Effect of Global Cardiac Ischemia on Human Ventricular Fibrillation: Insights from a Multi-scale Mechanistic Model of the Human Heart Ivan V. Kazbanov 1 , Richard H. Clayton 2,3 , Martyn P. Nash 4,5 , Chris P. Bradley 4 , David J. Paterson 6 , Martin P. Hayward 7 , Peter Taggart 7 , Alexander V. Panfilov 1,8 * 1 Department of Physics and Astronomy, Ghent University, Ghent, Belgium, 2 INSIGNEO Institute for In-Silico Medicine, University of Sheffield, Sheffield, United Kingdom, 3 Department of Computer Science, University of Sheffield, Sheffield, United Kingdom, 4 Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand, 5 Department of Engineering Science, University of Auckland, Auckland, New Zealand, 6 Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom, 7 Departments of Cardiology and Cardiothoracic Surgery, University College Hospital, London, United Kingdom, 8 Moscow Institute of Physics and Technology (State University), Dolgoprudny, Moscow Region, Russia Abstract Acute regional ischemia in the heart can lead to cardiac arrhythmias such as ventricular fibrillation (VF), which in turn compromise cardiac output and result in secondary global cardiac ischemia. The secondary ischemia may influence the underlying arrhythmia mechanism. A recent clinical study documents the effect of global cardiac ischaemia on the mechanisms of VF. During 150 seconds of global ischemia the dominant frequency of activation decreased, while after reperfusion it increased rapidly. At the same time the complexity of epicardial excitation, measured as the number of epicardical phase singularity points, remained approximately constant during ischemia. Here we perform numerical studies based on these clinical data and propose explanations for the observed dynamics of the period and complexity of activation patterns. In particular, we study the effects on ischemia in pseudo-1D and 2D cardiac tissue models as well as in an anatomically accurate model of human heart ventricles. We demonstrate that the fall of dominant frequency in VF during secondary ischemia can be explained by an increase in extracellular potassium, while the increase during reperfusion is consistent with washout of potassium and continued activation of the ATP-dependent potassium channels. We also suggest that memory effects are responsible for the observed complexity dynamics. In addition, we present unpublished clinical results of individual patient recordings and propose a way of estimating extracellular potassium and activation of ATP- dependent potassium channels from these measurements. Citation: Kazbanov IV, Clayton RH, Nash MP, Bradley CP, Paterson DJ, et al. (2014) Effect of Global Cardiac Ischemia on Human Ventricular Fibrillation: Insights from a Multi-scale Mechanistic Model of the Human Heart. PLoS Comput Biol 10(11): e1003891. doi:10.1371/journal.pcbi.1003891 Editor: Olivier Bernus, Universite ´ Bordeaux Segalen, France Received February 18, 2014; Accepted September 3, 2014; Published November 6, 2014 Copyright: ß 2014 Kazbanov et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was funded by Fonds Wetenschappelijk Onderzoek, Belgium, http://www.fwo.be/en and Health Research Council of New Zealand, http:// www.hrc.govt.nz/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * Email: Alexander.Panfilov@UGent.be Introduction The heart is an electromechanical pump, where contraction is triggered and synchronized by electrical activation originating from the sinoatrial node. Abnormal initiation or conduction of the electrical impulses could result in a cardiac arrhythmia. Cardiac arrhythmias are an important cause of sudden and premature death in the industrialized world. In many cases the lethal event is ventricular fibrillation (VF). During VF, rapid and self-sustaining electrical activity in the ventricles acts to suppress the natural pacemaker, resulting in uncoordinated, weak and rapid contrac- tions, which lead to death within several minutes [1]. VF often occurs as a result of acute regional cardiac ischemia, which is a condition when blood flow to part of the heart is substantially decreased, for example by reduced flow through a coronary artery [2]. In addition, global ischemia unavoidably accompanies VF, because the abrupt fall in cardiac output resulting from VF also results in compromised myocardial perfusion. Thus an episode of spontaneous VF will result in a progressively ischemic heart. The effect of this secondary ischemia on electrical activity during VF is important clinically, because defibrillation typically occurs several minutes after the onset of VF, and thus the mechanism is likely to have been modified by ischemia [3,4]. It is known that ischemia profoundly affects the electrophysi- ological properties of cardiac cells and tissue [5]. During VF, the rapidly changing patterns of electrical activity in the ventricles are sustained by re-entry, in which waves of electrical activation continually propagate into regions of recovered tissue [6]. Re- entry is seen as a spiral wave on the surface of the heart, and a scroll shaped activation wave in 3D cardiac tissue [7]. The question of how ischemia influences the behaviour of re-entrant activity during VF is important, and has been addressed by clinical, experimental and modeling studies. Two important characteristics of VF are the frequency and spatiotemporal complexity of activation patterns, and these have been studied in animal heart experiments. Experiments on canine hearts [6] have shown that both activation rate and pattern PLOS Computational Biology | www.ploscompbiol.org 1 November 2014 | Volume 10 | Issue 11 | e1003891