Genetics and Physiology of the heartbeat generation – Beat-Genesis

Heart automaticity is a fundamental physiological function in animals. In the adult heart of higher vertebrates, automaticity is generated in the sino-atrial node by specialized “pacemaker” cells having low contractility and generating a periodic electrical oscillation. The readout of cardiac automaticity is heart rate, which is a primary determinant of the capability of the organism to fulfill the physiological demand of the environment. Heart rate is also positively correlated with cardiovascular mortality and constitutes an important epidemiological parameter. However, despite of its importance, the signalling pathways involved in the genesis of pacemaking and heart rate regulation are not completely understood and some essential aspects of the cardiac pacemaker mechanism are still hotly debated. Development of therapeutically active molecules, able to control heart rate, is thus of outstanding interest. The clinical development of ivabradine (©Procoralan) for stable angina pectoris is a striking example of the potential importance of heart rate control in cardiac pathologies. However, the lack of knowledge on the importance of some mechanisms underlying pacemaking is a major obstacle in the development of heart rate controlling drugs and cellular therapy of heart diseases. The Beat-Genesis consortium proposes a cutting edge research program to reach two main objectives. First, we aim to define the role of critical ion channels and protein involved in intracellular Ca2+ signalling in cardiac automaticity and in the determination of heart rate and secondly, we will explore the potential cardioprotective effect of gene inactivation or pharmacological inhibition of critical ion channels (L-type Cav1.3, T-type Cav3.1 and HCN) against cardiac ischemia. The Beat-Genesis research program is based on recent advances in the understanding of heart rate regulation obtained by already established and fruitful collaborations between partners. The project is based on a unique collection of genetically-modified mouse strains which is the outcome of an eight years long strategic investment to target key points of the complex cellular pathway underlying cardiac automaticity. This mouse line collection will allow definition of the respective functional roles of Cav1.3 and HCN channels in cardiac automaticity and heart rate control of adult hearts. Furthermore, we propose to investigate the minimal or predominant mechanism required for generating viable automaticity during the adulthood and to study how the loss of Cav1.3 and HCN channels influences automaticity and cellular differentiation of pacemaker cells differentiated from skeletal muscle derived stem cells. Finally, we propose to investigate the potential cardioprotective role of genetic inactivation or pharmacological inhibition of Cav1.3 and Cav3.1 channels.