Scientific Publications by FDA Staff

Biophys J 2013 Jan 8;104(1):268-78

Quantification of Transmembrane Currents during Action Potential Propagation in the Heart.

Gray RA, Mashburn DN, Sidorov VY, Wikswo JP

The measurement, quantitative analysis, theory, and mathematical modeling of transmembrane potential and currents have been an integral part of the field of electrophysiology since its inception. Biophysical modeling of action potential propagation begins with detailed ionic current models for a patch of membrane within a distributed cable model. Voltage-clamp techniques have revolutionized clinical electrophysiology via the characterization of the transmembrane current gating variables; however, this kinetic information alone is insufficient to accurately represent propagation. Other factors, including channel density, membrane area, surface/volume ratio, axial conductivities, etc., are also crucial determinants of transmembrane currents in multicellular tissue but are extremely difficult to measure. Here, we provide, to our knowledge, a novel analytical approach to compute transmembrane currents directly from experimental data, which involves high-temporal (200 kHz) recordings of intra- and extracellular potential with glass microelectrodes from the epicardial surface of isolated rabbit hearts during propagation. We show for the first time, to our knowledge, that during stable planar propagation the biphasic total transmembrane current (I(m)) dipole density during depolarization was approximately 0.25 ms in duration and asymmetric in amplitude (peak outward current was approximately 95 muA/cm(2) and peak inward current was approximately 140 muA/cm(2)), and the peak inward ionic current (I(ion)) during depolarization was approximately 260 muA/cm(2) with duration of approximately 1.0 ms. Simulations of stable propagation using the ionic current versus transmembrane potential relationship fit from the experimental data reproduced these values better than traditional ionic models. During ventricular fibrillation, peak I(m) was decreased by 50% and peak I(ion) was decreased by 70%. Our results provide, to our knowledge, novel quantitative information that complements voltage- and patch-clamp data.