The Ischemic Heart: What Causes Ectopic Beating? Xiao Jie a , Blanca Rodríguez b , Natalia Trayanova a a Department of Biomedical Engineering, Tulane University, New Orleans, LA 70118, USA b Oxford University Computing Laboratory, Oxford, United Kingdom Abstract—The mechanisms by which spontaneous electrical activity originates in the ischemic heart and leads to arrhythmia remain unknown, however mechanical stretch of the diseased region has been hypothesized to play a role. The goal of this study is to investigate the conditions that favor the initiation of stretch-induced premature beats in the ischemic heart. We employ a mathematical model of the ischemic cell subjected to stretch. The study found that upon stretch, spontaneous beats occur in the ischemic cell, which are due to the stretch-induced re-activation of the L-type calcium current. I. INTRODUCTION CUTE myocardial ischemia is the most common cause of ventricular arrhythmias and sudden cardiac death [1]. Despite intense research, the mechanism by which ectopic (out of the normal rhythm) activity originates in the ischemic heart remains a mystery. This ectopic activity disturbs the normal cardiac rhythm, leads to premature contractions and arrhythmias, and often degrades into lethal ventricular fibrillation. Thus, understanding the mechanism by which ectopic activity originates in the ischemic heart is paramount for the development of anti-arrhythmia therapies. A recent study [2] has demonstrated that the origin of arrhythmias in the later phase of ischemia (20-30 min following coronary vessel occlusion, termed ischemia 1B phase) could be ectopic activations arising at the border between normal and severely ischemic tissue. Since severely ischemic tissue looses its ability to contract [3], the border tissue is subjected to excessive stretch during the normal contraction of the heart. Myocardial cells subjected to excessive stretch are known to respond by opening of a type of mechano-sensitive ionic channels termed stretch-activated channels (SAC) [4]. We hypothesize that under certain conditions the current that passes through these SACs could result in a local ectopic activation and premature contraction. The goal of this study is to investigate the conditions that favor the initiation of stretch-induced premature activations in the ischemic heart and to provide an insight into the underlying mechanisms. To achieve the goal, we employ a mathematical model of an ischemic cell in which opening of SAC ensues following stretch. II. METHODS To represent the baseline electrical behavior of the normal cardiac cell, the latest version of the Luo-Rudy dynamic membrane model [5] was used. The model comprises of seventeen ordinary differential equations describing the membrane currents and ionic concentrations. We modified the model to represent inhibitions of numerous ionic currents under the conditions of ischemia 1B, which include hyperkalemia, acidosis and hypoxia [6]. The changes in parameters implemented in the ischemic membrane model are presented in Table I, and are based on a survey of available experimental data [6, 7, 8]. In addition, a formulation of the ATP-dependent potassium current (I KATP ) [9] activated upon oxygen depletion was incorporated in the model; this current is governed by ischemic changes in intracellular ATP, ADP, and magnesium concentrations ([ATP] i , [ADP] i and [Mg 2+ ] i ) [10, 11, 12]. TABLE I MODEL PARAMETERS Normoxia Ischemia [K + ] o (mmol/L) 5.4 9.0 [Na + ] i (mmol/L) 10 15 [ATP] i (mmol/L) 6.8 5.0 [ADP] i (µmol/L) 15 82 [Mg 2+ ] i (mmol/L) 0.5 4 I Na Inhibition † 1.0 0.5 I CaL Inhibition † 1.0 0.5 I NaCa Inhibition † 1.0 0.2 I NaK Inhibition † 1.0 0.3 I over Inhibition † 1.0 0.65 I rel Inhibition † 1.0 0.05 I up Inhibition † 1.0 0.9 I Cab Inhibition † 1.0 1.3 I nsCa Inhibition † 1.0 1.7 † Scaling factors, in normoxia and ischemia, of the fast sodium current (INa), L-type calcium current (ICaL), sodium-calcium exchange current (INaCa), sodium-potassium pump current (INaK), calcium release from the sarcoplasmic reticulum (Irel), calcium release under calsequestrin buffer overload (Iover), calcium uptake into the sarcoplasmic reticulum (Iup), background calcium current (ICab), and calcium-sensitive nonselective current (InsCa). To the system of equations representing cellular behavior under normal and ischemic conditions we added an equation representing the current through SAC recruited upon cellular stretch. The formulation of this current remains controversial. Some studies have documented a monotonic SAC current-voltage relationship [13, 14, 15] with a reversal potential in the range -16mV to -6mV, while others [16, 17, 18] have argued that this relationship is non-monotonic, with decreasing inward currents at negative transmembrane potential (V m ) values. Therefore, two different SAC formulations were implemented in the study (Fig.1): Monotonic Formulation 22 m rev stretch stretch V E I G - = A Proceedings of the 2005 IEEE Engineering in Medicine and Biology 27th Annual Conference Shanghai, China, September 1-4, 2005 0-7803-8740-6/05/$20.00 ©2005 IEEE. 7194