Vulnerability to Reentry during the Acute Phase of Myocardial Ischemia: a Simulation Study JM Ferrero (Jr), B TrØnor, F Montilla, J SÆiz, JM Alonso, G Molt Centre for Research and Innovation in Bioengineering, Universidad PolitØcnica, Valencia, Spain Abstract The aim of this work was to analyze the vulnerability to reentry in a two-dimensional sheet of regionally- ischemic and anisotropic myocardial tissue at different stages of acute myocardial ischemia. We used computer modelling in order to elucidate the main factors responsible for initiation and maintenance of reentry. Simulations were carried out using a modified version of the Luo-Rudy-II model. The simulated 2D tissue included a central ischemic zone, a border zone and a normal zone and was prematurely stimulated. The degree of severity of the central zone was changed depending on the stage of acute ischemia. Our results offer a theoretical explanation of the existence of a vulnerable phase for reentry between the fifth and tenth minute of acute ischemia, and lead to the conclusion that (a) strong hyperkalemia is needed to sustain reentry and (b) severe degrees of hypoxia tend to reduce myocardial vulnerability to reentry. 1. Introduction Ventricular tachycardia and ventricular fibrillation are potentially mortal arrhythmias caused by reentrant electrical activity in the heart ventricles [1]. Although they may occur in normal healthy myocardium under certain circumstances, they are usually a consequence of the electrophysiological changes caused by acute myocardial ischemia [1,2]. If ischemia is regional, the inhomogeneities developed in the myocardium seriously predispose the substrate to reentry [1-5]. Experimental evidence has shown that several minutes after coronary artery occlusion, reentrant activity following premature stimulation may have the form of a figure-of-eight, with two parallel reentrant circuits circulating around an area of functional block [3-6]. This pattern may be stable (ventricular tachycardia) or may destabilize, leading to ventricular fibrillation [3,5]. Other experimental works show that the incidence of these types of arrhythmias is higher during the fifth and sixth minute after the occlusion, ceasing after 10 minutes of ischemia [7,8]. In this paper, we present a theoretical study of the mechanisms of figure-of-eight reentry during the acute phase of regional myocardial ischemia, focusing on the influence of the degree of hypoxia (and, therefore, the degree of activation of the ATP  sensitive K + current, I K(ATP) [9,10]), acidosis and hyperkalemia on the vulnerability to reentry. Mathematical models were used to simulate electrical activity of a virtual tissue which imitated the conditions of regional acute ischemia. The main results show that the likelihood of figure-of-eight reentry increases with time after the coronary artery occlusion, reaches a peak and finally decreases to zero after 10-12 minutes of ischemia. 2. Methods The dynamic Luo-Rudy (phase II) equations [11,12] were chosen as the model to simulate the cardiac action potentials and the underlying ionic currents due to its comprehensiveness. To simulate acute ischemia, its three main components were considered. Firstly, hypoxia was modelled by partially activating the ATP-sensitive K + current (I K(ATP) ), using the mathematical formulation of Ferrero Jr et al [10]. Secondly, hyperkalemia was simulated by elevating extracellular K + concentration ([K + ] o ). Finally, acidosis was modelled by its effect on the Na + and Ca 2+ currents [13,14] as described below. Although the myocardium is a three dimensional structure, we used a 5.5 cm x 5.5 cm two-dimensional tissue in our simulations. Figure 1 shows the structure of the virtual tissue which, in order to properly simulate regional acute ischemia, comprises three different zones. A circular shaped central ischemic zone (CZ, 20 mm in diameter [15]) is formed by cells directly affected by the lack of blood flow. Inside this zone, the values of the parameters affected by ischemia were chosen to correspond to their experimental values measured at different instants after the onset of ischemia. [K + ] o was set to a value in the range 5.4-12.5 mmol/L [9,15] to simulate hyperkalemia; the fast inward Na + current (I Na ) and the Ca 2+ current through the L-type channels (I Ca(L) ) were scaled by a factor f pH in the range 1.0-0.7 to simulate the main effects of intracellular and extracellular acidosis [13,14]; and intracellular levels of ATP and ADP 0276-6547/03 $17.00 © 2003 IEEE 425 Computers in Cardiology 2003;30:425-428.