Research Project: Quantifying Transmembrane Currents during Impulse Propagation
Principal Investigator: Richard Gray
The electrical activity in the heart is measured both globally via electrodes on the patient’s chest (electrocardiogram or ECG) and locally via electrograms in contact with cardiac tissue. During impulse propagation, these cardiac potentials are the result of an interdependence of ionic currents along the direction of propagation AND currents flowing across the cardiac cell membrane. The measurement of transmembrane ionic currents (and the effects of pharmaceuticals) has been achieved via sub-cellular measurements in which the transmembrane potential (Vm) is held constant, i.e., clamped. These studies have provided much information about the dynamics of transmembrane ionic currents at a microscopic level but large-scale clinical trials of the resulting antiarrhythmic drugs have been terminated due to increased fatalities. These tragedies were, in large part, due to the fact that heart disease results not only from altered membrane kinetics but also from impaired action potential propagation. The purpose of this study is to experimentally quantify transmembrane ionic currents during stable and unstable propagation in the intact heart. Our goal is to provide the first characterization of the individual components of transmembrane currents during action potential propagation in the heart at thousands of sites (i.e., transmembrane current imaging) by combining measurements of transmembrane potential from high-speed fluorescence imaging and glass microelectrodes. Our results will include the first quantitative demonstration of the spatio-temporal dynamics of both the capacitive and resistive transmembrane ionic currents responsible for depolarization during stable propagation as well as qualitative estimates of total transmembrane current throughout the action potential during unstable propagation, including reentry and cardiac fibrillation. This study is relevant to CDRH for a variety of reasons. Since most patients with medical devices are taking drugs the detailed study of the effect of drugs on transmembrane currents and propagation are of paramount importance. These studies will help understand drug-device interactions as well as provide a novel tool to study the effect of drugs during propagation for the first time. A better understanding and quantification of transmembrane ionic currents should lead to the elucidation of the relative roles and spatial heterogeneity of membrane dynamics and tissue resistivity during health and disease thus leading to improved therapies for dangerous cardiac arrhythmias (and other conduction abnormalities).