Mechano-Electric Coupling in the Heart: Mechanisms and Relevance for Cardiac Autoregulation

The heart beats 3 to 4 billion times in a human lifetime. In all vertebrates, for normal function of each heartbeat, tight control of electrical and mechanical activity is needed. Electrical and mechanical activity in the heart are linked in both the forward and reverse direction. Electrical excitation causes mechanical contraction through a process called excitation-contraction coupling and the mechanical environment changes electrical activity through a process called mechano-electric feedback. Cardiac excitation-contraction coupling has been studied in great detail and is well understood. However, the importance of mechano-electric feedback in the heart is generally ignored and the way in which it works is not well defined. The long-term goal of my research program is to determine the importance of mechano-electric feedback for regulation of heart function and to discover how this process works. The specific objectives of the first five years of work are to examine mechano-electric feedback in the region of the heart responsible for initiating the heartbeat, called the sinoatrial node (the heart's natural pacemaker). Studies will involve measuring the electrical activity of individual cells and intact tissue from the sinoatrial node using state-of-the-art fluorescence imaging, while they are being subjected to physiological stretch. The ionic currents responsible for changes in electrical activity that occur with stretch will be determined by blocking them with specific pharmacological agents. These experiments will be carried out using cells and tissue from multiple species to test for evolutionary similarities and differences, as well as to determine the most appropriate animal model for future research. Importantly, the proposed studies will provide an excellent learning environment for the trainees involved by introducing them to a range of advanced experimental techniques. Overall, results will show us how the heart's pacemaker adapts to changes in physiological demand. Currently, our understanding of the adaptation of the sinoatrial node, as well as the rest of the heart, is based mostly on studies in which the mechanical environment was not controlled. Thus, my research will address a poorly understood fundamental aspect of heart regulation that is essential for a complete understanding of normal heart function and overall systems physiology.