IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 58, NO. 11, NOVEMBER 2011 3175 The Maximal Downstroke of Epicardial Potentials as an Index of Electrical Activity in Mouse Hearts Kwanghyun Sohn, Frank B. Sachse, Member, IEEE, Alonso P. Moreno, Philip R. Ershler, Adam R. Wende, E. Dale Abel, and Bonnie B. Punske* Abstract—The maximal upstroke of transmembrane voltage (dV m /dt max ) has been used as an indirect measure of sodium cur- rent I Na upon activation in cardiac myocytes. However, sodium influx generates not only the upstroke of V m , but also the down- stroke of the extracellular potentials V e including epicardial sur- face 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 relation- ship of dV m /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 dur- ing hyperkalemia, ischemia, and hypoxia, which are conditions that decrease I Na . Values of |dV es /dt min | from each electrode were nor- malized (|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 dV m /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 simi- lar to dV m /dt max during alterations of G Na , [K + ] o , and [Na + ] i . Our results demonstrate that |dV es /dt min | na is a robust global in- dex of electrical activation for use in mouse hearts and, similar to dV m /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. Manuscript received January 28, 2011; revised June 17, 2011 and July 24, 2011; accepted July 25, 2011. Date of publication August 18, 2011; date of current version October 19, 2011. This work was supported by the Richard A. and Nora Eccles Fund for Cardiovascular Research and Awards from the Nora Eccles Treadwell Foundation. Asterisk indicates corresponding author. K. Sohn was with Nora Eccles Harrison Cardiovascular Research and Train- ing Institute and Bioengineering Department, University of Utah, Salt Lake City, UT 84112 USA. He is now with Massachusetts General Hospital, Cardiovascular Research Center, Charlestown, MA 02129 USA (e-mail: ksohn@partners.org). F. B. Sachse is with Nora Eccles Harrison Cardiovascular Research and Train- ing Institute and Bioengineering Department, University of Utah, Salt Lake City, UT 84112 USA (e-mail: fs@cvrti.utah.edu). A. P. Moreno is with Nora Eccles Harrison Cardiovascular Research and Training Institute and the School of Medicine, University of Utah, Salt Lake City, UT 84112 USA (e-mail: moreno@cvrti.utah.edu). P. R. Ershler is with Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112 USA (e-mail: ershler@cvrti.utah.edu). A. R. Wende and E. D. Abel are with the Division of Endocrinol- ogy, Metabolism and Diabetes, School of Medicine, University of Utah, Salt Lake City, UT 84112 USA (e-mail: adam.wende@u2m2.utah.edu, dale.abel@u2m2.utah.edu). *B. B. Punske is with Nora Eccles Harrison Cardiovascular Research and Training Institute, the School of Medicine, and Bioengineering De- partment, University of Utah, Salt Lake City, UT 84112 USA (e-mail: punske@cvrti.utah.edu). Digital Object Identifier 10.1109/TBME.2011.2164075 Index Terms—Bidomain model, epicardial mapping, extracellu- lar potential, hyperkalemia, hypoxia, ischemia, tissue electrophys- iology. I. INTRODUCTION T HE influx of Na + ions into cardiac myocytes generates not only the upstroke of the transmembrane voltage V m , but also the downstroke of the extracellular potentials V e including epicardial surface potentials V es . The maximum upstroke of V m (dV m /dt max ) has been widely used as an index of sodium chan- nel activation and availability [1]–[17]. Several studies have demonstrated that changes in dV m /dt max are closely associated with the physiological or pathophysiological changes in car- diac tissue during ischemia or hypoxia. Hyperkalemia has been shown to decrease dV m /dt max during ischemia [18]–[20]. Sec- ondary to hyperkalemia, acidosis has been shown to also reduce dV m /dt max during ischemia [21]–[23]. While the relationship of the time of the maximal upstroke of V m with the time of the maximal downstroke of V es as the moment of cellular activation has been well defined and widely used [24]–[27]; the use of the magnitude of |dV es /dt min | has not been thoroughly explored as an electrical index. The magnitude of |dV es /dt min | has been used to classify tissue as normal or in- farcted [28] and as a way to characterize local and distant effects in unipolar electrograms [29]. Our previously published compu- tational studies using an anisotropic bidomain model of cardiac tissue demonstrated a linear relationship between normalized |dV es /dt min | (|dV es /dt min | n ) and dV m /dt max (|dV m /dt max | n ) for various directions of electrical conduction [30]. However, the magnitude of |dV es /dt min | has not been evaluated as a global in- dex of electrical activation for assessment of electrical activity in mouse hearts. The purpose of this study was to evaluate the use of the magnitude of the maximal downstroke of V es , specifically, |dV es /dt min | na , as a global index of electrical activation, based on the previously established relationship of dV m /dt max to I Na . We hypothesized that measured values of |dV es /dt min | na would decrease during hyperkalemia, ischemia, and hypoxia similarly to results reported for dV m /dt max under these conditions. For the first aim of this study, we performed experiments measuring V es from isolated mouse hearts. From these potentials we measured changes in |dV es /dt min | na in mouse hearts during hyperkalemia, ischemia, and hypoxia. We compared the |dV es /dt min | na changes with other electrical parameters, including total activation time (TAT) and propagation sequence. Our approach for measuring extracellular surface potentials in mouse hearts was based on flexible electrode arrays, which 0018-9294/$26.00 © 2011 IEEE