of the conduction system components strongly suggest that they originate from myocardial precursors, which in turn are derived from mesoderm and pericardial wall mesenchyme.