The heart is composed of muscle cells called cardiomyocytes, including a specialized population named pacemaker cells that form the cardiac conduction system (CCS), which is responsible for generating the action potential dictating heart contractions. Failure of the CCS system leads to cardiac arrhythmias, which require complicated therapies and often the surgical implantation of electrical pacemakers. However, recent research has focused on the development of novel therapies using biological pacemakers that aim to substitute electrical devices. While most signaling pathways and transcription factors involved in the development of the pacemaker cells are known, the upstream regulatory networks need to be predicted through computer-based databases, mathematical modeling, as well as the functional testing of the regulatory elements in vivo, indicating the need for further research. Here, we summarize the current knowledge about the vertebrate myocardial CCS system and the development of the pacemaker cells, as well as emphasize the areas of future research to clarify the regulation of muscle pacemaker cells and the ease of development of biological therapies.

Heart is composed of muscle cells called cardiomyocytes, including a specialized population, named pacemaker cells, that form the Cardiac Conduction System (CCS), responsible for generating the action potential dictating heart contractions. Failure of the CCS system leads to cardiac arrhythmias requiring complicated therapies and often surgical implantation of electrical pacemakers. However, recent research focusses on development of novel therapies using biological pacemakers aiming to substitute electrical devices. While most signalling pathways and transcription factors involved in the development of the pacemaker cells are known, the upstream regulatory networks need to be predicted through computer-based databases, mathematical modelling as well as functional testing of the regulatory elements in vivo, indicating the need for further research. Here we summarise the current knowledge about the vertebrate myocardial CCS system and development of the pacemaker cells and emphasise areas of future research to clarify the regulation of muscle pacemaker cells and ease development of biological therapies.