It is known from experimental studies using either animal models or tissue from explanted human hearts that expression of key ion channels and calcium handling proteins is altered during heart failure. Specifically, it is known that the repolarizing currents Ik1 (the instantaneously activating outward potassium (K) current) and Ito (the transient outward K current) are both down-regulated. In addition, expression of the Serca2a pump protein (an energy requiring pump that moves calcium from the cytosol into sarcoplasmic reticulum) is reduced, and expression of the sodium-calcium exchanger protein increased during heart failure. Each of these changes contributes to increased action potential duration (APD), which in turn predisposes ventricular cells to a type of abnormal repolarization during Phase 3 of the action potential known as an early after-depolarization (EAD). We have hypothesized that EADs may trigger arrhythmias leading to sudden cardiac death in heart failure.

This hypothesis is tested in the simulation shown here. In this simulation, APD is increased sufficiently within a region of the heart so that cells within this region generate EADs. The model is heart is activated only once by endocardial stimulation. The EADs generated in response to this single activation pulse trigger reentrant waves within the heart which lead to a sustained arrhythmia.

3-D Heart Geometry

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This image and movie displays the three-dimensional (3D) structure of the normal canine right and left ventricle. Anatomical data on which this reconstruction is based was provided by Dr. Peter Hunter, University of Auckland, New Zealand. Images were rendered with Open GL on a Silicon Graphics O2 workstation using a software tool developed by Dr, Prasad Gharpure called AVIEW . Animations were generated using AVID MCXpress.

Activation in a 3D Computer Model of the Normal Heart

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This image and movie shows normal electrical activation in the 3D canine heart model. In this model, biophysical properties of cardiac tissue are modeled using either the Oxsoft HEART V4.2 ventricular cell equations, or using a model of the canine ventricular cell action potential developed in collaboration with researchers in the Division of Cardiology at The Johns Hopkins University School of Medicine. In this simulation, the heart is activated by periodic current injection (period 1 Sec) at the sites of initial pacemaker potential breakthrough on the cardiac endocardial surface, as described by mapping studies of Durrrer et al. Membrane potential (in units of mV) is shown according to the color bar in the right-hand side of each frame. Red corresponds to -80 mV, and blue corresponds to +50 mV. A simulated ECG is shown below this animation. The green ball displayed on the ECG trace marks the time location of the each frame as it is displayed. Computations were performed in parallel using a Silicon Graphics Power Challenge XL server configured with 12 R8000 processors, 1 Gbyte memory, and a 60 Gbyte disk array. Work done by MD/PhD candidate David Scollan.

Effects of Drug on Reentrant Arrhythmia: Low Drug Concentration

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The previous simulation shows that EADs can trigger sustained reentrant arrhythmias in a 3D computer model of the failing heart. A drug which prevents EADs in single cardiac cells may therefore act to prevent these reentrant arrhythmias in the failing heart. In this simulation, we model the action of a class of compounds known to increase the open probability of ATP-modulated K-channels, thereby shortening the the repolarizing phase of the cardiac action potential, and which our computer simulations have shown can reduce the occurrence of EADs at the single cell level. Here, we simulate the action of a low concentration of this drug on the 3D reentrant arrhythmia shown previously. In this case, the 3D heart model is stimulated repetitively at a period of 1 Sec to evoke successive waves of depolarization. Note that while the activation pattern of the heart is not completely normal (as seen by the shape of the ECG), the action of the drug is to eliminate the sustained reentrant arrhythmia seen previously.

Effects of Drug on Reentrant Arrhythmia: High Drug Concentration

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This simulation shows the effects of increasing drug concentration on activation and repolarization in the model 3D heart. Drug concentration was increased by a factor of twenty. Note the "wavelets" that break off and propagate near the base of the heart following action potential repolarization. These wavelets represent a cardiac arrhythmia generated in response to the high drug dosage. This simulation therefore shows that the 3D computer models provide insight into the therapeutic level of drug that should be used.