The Maximal Downstroke of Epicardial Potentials as an Index of Electrical Activity in Mouse Hearts

The maximal upstroke of transmembrane voltage (dVm/dt_max) has been used as an indirect measure of sodium current I_Na upon activation in cardiac myocytes. However, sodium influx generates not only the upstroke of Vm, but also the downstroke of the extracellular potentials V including epicardial surface potentials V_es. The purpose of this study was to evaluate the magnitude of the maximal downstroke of V_es (|dV_es/dt_min|) as a global index of electrical activation, based on the relationship of dVm/dt_max to I_Na. To fulfill this purpose, we examined |dV_es/dt_min| experimentally using isolated perfused mouse hearts and computationally using a 3-D cardiac tissue bidomain model. In experimental studies, a custom-made cylindrical “cage” array with 64 electrodes was slipped over mouse hearts to measure V_es during hyperkalemia, ischemia, and hypoxia, which are conditions that decrease I_Na. Values of |dV_es/dt_min| from each electrode were normalized (|dV_es/dt_min|n) and averaged (|dV_es/dt_min|_na). Results showed that |dV_es/dt_min|_na decreased during hyperkalemia by 28, 59, and 79% at 8, 10, and 12 mM [K⁺]o, respectively. |dV_es/dt_min| also decreased by 54 and 84% 20 min after the onset of ischemia and hypoxia, respectively. In computational studies, |dV_es/dt_min| was compared to dVm/dt_max at different levels of the maximum sodium conductance G_Na, extracellular potassium ion concentration [K⁺]o, and intracellular sodium ion concentration [Na⁺]i, which all influence levels of I_Na. Changes in |dV_es/dt_min|n were similar to dVm/dt_ma- during alterations of G_Na , [K⁺]o, and [Na⁺]i. Our results demonstrate that |dV_es/dt_min|_na is a robust global index of electrical activation for use in mouse hearts and, similar to dVm/dt_max, can be used to probe electrophysiological alterations reliably. The index can be readily measured and evaluated, which makes it attractive for characterization of, for instance, genetically modified mouse hearts and drug effects on cardiac tissue.