The overall objective of our studies is to further our understanding of the cellular and subcellular mechanisms of heart rate and atrioventricular conduction. We will concentrate our efforts on the detailed analysis of the dynamics and mechanisms of pacemaker synchronization in the mammalian sinoatrial (SA) node. We will use a combination of highly sophisticated techniques, including current and voltage clamping in single cells, double patch clamping in cell pairs, high resolution optical mapping in isolated tissues and supercomputer and massively parallel computer modelling to pursue two major specific goals: 1) we will continue our studies on the cellular and subcellular mechanisms of synchronization, as well as the dynamics of synchronization in the SA node. The phase-resetting and entrainment behaviors of single, spontaneously active SA nodal cells will be characterized especially with regard to the development of phase-locking and irregular dynamics. In addition, the specific ionic currents responsible for phase delay and phase advance in response to brief current pulses applied during diastole will be determined. Furthermore, junctional conductance in pairs of spontaneously beating SA nodal cell will be measured in relation to the ability of their action potentials to mutually entrain. 2) we will continue our studies on the dynamics, mechanisms and sequence of activation of the sinoatrial region. For this purpose, we will use high resolution optical mapping in experimental preparations as well as mathematical modelling to study normal patterns of activation in the sinus node, and the effects of vagal stimulation, and pharmacological agents on these patterns. The same techniques will be used to determine the way in which sinus activity is propagated to the atrium. Patterns of activation within the SA node and in adjacent atrial tissue in response to atrial extrasystoles and atrial fibrillation will also be investigated. Finally, we will study the non-linear dynamics of propagation between the SA node and atrium. These data will allow us to determine whether chaotic dynamics are properties of the activity in the sinoatrial region. The overall study should provide a quantitative basis for the understanding of normal and abnormal SA node synchronization, and should lead to an accurate description of the dynamics and cellular mechanisms of sinoatrial impulse initiation and propagation.
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