Original article Theoretical investigation of the mechanism of heart failure using a canine ventricular cell model: Especially the role of up-regulated CaMKII and SR Ca 2+ leak Yunliang Zang a , Ling Dai a , Heqing Zhan a , Jianhong Dou a, b , Ling Xia a, ⁎, Henggui Zhang c a Department of Biomedical Engineering, Zhejiang University, Hangzhou 310027, China b General Hospital of Guangzhou Military Command, Guangzhou 510010, China c School of Physics & Astronomy, The University of Manchester, Manchester, M13 9PL, UK abstract article info Article history: Received 8 July 2012 Received in revised form 21 November 2012 Accepted 28 November 2012 Available online 7 December 2012 Keywords: Computational model CaMKII Heart failure SR leak current Heart failure (HF) is associated with susceptibility to sudden cardiac death. However, the underlying mechanism of electrical instability and mechanical dysfunction associated with HF remains poorly understood. In this study, a new canine ventricular cell model based on the Hund–Rudy dynamic (HRd) model and recently published experimental data was developed to investigate the electrical changes and calcium handling dysfunction in HF. Simulation results suggest that: 1) acute Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) over-expression (CaMKII-OE) affects the action potential (AP) profile, while AP prolongation is mainly caused by the down-regulation of K + currents; 2) enhanced late Na + current (I NaL ) alone cannot adequately lead to [Na + ] elevation in HF; 3) enhanced sarcoplasmic reticulum (SR) leak current (I leak ) causes disturbed Ca 2+ han- dling and there is little contribution from Na + /Ca 2+ exchanger (NCX); 4) at high SR Ca 2+ load, a steeper frac- tional SR Ca 2+ release is observed in HF than that in control, causing alternans to occur more easily; and 5) I leak block restores the contraction and relaxation function, but cannot eliminate alternans. By inhibiting CaMKII, alternans is eliminated, but contractility is not improved. Partial CaMKII inhibition in combination with I leak block could augment mechanical function and depress alternans, suggesting a new possible therapeutic target for HF treatment. © 2012 Elsevier Ltd. All rights reserved. 1. Introduction The number of patients suffering from heart failure (HF) has been increased dramatically over the last several decades. Up to 50% of deaths in patients with HF are unexpected due to ventricular arrhythmias [1]. One of the main hallmarks of HF is the prolongation of action potential (AP) duration (APD, 90% repolarization), which favors the development of early afterdepolarizations [2]. In HF, disturbed Ca 2+ handling reduces contraction–relaxation dynamics in correspondence with decreased systolic Ca 2+ transient amplitude (CaT sys , the level at peak) and elevat- ed diastolic Ca 2+ (CaT dias , the level at rest). Elevated intracellular [Na + ] also plays important roles in Ca 2+ handling for its interplay with [Ca 2+ ] by Na + /Ca 2+ exchanger (NCX). In addition, HF enhances the suscepti- bility to arrhythmogenic alternans [3]. Understanding the mechanism of electrical instability and mechan- ical dysfunction in HF would help in developing therapeutic treatment. The properties of canine ventricular cells have been studied experimen- tally to understand the mechanisms of HF. It has been reported that Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) was associated with the function of numerous ionic channels and Ca 2+ transport pro- teins [4–7]. In HF, over-expressed CaMKII activity has been observed, which could contribute to arrhythmogenesis [5]. Different canine ven- tricular cell models have been developed to understand the underlying mechanisms of cardiac diseases, including the Fox–McHarg–Gilmour (FMG) model [8], the Winslow–Rice–Jafri (WRJ) HF model [9] and the Hund–Rudy dynamic (HRd) model [10]. However, these models were limited in their ability to simulate HF. The aim of this study was to develop an improved canine epicardial cell model based on the framework of the HRd model [10] and recently published experimental data. The HRd model was selected due to its in- corporation of dynamic CaMKII regulation. The developed model was then used to investigate: 1) the effect of different ionic current changes on electrical properties in HF; 2) whether enhanced late Na + current (I NaL ) could explain [Na + ] elevation in HF; 3) the mechanism of dis- turbed Ca 2+ handling in HF; 4) the mechanism of enhanced susceptibil- ity to alternans in HF; and 5) new possible therapeutic targets to treat patients with HF. 2. Methods In the new model, Ca 2+ handling system was reconstructed. Fast Na + current (I Na ), I NaL , transient outward K + current (I to ), time-independent K + current (I K1 ), rapid-activating delayed rectifier K + current (I Kr ), and L-type Ca 2+ current (I CaL ) were reformulated using published experimental data. Increased conductance of Na + /K + Journal of Molecular and Cellular Cardiology 56 (2013) 34–43 ⁎ Corresponding author. Tel.: +86 571 87951284. E-mail address: xialing@zju.edu.cn (L. Xia). 0022-2828/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.yjmcc.2012.11.020 Contents lists available at SciVerse ScienceDirect Journal of Molecular and Cellular Cardiology journal homepage: www.elsevier.com/locate/yjmcc