Organophosphonate Caused 

Cardiac Toxicity: Action Potential 

Dynamics in Atria1 Tissue 

by Csaba K. Zoltani and Steven I. Baskin 

Approved for public release; distribution is unlimited. 

20020617 027 
The findings in this report are not to be construed as an 

official Department of the Army position unless so 

designated by other authorized documents. 

Citation of manufacturer’s or trade names does not 

constitute an official endorsement or approval of the use 

thereof. 

Destroy this report when it is no longer needed. Do not 

return it to the originator. 
Army Research Laboratory 

Aberdeen Proving Ground, MD 21005-5067 

ARL-TR-2738 Mav 2002 

. 

Organophosphonate Caused 

Cardiac Toxicity: Action Potential 

Dynamics in Atria1 Tissue 

Csaba K. Zoltani 

Computational and Information Sciences Directorate, ARL 

Steven I. Baskin 

U.S. Army Medical Research Institute of Chemical Defense 

Approved for public release; distribution is unlimited. 
Abstract 

Highly effective treatments for the effect of organophosphonate and 

organophosphate (OP) nerve agents have eluded the medical community. It is 

known that acetylcholine overload is one of the effects of OF’ toxicity, but the 

cellular processes leading to cardiac toxicity are still incompletely understood. 

This study details high performance computer simulations of the 

electrophysiology in atrial toxicity. It shows that hyperkalemia of the tissue, one 

of the manifestations of OP intoxication, promotes the processes leading to 

reentry, a precursor of atrial fibrillation. Then, we demonstrate that changes in 

two of the potassium membrane currents, iKr and iti , can modulate the reentry 

process. This suggests that Class III anti-arrhythmic agents that primarily block 

these currents in the cardiac cells are important candidates for therapeutics of OF’ 

poisoning. 

. 

ii 
Acknowledgments 

It is a pleasure to thank Dr. John Portmann from Duke University for making 

CardioWave available and giving expert advice on its use. 

. . . 

ill 
, 

iv 
Contents 

Acknowledgments 

. . . 111 

List of Figures vii 

List of Tables vii 

. 

1. 

2. 

3. 

4. 

5. 

Introduction 1 

Materials and Methods 2 

2.1 Prior Work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 

2.2 The Simulation Setup . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 

2.3 Computational Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 

Results 5 

Discussion 8 

4.1 OP Toxicity Modeled as Extracellular Potassium Concentration . . . . . . . . ...9 

4.2 Reentry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 

4.3 Modulation of Reentry in the Atria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 

4.4 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 

References 11 

Distribution List 13 

Report Documentation Page 15 

V 
. 

vi 
List of Figures 

. 

Figure 1. Performance of the code using the shared-memory Origin 3000. . . . . . . . . . . . 5 

Figure 2. Frame sequence showing the evolution of the action potential in 

atria1 tissue using the Nygren model for the electrophysiology of the 

tissue. The times of the frames going clockwise are (a) 25 ms, (b) 60 ms, 

(c) 140 ms, and (d) 200 ms. The stimulus consisted of a current pulse of 

40 PA/ cm* delivered to the left-most column of atria1 cells. The stimulus 

lasted for 2 ms; VM in the legend is the voltage in mV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 

Figure 3. The action potential in an atria1 tissue containing a single 

hyperkalemic, cardioplegic subregion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 

Figure 4. The effect of blocking ik,. and ib currents on the action potential. . . . . . . . ...8 

List of Tables 

Table 1. Effect of ACh on atrial myocytes from Komni et al. [17]. . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 

L 

Vii 
. 

. . . 

Vlll 
1. Introduction 

Organophosphates (OP) and organophosphonates’ constituents of insecticides 

and nerve agents, respectively, are highly toxic substances with severe 

cardiovascular ramification upon exposure. An estimated 95% of the contacting 

agent winds up within and is transported by the vasculature and is primarily 

deposited in tissues of the cardium. For a review of its effects, see Baskin and 

Whitmer [l], Roth et al. [2], and Hassler et al. [3]. 

Toxicity is expressed when OF’ binds to acetylcholinesterase (AChE), preventing 

hydrolysis and resulting in an accumulation of acetylcholine (ACh) in the tissue. 

This overload causes negative inotropy and arrhythmia not only in the atria 

(bradyarrhythmia), but also in the Purkinje fibers, and produces electrical 

conduction anomalies. In addition, the absence of choline@ agonists increases 

the calcium influx and stimulates its uptake in the sarcoplasmic reticulum (SR), 

thereby increasing the intracellular calcium. Accompanying this process is an 

increase in the vagal tone that may contribute to the generation of atria1 

fibrillation. Choline+ stimulation of atria1 tissue reproducibly induces atria1 

fibrillation (AF) [4-71. 

The physiological events that culminate in AF upon cholinergic stimulation are 

only incompletely understood. Some of the known factors ancillary to AF are 

(1) non-uniform shortening of the myocardial refractory period [7J, 

(2) production of intra-atria1 conduction delays, 

(3) bradycardia that increases susceptibility to reentry, 

(4) shortening of the atria1 action potential duration, 

(5) cholinergic stimulation may be a sine non quo for the preparation of the 

subtrate where atria1 reentry may occur, 

(6) inhomogeneous repolarization may be necessary for atria1 arrhythmia, and 

(7) heterogeneity of the substrate. 

OP toxicity is accompanied by elevation of the concentration of [K+]o, the 

extracellular potassium concentration that influences the transmembrane 

resistance in Purkinje fibers, and [Na+]o, whose elevation mimics ischaemia. Ii-t 

the atria, a biphasic behavior of conduction velocity as a function of potassium 

concentration has been noted. Moderate elevation of extracellular potassium (up 

to 8 mM) increases the conduction velocity; but in the concentration range of 

8-16 mM, slowdown and eventual termination of conduction has been observed. 

Changes in the action potential due to toxicology-caused shifts in potassium 
concentration also form the basis of an updated model of soman-caused cardiac 

toxicity [8]. 

The tremendous increase in computational resources, especially parallel 

processing coupled with novel experimental techniques, has allowed the 

emergence of models of subcellular dynamics. Thus, it is possible to emulate 

cellular processes and study the effect of the presence of toxic agents at a 

fundamental level effectively and without animal experimentation. 

The following sections describe a computer study of the effect of ACh overload 

on the electrophysiology of atria1 tissue, especially the processes leading to 

reentry, that subsequently and usually culminate in AF, the precursor of sudden 

cardiac death (SCD). 

2. Materials and Methods 

This report details our approach to the simulation of cardiac toxicity created by 

the presence of OP in atria1 tissue. This study especially seeks to identify 

conditions that promote the modulation of membrane currents that may lead to 

reentry, a precursor of AF and ventricular fibrillation (VF). Conversely, it seeks 

to answer the question of whether it is possible to identify conditions whose 

modulation may reverse the process and thus suggest strategies for therapies. 

The approach was to simulate conditions that result from OF’ intoxication and to 

see if these conditions favor reentry of the action potential. 

2.1 Prior Work 

Two models of AF have been advanced- the rapidly discharging focus and 

reentrant excitation. Here we discuss the latter, where atria1 fibrillation is 

manifested by rapid, irregular action potential waves of variable wavelength and 

timing [g-11] along reentrant paths extinguishing that are also being 

reestablished. These irregular waves prevent the proper functioning of the atria 

due to the shortening of the refractory period and the loss of the normal 

lengthening of refractoriness when the heart slows down. The wave of excitation 

returns to the tissue it previously exited and reexcites it, hence the name reentry. 

Until quite recently, it was believed that below a certain volume of atria1 tissue 

reentry, one of the forms of AF could not be sustained. However, the work of 

Wakimoto et al. [12] showed that even in murine atria, AF is inducible. The 

breakup of the spiral waves signals the transition from tachycardia to fibrillation. 

Moe and his collaborators [13] were the first to give a mathematical description 

of atria1 fibrillation. Several electrophysiological models of the atria, such as 

those of Ramirez et al. [14], Lindblad et al. [15], and Nygren et al. [16], based on 

the Hodgkin and Huxley formalism and patch clamp data, are now available. 

2 
These models allow in siZico* studies of the effect of changes in the membrane 

currents caused by pathological conditions and their effect on the subsequent 

changes in the action potential to be studied without resort to in viva 

experiments. 

Table 1, from Koumi et al. [17], gives an indication of the effect of ACh on atria1 

myocytes. Significant (38%) decrease in the action potential duration was noted 

when 1 l.tM of ACh was applied to the atria1 tissue. ACh also increases 

conductance of the tissue and especially that of the iti channel, which occurs 

during myocardial ischemia. 

Table 1. Effect of ACh on atria1 myocytes from Koumi et al. [171. 

Resting Membrane Action Potential 

Potential Amplitude 

Action Potential 

Duration at 90% 

Repolarization 

(mV> (mv) b-is> 

Control -73.0 5 7.2 16.8 k 5.0 289.4i23.0 

l@ACh -77.4 f 6.1 -8.1+ 4.8 112.6 k 14.5 

2.2 The Simulation Setup 

For these calculations, an atria1 tissue, 3 x 3 cm, and ubsequently one of 

3 x 4 cm, with its electrophysiology described by the Nygren et al. [16] model, 

was stimulated by a pulse of 40 @/cm2 of 2 ms in duration at one edge. The 

presence of OPs was modeled by patches of tissue having a [K+]o of 10.8 up to 

25.0 mM instead of the ambient 5.4 mM. This expressed the observation that 

hyperkalemia is one manifestation of OP toxicity. In these regions, the resting 

membrane potential is less negative, and depends on the potassium 

concentration. Admittedly, this is coarse graining the problem since localized 

sodium and calcium concentration deviations, among other changes found in the 

presence of OP, are also indicators of the change of the state of the cell. For these 

calculations, the tissue was represented as a slab of 300 x 300 x 1 nodes and also 

as 300 x 400 x 1 with node spacing of 0.01 cm. The pacing used to establish the 

initial conditions consisted of ten 10 pulses at 300-ms intervals. 

2.3 Computational Approach 

The computational experiments reported were designed to establish and 

simulate conditions that favor the establishment of reentry in atria1 tissue 

affected by OP. 

* In silica refers to the modeling of living processes on the computer. 

3 
Cardiac tissue is usually modeled as a bidomain, as two interpenetrating 

domains representing the inside and the outside of the cell, separated by a 

membrane through which the current transits from one domain to the other. In 

each of these domains, the potential is described by 

V. DiVei=flm-'si 

and 

(1) 

V . D,Vqbe = -fl,,, -I,, . (2) 

Here, the & and & are intracellular and interstitial potentials, D’s are the 

diffusion tensors, and the /? is the cellular surface to volume ratio. I,,, is the 

membrane current, and Isi and I,, are the current source densities. When the 

diffusion tensors of the two domains are proportional to each other, as was 

assumed here, the bidomain equations simplify to the monodomain model. 

Monodomain calculations are considerably less expensive to perform than 

bidomain calculations. For the calculations reported here, fiber orientation (one 

of the diffusion matrix entries) was assumed to be uniform. 

Two other sets of equations need to be solved: equations describing the gating of 

the ion channels and equations for the concentration changes of the ions. 

Generically, these may be written as follows: 

dyldt = (yc.z - y)lr, , (3) 

where y represents a gating variable and z, the time constant. In addition, the 

ion concentrations had to be followed. For calcium, for example, the equation is 

as follows: 

d[Cu], ldr = -104Z,, + 0.07(104 - [Cali). (4) 

In equation (4), the quantities in the square brackets are the ion concentrations 

and Isi represents the L-type Ca ++ current. Finally, the individual membrane 

currents from experimental measurements are included. No-flux boundary 

conditions were enforced at the edge of the tissue. 

The solution consists of three steps: (1) calculation of the ionic currents, I,,,, (2) the 

determination of the transmembrane potential V,, the difference between the 

intra and the interstitial potentials, and (3) the upgrading of the field potentials. 

In step (3) conjugate-gradient was the solution method used. 

Equal grid size, 0.01 cm in both directions, was used. Some experimentation 

with time step size was required, but 0.001 ms yielded stable results. 
The calculations were carried out with the code CardioWave on the computer 

assets of the Major Shared Resource Center (MSRC) at Aberdeen Proving 

Ground, MD. 

In parallel mode, a typical run on 16 nodes on a SGI Origin 3000 required in 

excess of 7 hr (in non-dedicated mode) for a grid of 300 x 300 to simulate 300-ms 

real time. For a larger number of processors improvement in wall clock time was 

achieved, but the speedup was not absolutely linear, as seen in Figure 1. 

Figure 1. Performance of the code using the shared-memory Origin 3000. 

x i/ 

90 

80 

70 9 ICI 

60 1 

50 w 

4 m 

.'-\\, 

t;i )\ I/ 40 

3 r 30 -l. 2 -i., B--------- r 20 

' y/d ) ----IT : 10 

OO 

I I I I I I I I I I I I- 50 100 0 

Number of Processors 

3. Results 

We report on three computational experiments. 

(1) A pulse of 40 PA/cm* of 2 ms duration, starting at the left edge, propagates 

into the tissue, where it encounters two subregions of higher than normal 

potassium concentration. Each of these subregions was 1 cm* in size. The 

first was located along the central axis, flush with the left-hand boundary. 

The second, of the same size, was located along the lower edge of the 

tissue, 1 cm from the left boundary. 

5 
(2) The second in silica experiment consisted of the same tissue with one region 

of higher potassium concentration along the central axis of the tissue, 1 cm2 

in size, located at the left-hand boundary, aligned normally to the action 

potential advancing from the left-hand boundary. 

(3) Finally, the same field of the action potential used as in (2) was examined, 

but with the iti and i& currents blocked to 99% of its nominal value. This 

was based on the insight that new Class III antiarrhythmic drugs, such as 

Azimilide, are potassium channel antagonists. Modulating these currents 

prolongs the duration of the action potential and the effective refractory 

period. It was felt that this antiarrhythmic characteristic may translate into 

modulating the processes that favor reentry since it is known that this drug 

reduces the incidence of AF and atria1 flutter. 

Figure 2, panels (a-d) show the encounter of the action potential, started at the 

left edge of the atria1 tissue as it encounters a subregion with a potassium 

concentration, double the nominal value. This mimics cardiac toxicity caused by 

the presence of an Or-based substance. 

In Figure 3, the action potential speeds up in the region with the higher than 

normal potassium concentration. The curvature in the action potential wave 

front is accentuated as time progresses. Behind and directly in line with the 

concentration, V, the voltage, continues to drop sharply in contrast to the 

adjacent areas where the drop is more gradual and in line with healthy tissue 

dynamics. 

The front continues to distort, and aft of the heterogeneous region boundary 

undulations in the voltage equipotential lines appear. The front is no longer 

coherent, and the breakup of the integrity of the wave has commenced. 

The second set of computer experiments with multiple regions of higher than 

normal potassium concentrations shows similar evolution of the wave. The time 

history of the action potential at a particular location next to the high potassium 

concentration mirrors the trend toward disorganization in the wave structure, 

signaling eventual breakup. 

In the final Figure 4, the ic and ie currents have been reduced, mimicking the 

effect of antiarrhythmic drug treatment for AF. Lengthening the action potential 

duration (APD) is one of its effects. This effect is also apparent when contrasting 

Figures 3 and 4. The change in behavior is a clear indicator that the search for a 

therapy for OP toxicity needs to be investigated because pharmaceutics that 

modulate the potassium currents prolong APD, thus preventing reentry. 

6 
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Figure 2. Frame sequence showing the evolution of the action potential in atria1 tissue using the 

Nygren model for the electrophysiology of the tissue. The times of the frames going 

clockwise are (a) 25 ms, (b) 60 ms, (c) 140 ms, and (cl) 200 ms. The stimulus consisted 

of a current pulse of 40 @I/ cm2 delivered to the left-most column of atria1 cells. The 

stimulus lasted for 2 ms; VM in the legend is the voltage in mV. 
- ---- 

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Figure 3. The action potential in an atria1 tissue containing a single hyperkalemic, 

cardioplegic subregion. 

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Figure 4. The effect of blocking iKr and i&-currents on the action potential. 

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4. Discussion 

In this study we examined the conditions, in terms of membrane currents, that 

promote atria1 reentry, the precursor of the processes leading to AF. One of the 

underlying assumptions was that OP-induced ACh overload results in patches of 

tissue with [K+]o in excess of normal values. When an action potential encounters 

such a region, processes leading to reentry are commenced. Conditions through 

the modulation of iK currents were sought that could antagonize reentry. This is 

important, since it is believed that the morphology of AF is a progression from 

8 
tachycardia, through the disintegration of spiral waves in the atria1 tissue, to 

fibrillation. 

4.1 OP Toxicity Modeled as Extracellular Potassium Concentration 

Changes in K+ ion movement are central to the expression of OP-induced cardiac 

toxicity. An ancillary aspect is that the accumulation of K+ ions in the interstitial 

space may play an important role in the overall behavior. The reasoning is as 

follows: excessive parasympathetic stimulation results in excessive ACh release. 

ACh binds to MZ muscarinic receptors, activates the G-protein, and contributes to 

the hyperpolarization of the the SA node. When ACh activates iK,Ach, K+ exits the 

cell. The Or-induced ACh overload results in more receptors than usual being 

bound, leading also to an increase in the external concentration of potassium 

ions. 

At high [K+]o in the tissue, similar to the condition of ischemia or during 

&enUOUS exercise, Opening 1eSS than 1% Of iK,ATP channels causes Significant 

shortening of AI’. 

Excessive concentration of potassium ions changes the concentration gradients 

and the response of the Na-K pump. In the initial stages of the accumulation of 

the potassium ions, the cells are more excitable, but as the membrane potential 

drops below the excitation threshold, the generation of an action potential is no 

longer possible. Hyperkalemia suppresses automaticity of the heart, slows 

conduction, and leads to bradycardia. 

4.2 Reentry 

It was shown that the process that can culminate in reentry in atria1 tissue when 

a supra-threshold stimulus 40 @/cm2 was applied, since propagates into an 

Or-modified heterogeneous atria1 tissue. The wave front that resulted was a 

spiral due to the refractory state of the tissue. Reentry is characterized by the 

action potential that instead of transiting and exiting the tissue, reenters 

previously traversed tissue. 

With an ectopic beat present in the tissue, the encounter between the original 

stimulus and the stimulas representing the ectopic event produces a turning 

wave front, a precursor for reentry. 

4.3 Modulation of Reentry in the Atria 

@.I et al. [18] noted in their study of reentry in ventricular tissue that the 

condition for spiral wave breakup, and thus the condition for VF, was reached 

when the slope of the action potential restitution curve exceeded one. Flattening 

the restitution curve can exert an anti-fibrillatory effect. 

9 
In the atria1 tissue studies reported here, ik and iKs currents were modulated. At 

1% of nominal value, considerable modulation of the action potential dynamics 

is observed. The block of the inward current can contribute to APD 

prolongation, especially at shorter cycle lengths. This suggests that Class III 

drugs that prolong APD have the potential for prophylaxis or treatment of 

OP-caused atria1 arrhythmias. 

4.4 Summary 

Computer experiments to simulate reentry in atrial tissue with OF’-induced ACh 

overload were performed. The presence of the OP was modeled as local 

potassium overload. The experiments showed the incipient processes that can 

enhance transition from atria1 tachycardia to atria1 fibrillation. It was 

demonstrated that modulation of membrane current affects changes in the 

process leading to reentry. Possible conditions for the elimination for reentry in 

this tissue model were found. This suggests viable new approaches to preventing 

and treating OP toxicity. Further computer studies and planned in viva 

experiments at the U.S. Army Medical Research Institute of Chemical Defense 

(USAMRICD), Aberdeen Proving Ground, MD, in the near future should help to 

validate this approach. 

10 
5. References 

1. 

2. 

3. 

4. 

5. 

6. 

7. 

8. 

9. 

Baskin, S. I., and M. P. Whitmer. “The Cardiac Toxicology of 

Organophosphorus Agents.” Cardiac Toxicology, edited by S. I. Baskin, Boca 

Raton, FL: CRC Press, 1991. 

Roth, A., I. Zellinger, M. Arad, and J. Atsmon. “Organophosphates and the 

Heart.” Chest, vol. 103, pp. 576-582,1993. 

Hassler, C. R., R. R. Moutvic, D. B. Stacey, and M. P. Hagerty. “Studies of 

the Action of Chemical Agents on the Heart.” AD-A209 219, U.S. Army 

Medical Research and Development Command, Fort Detrick, MD, 1988. 

Burn, J. H., E. M. Vaughn Williams, and J. M. Walker. “Effects of 

Acetylcholine in Heart-Lung Preparations Including the Production of 

Auricular Fibrillation.” Journal of Physiology, vol. 128, pp. 277-293,1955. 

Nahum, L. H., and H. E. Hoff. “Production of Auricular Fibrillation by 

Application of Acetyl-Beta-Methylcholine Chloride to Localized Region of 

the Auricular Surface.” American Journal of Physiology, vol. 129, pp. 428-436 

1940. 

Schuessler, R. B., L. V. Rosenshtraukh, and J. I’. Boineau, et al. “Spontaneous 

Tachyarrhythmias After Cholinergic Suppression in the Isolated Perfused 

Canine Right Atrium.” CircuZution Research, vol. 69, pp. 1075-1087,199l. 

Allessie, M., W. Lammers, J. Smeets, F. Bonke, and J. Hollen. “Total Mapping 

of Atria1 Excitation During Acetylcholine-Induced Atria1 Futter and 

Fibrillation in the Isolated Canine Heart.” Atrial Fibrillation, edited by H. E. 

Kulbertus, J. B. Olsson, and M. Schlepper, Moldal, Sweden, 1982. 

Zoltani, C. K., and S. I. Baskin. “Simulation of Acetylcholine Cardiac 

Overload Caused by Soman, a Cholinesterase Inhibitor.” Proceedings of the 

Computers in Cardiology 2000, vol. 27, IEEE Press, pp. 243-246,200O. 

Falk, R. H. “Atria1 Fibrillation.” Nezu EngZand Journal of Medicine, vol. 344, pp. 

1067-1078,200l. 

10. Allessie, M. A. “Reentrant Mechanisms Underlying Atria1 Fibrillation.” 

Cardiac Electrophysiology: From Cell to Bedside, 2nd ed., edited by D. P. Zipes, 

and J. Jalife, Philadelphia, PA: W. B. Saunders, pp. 562-566,1994. 

11. Scheinman, M. M. “Mechanism of Atria1 Fibrillation: Is a Cure at Hand?” 

Journal American College of Cardiologists, vol. 35, pp. 1687-1692,200O. 

11 
12. Wakimoto, H., C. T. Maguire, P. Kovoor, I’. E. Hammer, J. Gehrmann, J. K. 

Triedman, and C. I. Berul. “Induction of Atrial Tachycardia and Fibrillation 

in the Mouse Heart.” Cardiovascular Research, vol. 50, pp. 463-473,200l. 

13. Moe, G. K., W. C. Rheinboldt, and J. A. Abildskov. “A Computer Model of 

Atria1 Fibrillation.” American Heart Journal, vol. 67, pp. 200-220,1964. 

14. Ramirez, R. J., S. Nattel, and M. Courtemanche. “Mathematical Analysis of 

Canine Atria1 Action Potentials: Rate, Regional Factors, and Electrical 

Remodeling.” American Journal of Physiology, Heart Circulation Physiology, vol. 

279, pp. H1767-H1785,2000. 

15. Lindblad, D. S., C. R. Murphey, J. W. Clark, and W. R. Giles. “A Model of the 

Action Potential and Underlying Membrane Currents in a Rabbit Atria1 Cell.” 

American Journal of Physiology, vol. 271, pp. H1666-H1696,1996. 

16. Nygren, A., C. Fiset, L. Firek, J. W. Clark, D. S. Lindblad, R. B. Clark, and W. 

R. Giles. “Mathematical Model of an Adult Human Atria1 Cell. The Role of 

K+ Currents in Repolarization.” Circulation Research, vol. 82, pp. 63-81,1998. 

17. Koumi, S., C. E. Arentzen, C. L. Backer, and A. Wasserstrom. “Alterations in 

Muscarinic K+ Channel Response to Acetylcholine and to G-Protein-Mediated 

Activation in Atria1 Myocytes Isolated From Failing Human Hearts.” 

Circulation, vol. 90, pp. 2213-2224,1994. 

18. Qu, Z., F. Xie, A. Garfinkel, and J. N. Weiss. “Origin of Spiral Wave Meander 

and Breakup in a Two-Dimensional Cardiac Tissue Model.” Annals of 

BiomedicaZ Engineering, vol. 28, pp. 755-771,200O. 

12 
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WEST POINT NY 109961786 

DIRECTOR 

US ARMY RESEARCH LAB 

AMSRL D 

DR D SMITH 

2800 POWDER MILL RD 

ADELPHI MD 20783-1197 

DIRECTOR 

US ARMY RESEARCH LAB 

AMSRL CI AI R 

2800 POWDER MILL RD 

ADELPHI MD 20783-1197 

3 DIRECTOR 

US ARMY RESEARCH LAB 

AMSRL CI LL 

2800 POWDER MILL RD 

ADELPHI MD 20783-1197 

3 DIRECTOR 

US ARMY RESEARCH LAB 

AMSRL CI IS T 

2800 POWDER MILL RD 

ADELPHT MD 20783-1197 

ABERDEEN PROVING GROUND 

2 DIR USARL 

AMSRL CI LP (BLDG 305) 

13 
NO. OF 

COPIES ORGANIZATION 

ABERDEEN PROVING GROUND 

3 CDR 

USAMRICD 

S BASKIN 

3100 RICKEl-TS PT RD 

APG MD 21010-5400 

10 DIR USARL 

AMSRL CI 

N RADHAKRISHNAN 

AMSRL CI H 

C NIETLJBICZ 

AMSRL CI HC 

AMARK 

M HURLEY 

D SHIRES 

R NAMBURU 

D PRESSEL 

AMSRL WM BC 

J DESPIRITO 

J SAHU 

AMSRL WI BF 

H EDGE 

. 

14 
REPORT DOCUMENTATION PAGE Fom Approved 

OMB No. 0704-0188 

‘ublk mpo~lng burden for thla mlkilon of lnlormatlon Is mlmated to average 1 hour p-sf response, lncludlng the time for revlewlng InstructIons. seanhlng exlstlng data S’~“rcBs, 

,B,herIng md ma,ln(ei”lng tha date needed, and cxS’“pletlng md ravlewlng th.3 ~Ik”c,n 0, Inlormatlon. Ssnd comm”t8 re(larfflng this butden SglmatS OT any 0”~ =P==t Of thk 

olktlon of Infomv,tlon, including suggestIons for nwludng this burden, ,o Washington Heedquarlera Services, Dlr(ytorato lor Info”mtIon O,MatlOnS end Repot’% 1215 Jafkmon 

Csaba K. Zoltani and Steven I. Baskin* 

ARL-TR-2738 

Aberdeen Proving Ground, MD 210055067 

,I. SUPPLEMENTARY NOTES 

* U.S. Army Medical Research Institute of Chemical Defense, 3100 Ricketts Point Road, Aberdeen Proving Ground, 

MD 21010-5400 

l2a. DlSTRlBUTlON/AVAlLABlLlTY STATEMENT 12b. DISTRIBUTION CODE 

\pproved for public release; distribution is unlimited. 

13. ABSTRACT(Maximum 200 words) 

Highly effective treatments for the effect of organophosphonate and organophosphate (OP) nerve agents have eluded 

the medical community. It is known that acetylcholine overload is one of the effects of OP toxicity, but the cellular 

processes leading to cardiac toxicity are still incompletely understood. This study details high performance computer 

simulations of the electrophysiology in atrial toxicity. It shows that hyperkalemia of the tissue, one of the 

manifestations of OP intoxication, promotes the processes leading to reentry, a recursor of atrial fibrillation. Then, 

we demonstrate that changes in two of the potassium membrane currents, i ti and iKs, can modulate the reentry 

process. This suggests that Class III anti-arrhythmic agents that primarily block these currents in the cardiac cells are 

important candidates for therapeutics of OP poisoning. 

14. SUBJECT TERMS 15. NUMBER OF PAGES 

:ardiac toxicity, electrophysiology, cardiac cell modeling, high performance computing, 21 

)arallel simulation, organophosphate poisoning 16. PRICE CODE 

17. SECURITY CLASSIFICATION 18. SECURITY CLASSIFICATION 19. SECURITY CLASSIFICATION 20. LIMITATION OF ABSTRACT 

OF REPORT OF THIS PAGE OF ABSTRACT 

UNCLASSIFIED UNCLASSIFIED UNCLASSIFIED UL 

GN 7540-01-280-5500 Standard Form 298 (Rev. 2-89) 

IS Pmscrihed hv ANSI Std. 239-18 296-l 02 
INTENTIONALLY LEFT mAivK. 

16