Computer Study of the Ionic Mechanisms of 

Organophosphorous-Caused Long-QT Syndrome (LQTS) 

by Csaba K. Zoltani and Steven I. Baskin 

ARL-TR-2902 February 2003 

Approved for public release; distribution is unlimited. 
NOTICES 

Disclaimers 

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-2902 February 2003 

Computer Study of the Ionic Mechanisms of 

Organophosphorous-Caused Long-QT Syndrome (LQTS) 

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. 
i

Acknowledgments 

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

available and giving expert advice on its use. 
ii

Contents 

Acknowledgments i

List of Figures iii

List of Tables iv

1. Introduction 1

2. Methods and Materials 4

2.1 The OP-Affected Tissue Characterization ......................................................................4 

2.2 The Simulation Setup ......................................................................................................5

3. Simulation 6

4. Results 8

5. Discussion 13

6. References 19

Report Documentation Page 21
iii

List of Figures 

Figure 1. The baseline behavior (lower trace) of the ventricular action potential contrasted 

with the reduction in potassium channel conductivity to 10% of control (upper trace). 

Data points were included for emphasis of the lengthening of the cycle. .................................9 

Figure 2. Action potential of the ventricular tissue at various values of the potassium channel 

conductivity. The baseline is the lowest curve and proceeding upward, the corresponding 

curves are at 80%, 60%, and 40% values of the conductivity. The cycle lengthening is 

apparent....................................................................................................................................10 

Figure 3. The effect of lowering both the gK and the gK1 conductivity to 60% (lower curve) 

and 40% (upper curve). Significantly, the reduction to 40% results in the action potential 

unlikely returning to the rest state, thus there is a cessation of electrical activity of the 

ventricle....................................................................................................................................11 

Figure 4. With a 40% value of the gK1 and gK, the action potential does not return to the 

resting state. This data gives an appearance of TdP activity. .................................................12 

Figure 5. The effect of the calcium overload (twice normal, typical of OP-caused condition) 

while the potassium channel conductivity is lowered to 60% (lower) and 40% (upper) 

curve. In the latter case, the ventricle ceases to function.........................................................13 

Figure 6. The effect of lowering the background current (lower trace) and increasing the 

inward Ca++ ion flow (upper trace) on action potential configuration....................................14 

Figure 7. With high background current (Na+ and Ca++), the action potential does not reach 

the overshoot domain. The second stimulus, of the same magnitude, has a considerably 

shortened cycle length. The baseline action potential (top trace) is shown in green..............15 

Figure 8. The effect of the interaction of two waves running perpendicularly, with the 

second started at 425 ms. .........................................................................................................16 

Figure 9. A three-dimensional plot of the action potential at t = 500 ms showing the 

development of the reentry. .....................................................................................................17 

Figure 10. Estimated dose-response curve based on the effect of the lengthening of the cycle 

due to the presence of the OP in the virtual tissue...................................................................18 
iv

List of Tables 

Table 1. OP-caused ECG changes. .................................................................................................2 

Table 2. Effects of OPs on cardiac tissue. ......................................................................................3 

Table 3. Parameters for simulation of the effect of OP toxicity. ....................................................6 

Table 4. Simulation parameters. .....................................................................................................7 

Table 5. Wall-clock time required on the SGI Origin 3000 server for a 300 H 300 node 

calculation..................................................................................................................................8 
1

1. Introduction

Organophosphorous (OP) compounds, ingredients in insecticides and military nerve agents, 

cause repolarization abnormalities of the ventricles, a precursor to the often fatal cardiac 

arrhythmia. 

OP in the cardium is expressed by an overload of acetylcholine (ACh), lesions in the tissue and 

blockage of the second messenger system, the vasoactive intestinal peptide (VIP), and a peptide 

instrumental in increasing the heart rate. The ACh overload results from the OP binding to 

acetylcholinesterase (AChE) preventing the hydrolysis of ACh. But knockout murine 

experiments [1] as well as data from India [2] on insecticide production workers have shown that 

OPs can cause cardiac toxicity even in tissue that is devoid of or very low in concentration of 

AChE. This suggests that a complete description of OP poisoning requires the consideration of 

effects in addition to ACh overload. Tables 1 and 2 summarize the most important effects of OP 

expressed in the heart [3–8]. 

Kiss and Fazekas [3], Ludomirsky et al. [4], and Bar-Meir et al. [5] discuss clinical cases of 

OP-affected individuals that often progress from atrial bradycardia, at the onset of the poisoning, 

to Torsade de Pointes (TdP) that may culminate in ventricular fibrillation (VF) and sudden 

cardiac death (SCD). With OPs, there can be a delay of up to 2 weeks, also called the 

intermediate stage, before the VF manifests itself. 

Changes in the electrocardiogram (ECG) provide important clues to the changes caused in the 

electrophysiology by the presence of OPs (Table 1). Of special significance is the lengthening of 

the LQT segment and the changes in the T-wave, which often becomes pointed with the 

maximum voltage considerably elevated. Of special significance is the elongation of the LQT 

since it is an indicator and predictor of ventricular fibrillation. Both the T-wave and the LQT 

portion of the electrocardiogram are expressions of repolarization, thus changes in these reflect 

repolarization anomalies. Repolarization is primarily determined by and controlled through 

several potassium and calcium currents. Changes in these currents have a profound effect on the 

cardiac cycle because the action potential is changed. 

Table 2 summarizes the most important changes in the membrane currents in the presence of OP 

deposition. The three main effects are (1) the changes caused by the OP binding to the AChE, 

(2) the consequence of the lesions within the tissue, and (3) the blocking of the second 

messenger, the most important of which is the VIP. 

According to several investigators [3–5], ~85% of OP-affected individuals exhibit the Long-QT 

Syndrome (LQTS) [9–11], which is a lengthening of the time needed for repolarization of the 
2

Table 1. OP-caused ECG changes. 

QRS Complex QTLengthening ST 

Elevation/Depression 

T-wave P-wave Miscellaneous 

Activation of 

both ventricles, 

120 ms 

<440–460 ms ST-T wave 

ventricular recovery 

 Activation of 

atria <120 ms, 

PR-duration of 

AV conduction 

120–200 ms 

Prolonged Prolongedrepolarization 

disorder 

Ischemia/infarction Inversion Extracellular 

hyperkalemia 

reduces wave 

amplitude 

BP modulation 

Hyperkalemia IKr ↓↓ Hyperkalemia 

produces ST 

elevation 

Disappearance Reduces atrial, 

ventricular 

resting 

membrane 

potentials 

Sinus 

bradycardia 

(20–30 bpm) 

IKs ↓ Narrow peaked Ventricular 

tachycardia 

Torsade de 

Pointes (TdP) 

 Hypocalcemia Changes 

caused by 

alterations in 

duration of 

ventricular, 

atrial action 

potentials 

 Atrial 

fibrillation, 

AV block 

 Hyperkalemia 

shortens QT 

interval 

 Altered 

ventricular 

activation 

 Ventricular 

fibrillation 

 Changes in 

primary center 

of ventricular 

automation 
3

Table 2. Effects of OPs on cardiac tissue. 

Bound to AChE Lesions S

Acidosis Anoxia 

Modulated 

Ion Concentration 

Release of 

Catecholamines 

ACh overload causes bradycardia, slows conduction in AV 

(Intracellular proton 

accumulation), pH 

↓ , 

Na+/H+ exchange 

↑

Lowers ATP, cAMP, 

cGMP, ATPase inhibition 

Prolongs AP, [Na+] ↑ , 

Na+ - K+ ATPase antagonized 

Adact

Prevents hydrolysis [ATP] 

↓ IK(ATP) 

↑ (activated), 

[K+

]o ↑

Effect on velocity of propagation, inexcitability DAD enhanced If ↑

[Ca++] ↑

→ IKACh ↑ [K+

]o ↑, reduces IKr by 

increasing rate of deactivation, shifts voltage dependence of activation to more positive potentials 

AP shortened Difference for 

α, β

receptors 

OP Ca

adestim

affDA

Antagonizes adenylyl cyclase 

gK ↑Cytoplasmic [Ca++]↑

slows repolarization, reduces max diastolic 

potential 

[Na+] ↑

Na+/K+ pump inhibition Na+/Ca++ exchanger 

→

Ca++ influx 

[Ca++] ↑

Na+/Ca++ exchanger 

↓

reduced SR uptake 

[Mg++] ↑

(hydrolysis of ATP), activates enzymes Reduces ICa(L) , IK1 , 

IKACh, IKATP , IKs

Adrenergic 

α

stimulation: reperfusion arrhythmia (Ca++

overload), gap junction conductance 

↓ , 

exchanger stimulation, activates Na+/K+ pump 

Arrests cAMP synthesis 

ICa(L) 

↓

Depresses If

(pacemaker current) 

INa 

↓ (inactivation of fast 

Na+ channel) 

 Decreased excitability ACh inhibits adenylate cyclase 

CO2 accumulation 

Adrenergic βstimulation: stimulates adenylate cyclase, elevate cAMP, increase Ca++ influx, If activation, triggered activity improves modal conduction 

Intermediate Stage 

AF, VF 

Notes: g = conductivity of the tissue; [..] = concentration; I(.) = ionic current with the subscript denoting the channel type; 

↑ d

↓ denotes a decrease; 

→ means yields. 
4

ventricle. This condition has also been tied to mutations in several genes, including HERG, 

encoding ion channels, and can also be induced by medication (acquired LQTS). The result is 

modulated ion flow, an inflow of excess sodium, accumulation of calcium in the sarcoplasmic 

reticulum and reduced potassium outflow. The calcium ion distributions within the cells are also 

altered. A delayed influx of Ca++ ions suggested Ca/K exchange and contributes to early after 

depolarization (EAD), thought to trigger ventricular arrhythmias. 

Animal models and experimental data show that in OP-caused poisoning the slope of the onset of 

the depolarization, governed by the flux of the Na+

 ions, is changed. In addition, modulation of 

the potassium currents, iKr and iKs are observed. Plateau current imbalance and a blockage of the 

ion channel responsible for these currents are thought to be present. Under these circumstances, 

a prolongation of the repolarization time of the ventricles results. A repolarization lengthening 

by a few percent is an indicator of a precursor to arrhythmogenicity. Action potential duration 

(APD) lengthening enables EADs triggering focal arrhythmia. 

Zeng et al. [12], working with guinea pig ventricular myocytes, found that iKs is the major 

plateau repolarization current and that a block of either IKr or IKs results in abnormal 

repolarization. Viswanathan et al. [13] showed that the effect of the heterogeneity of IKs and IKr 

has a profound influence on action potential duration and may influence arrhythmogenesis. 

Differences in cardiac cell types contribute to this heterogeneity. Liu and Antzelevitch [14] 

found that smaller IKs prolong the action potential of the midmyocardial myocytes. 

The following sections describe a computer study of the effect of OP on the electrophysiology of 

ventricular tissue, especially the processes that favor LQTS, which subsequently may culminate 

in VF. Separately, this study does not address the effect of acidosis or hypoxia. Changes in the 

activation of muscarinic receptors are thought to be secondary to the ACh overload. In the atria, 

ACh overload can be associated with muscarinic responses. While in the ventricle, it may be 

directly coupled to K+

 ion conductance. The approach adopted is to modulate the conductivities 

of channels and regional ion concentrations affected by OP. The resulting change in current flow 

is reflected in the changed action potential dynamics. 

2. Methods and Materials 

2.1 The OP-Affected Tissue Characterization 

Histopathological examination of cardiac tissue shows that OPs produce lesions reminiscent of 

ischemia. In terms of the effect on membrane electrophysiology, this translates into elevated and 

heterogeneous accumulation of potassium and the development of acidosis [15]. The major 

effect of acidosis is calcium overload of the sarcoplasmic reticulum, which may lead to 
5

spontaneous action potential generation anywhere within the heart. In addition, very small 

changes in pH can substantially affect the strength of the contraction of the heart. The pH in the 

tissue, both intra- and extracellularly, drops linearly about 1 pH below the normal value of ~7.1. 

There is a significant reduction in the sodium current, INa, and a decrease in the resting 

membrane potential. ICa(L) decreases in tandem due to a change in the channel conductance. The 

decrease in conductance, at pH = 6.6, has been estimated as 50%. The inward rectifier potassium 

current, IK1 increases due to an elevation in the [K]o. Sympathetic nerve catecholamine release 

also leads to elevated norepinephrine release. 

As a consequence of anoxia, ATP declines, between 40% and 60% in value, and IK(ATP) channels 

open up and contribute to the repolarization current. IK(ATP) is inactive in healthy tissue. These 

changes are accompanied by a decline in the membrane excitability, the maximum value of the 

membrane voltage with respect to time. Its value is ~400 V/s but declines to about 100 V/s at 

[K+]o = 12 mM. In addition, increases in Na+ and Ca++ uptake take place. 

There are indications that OP also blocks the second messenger route that involves the VIP [16]. 

This peptide is abundantly present in cardiac tissue and works as agonist of adenylate cyclase. 

OP block of VIP antagonizes bradycardia, one of the initial manifestations of OP-intoxication. 

2.2 The Simulation Setup 

The dynamics and integrity of the action potential propagation in OP-affected ventricular tissue, 

whose normal electrophysiological behavior is described by the Luo-Rudy model [17], was 

simulated with the modifications noted in Table 3. The simulated tissue, 3 H 3 cm in size, was 

represented as a slab of 300 H 300 H 1 nodes. A stimulus was applied to the left-hand edge 

consisting of a pulse of 200 μA/cm2 of 2 ms in duration. The presence of OPs was modeled in 

the tissue varying the conductivity of selected ion channels. A possible cause is the blocking of 

the channels by a ligand. It should be noted that in an intoxicated tissue, OP is heterogeneously 

distributed in the heart and that hyperkalemia is one manifestation of OP toxicity. This is coarse 

graining the problem since localized sodium and calcium concentration deviations due to OP 

presence are also indicators of the change of the state of the cell. In addition to modulating the 

potassium current, OP-caused lesions in the tissue were modeled by including the effect of 

anoxia, simulated by modulation of calcium conductivity, and acidosis by a 25% reduction of the 

conductivity of the calcium and potassium channels, Table 3. Pacing was used to ensure stable 

initial conditions. 

Initially, a baseline calculation, using the parameters of Table 4, was performed. The ion 

concentrations were those of a normal tissue. In succeeding runs, to simulate the effect of OP 

toxicity, the parameters shown in Table 3 were varied. 
6

Table 3. Parameters for simulation of the effect of OP toxicity. 

Parameter Change from Luo and Rudy [17] Noted 

Computer Experiment No. 1 Computer Experiment No. 2 

gNa ↓

gK ↓

gCa ↑

gb (reformulated in Luo and Rudy [17]) ↓

[K+]i ↑

[Ca++]i ↑

3. Simulation 

The model of the ventricular action potential used in these calculations is the Luo-Rudy model 

[17] extending the earlier Beeler-Reuter formulation using guinea pig experimental data. The 

version adopted here simplifies the model in that the potassium currents are not split into fast and 

slow components but the earlier composite version is used. Intracellular calcium processes were 

not tracked in these calculations, but the overall calcium level, which has an effect on the resting 

voltage, was modulated. Assuming the cardiac tissue to be a continuum, the action potential was 

tracked through the domain according to the cable equation, a second-order partial differential 

equation. It relates the temporal change in membrane voltage V to the spatial change and the Iion, 

the transmembrane ionic current, describing the sodium, potassium, calcium and chloride 

currents, pumps, and exchangers. D is the diffusion constant and Cm the membrane capacitance. 

A value of 1 cm2/s was used for D and 1μF/cm2 for the capacitance. In the calculations fiber 

orientation (one of the diffusion matrix entries) was assumed to be uniform. Additional 

equations describe the gating variables of the ionic channels and the change of the ion 

concentrations. No flux boundary conditions were used. 

The calculations were carried out with the code CardioWave on the computer assets of the Major 

Shared Resource Center at Aberdeen Proving Ground, MD. 
7

Table 4. Simulation parameters. 

 Present Study Remarks 

Conductivity (mS/F) 

gNa (sodium channel) 16.0 

gK (potassium channel) 0.282([K+]o/5.4)0.5 function of [K+]o

gK1 (time indep potassium channel) 0.75 

gkp (plateau) 0.00552 Zeng et al. [12] 

gCa (calcium channel) 0.09 

gb (background) 0.04 (formerly) no longer used in Luo and Rudy [17]) 

Reversal potential (mV) 

ENa 54.4 

EK !77.0 

EK1 !87.26 

Eb !59.87 

ECa(L) ~ln[Ca++]i 

Gating parameters 

m 0.0008 changed from original formulation 

h 0.9937 

j 0.9957 

d 0.00000321 changed from original formulation 

f 0.99998 

x 0.029838 
8

In parallel mode, a typical calculation on 16 nodes of the SGI Origin 3000∗ server, with 

300-MHz IP27 processors and data cache size of 32 Kb, required 7 hr and 15 min nondedicated 

time. This time was improved with a larger number of processors, but the speedup was not linear 

(Table 5). 

Table 5. Wall-clock time required on the SGI Origin 3000 

server for a 300 H 300 node calculation. 

Number of Processors Nondedicated Wall Clock Time

16 7 hr 15 min 

32 4 hr 11 min 

64 2 hr 8 min 

4. Results 

The effect of the presence of OP in the cardiac tissue was simulated by modulating channel 

conductivities and ion concentrations. The action potential data, unless noted otherwise, is from 

a location, picked at random, located at 0.02 cm horizontally and 0.05 cm longitudinally from the 

left edge of the tissue. For the parameters used, the baseline cycle length was 400 ms, and the 

conduction velocity was 60 cm/s. The plateau, representing the repolarization, extended from 50 

to 300 ms, followed by a steep decline to the resting voltage of !84.0 mV. 

Figure 1 shows the effect of changing the potassium channel conductivities to one-tenth the 

normal value. The action potential shows considerable cycle lengthening when contrasted with 

the baseline. At 500 ms, the voltage is !18 mV, still far from the resting value. The slope of the 

action potential curve indicates that considerable time will elapse before the voltage drops to the 

initial state. The effect on the action potential of the reduction in conductivity of the potassium 

ion channels is shown in Figure 2. The lower trace is the baseline, and proceeding vertically, the 

curves represent 80%, 60%, and 40% values of the baseline channel conductivity. Already a 

20% reduction in conductivity lengthens the cycle by close to 10%. At 40% a 100 ms increase in

 ∗

 SGI Origin 3000 is a registered trademark of Silicon Graphics, Inc. 
9

Figure 1. The baseline behavior (lower trace) of the ventricular action potential contrasted with the reduction in 

potassium channel conductivity to 10% of control (upper trace). Data points were included for emphasis 

of the lengthening of the cycle. 

the cycle length is noted. At 60% more than doubling occurs. There is also an 8% decline in the 

slope of the depolarization when the potassium channel conductivity is lowered to 10% of 

baseline. Figure 3 shows that when both gK and gK1 conductivities are reduced by 60%, the cycle 

length becomes indeterminate. A calculation extended to 1000 ms shows that the voltage 

oscillates in the negative voltage range and does not return to the resting state (Figure 4). This 

behavior mimics Tdp, a precursor to VF. 

Increasing the Ca/K exchange current by doubling the channel conductivity more than doubled 

the peak of the potential voltage and extended the cycle time by several hundred milliseconds. 

When the background conductivity was doubled, the action potential oscillated in the negative 

voltage range, reaching only !20.0 mV (Figure 5). Cycle lengthening (not shown) was also 

observed when the gK1 was lowered to 0.1; indeed, a 25% increase was noted. 
10

Figure 2. Action potential of the ventricular tissue at various values of the potassium channel conductivity. The 

baseline is the lowest curve and proceeding upward, the corresponding curves are at 80%, 60%, and 40% 

values of the conductivity. The cycle lengthening is apparent. 

The effect of lowering the background current is shown in Figure 6. The cycle length increase to 

480 ms (an increase of ~37%). Separately increasing the inward calcium flow (upper trace) 

results in an indeterminate lengthening of the cycle length, a probable shutdown of the heart. 

Decreasing the background current by adjusting the conductivity to one-tenth the normal value 

had two effects: the maximum value of the depolarized voltage approached 50.0 mV, and the 

cycle lengthened to 500 ms. The repolarization plateau showed a gradual decline, with a 

precipitous drop from !25.0 to !84.0 mV commencing at 450 ms into the cycle. 

Figure 6 reinforces the observation that a calcium overload, twice the normal concentration and 

typical of OP-caused condition, in this case in tandem with potassium channel conductivity 

reduction, considerably expands cycle length, and probably shuts down the heart. 
11

Figure 3. The effect of lowering both the gK and the gK1 conductivity to 60% (lower curve) and 40% (upper curve). 

Significantly, the reduction to 40% results in the action potential unlikely returning to the rest state, thus 

there is a cessation of electrical activity of the ventricle. 

With anomalously increase Na+ and Ca++ concentrations and thus background current, the action 

potential stays in the negative domain, as shown in Figure 7. The second stimulus, of the same 

magnitude as the first one, has a considerably shortened cycle length and plateau. The potassium 

current that is fully activated at +10 mV has been affected. Here the effect of the increased 

sodium ions seems to outweigh the effect of the calcium ions that is known to enhance the 

potassium current in a dose-dependent fashion [18]. 

Reentry arrhythmia was observed when a second stimulus, perpendicular to the initial one, was 

launched at 425 ms (Figures 8 and 9). It should be noted that the second wave propagated 

transversally much faster in portions of the tissue that had longer to recover. The characteristic 

spiral presaging reentry was observed at the head of the wave front. 
12

Figure 4. With a 40% value of the gK1 and gK, the action potential does not return to the resting state. This data 

gives an appearance of TdP activity. 

We propose an estimated dose-response curve (Figure 10) based on the observation that the 

probability of the onset of fibrillation is directly related to, though not exclusively dependent 

upon, the flow of potassium ions, i.e., the conductivity of the channel. The OP-caused reduction 

of the conductivity is reflected in the prolongation of the repolarization. A prolongation of 10% 

of QT of the ECG is a predictor of fibrillation, thus the corresponding channel conductivity is 

related to the lethal dosage. Analogously, the estimated onset of TdP and tachycardia correspond 

to lesser conductivity changes, i.e., cycle prolongation.
13

Figure 5. The effect of the calcium overload (twice normal, typical of OP-caused condition) while the potassium 

channel conductivity is lowered to 60% (lower) and 40% (upper) curve. In the latter case, the ventricle 

ceases to function. 

5. Discussion 

Animal experimental data show that OP intoxication results in lesions of the cardiac tissue, 

acidosis, and anoxia. These effects in terms of the membrane currents can be expressed and 

simulated by ion channel conductivity changes. Potassium conductivity changes, which can be 

caused by ligand blocking the channel, are major contributors to increased cycle length and, 

consequently, LQTS. Modulating the channels that are affected by OP, LQTS can be simulated. 

It is clear that LQTS is a precursor to reentry and the onset of fibrillation. 
14

Figure 6. The effect of lowering the background current (lower trace) and increasing the inward Ca++ ion flow 

(upper trace) on action potential configuration. 

OP-intoxication of cardiac tissue produces modulation of ionic membrane currents that in turn 

affects the action potential. Using high performance computer experiments, variation in ion 

channel conductivities were used to gauge the effect on the magnitudes of membrane currents 

and the action potential. Emphasis was placed on processes thought to influence LQT, a 

precursor to VF and SCD. Acquired LQTS is characterized by prolongation of the repolarization 

period that may be the precursor to processes leading to sudden cardiac death. 

Reduction of the repolarization currents mimics the genetically caused loss of function in 

congenital LQT. Reduction in the conductivity of the potassium channels (reduced channel 

density) or an inactivation of the sodium gate allowing a persistent late current of only 0.1% of 

peak, prolongs the APD and mimics LQT3, a defect in the sodium channel. 
15

Figure 7. With high background current (Na+ and Ca++), the action potential does not reach the overshoot domain. 

The second stimulus, of the same magnitude, has a considerably shortened cycle length. The baseline 

action potential (top trace) is shown in green. 

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

tissue with [K+

]0 in excess of normal values. When an action potential encounters such a region, 

reentry can occur. Conditions were sought by modulation of membrane currents that could block 

reentry. This is important, since it is believed that the morphology of VF is a progression from 

tachycardia, through the breakup of spiral waves in the tissue, to fibrillation. 

There is considerable uncertainty on the ion channel conductivity values that are species specific 

and variable even within the same organ. In interpreting the results, the emphasis is on the 

trends and not on absolute values. 
16

Figure 8. The effect of the interaction of two waves running perpendicularly, with the second 

started at 425 ms. 

These simulations reproduced a number of the observed AP changes in vivo and provide insights 

to the requirements on the properties of antidotes for OP poisoning. 

These calculations suggest that, in addition to the blocking of ACh, the OP ligand interferes with 

the ion channels, changing the magnitude of currents. In addition, the results demonstrate that 

modulation of membrane currents, by blocking some of the potassium channels, favors processes 

leading to reentry. K+

, that is IK(ATP) channel openers such as nicorandil, shorten the QT interval 

and APD, and suppress EAD and thus TdP. Further research is still needed along these lines 

though since K+

 channel openers lower the blood pressure and may be arrhythmogenic. 

Potassium infusion [19] has been shown to abbreviate the QT interval in LQT2 patients with an 

IKr defect. 

Based on the insights from these computer experiments, the challenge for devising therapeutics 

for force protection is to formulate an antidote that acts as a channel opener by increasing 

potassium currents, lowers calcium accumulation within the cell, reverses acidosis, i.e., H+

overload, and also affects the rate of flow of sodium ions. We have made suggestions that meet 

these criteria. 
17

Figure 9. A three-dimensional plot of the action potential at t = 500 ms showing the development of the reentry. 
18

Figure 10. Estimated dose-response curve based on the effect of the lengthening of the cycle due to the presence of 

the OP in the virtual tissue. 
19

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21

Report Documentation Page Form Approved 

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PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. 

1. REPORT DATE (DD-MM-YYYY)

February 2003 

2. REPORT TYPE 

Final 

3. DATES COVERED (From - To) 

April–September 2002 

5a. CONTRACT NUMBER 

5b. GRANT NUMBER 

4. TITLE AND SUBTITLE 

Computer Study of the Ionic Mechanisms of Organophosphorous-Caused Long-QT 

Syndrome (LQTS)

5c. PROGRAM ELEMENT NUMBER 

5d. PROJECT NUMBER 

2U5/NC 

5e. TASK NUMBER 

6. AUTHOR(S) 

Csaba K. Zoltani and Steven I. Baskin*

5f. WORK UNIT NUMBER 

7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 

U.S. Army Research Laboratory 

ATTN: AMSRL-CI-HC 

Aberdeen Proving Ground, MD 21005-5067

8. PERFORMING ORGANIZATION 

 REPORT NUMBER 

ARL-TR-2902 

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Approved for public release; distribution is unlimited.

13. SUPPLEMENTARY NOTES 

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

21010-5400 

14. ABSTRACT 

An important clinical marker of organophosphorous (OP)-caused cardiac toxicity is long-QT syndrome, the prolongation of the 

repolarization period in the ventricles, as measured in an electrocardiogram. The primary membrane currents responsible for 

this condition are two potassium currents, IKr and IKs. This computer simulation investigated the effect of the modulation of the 

membrane currents most likely affected by the OP on the action potential in a two-dimensional slab of cardiac tissue. We have 

shown that modulation and reduction of the potassium currents, changes in the background current, and calcium overload of the 

cells mimic the experimentally observed change in slope of the depolarization in the presence of OPs as well as the prolongation 

and change in the shape of the plot of repolarization voltage vs. time. These changes are precursors to the onset of Torsade de 

Pointes and ventricular fibrillation and suggest the required pharmacology of antidotes for force protection. Based on these 

results, an estimated dose-response curve is presented.

15. SUBJECT TERMS

high performance computing, cardiac toxicity, organophosphorous 

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19a. NAME OF RESPONSIBLE PERSON

Csaba K. Zoltani 

a. REPORT 

UNCLASSIFIED 

b. ABSTRACT 

UNCLASSIFIED

c. THIS PAGE 

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UL 

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28 

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(410) 278-6650 

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 THE UNIV OF TEXAS AT AUSTIN 

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COPIES ORGANIZATION

2

ABERDEEN PROVING GROUND

 5 CDR USAMRICD 

 S I BASKIN 

 3100 RICKETTS POINT RD 

 APG MD 21010-5400 

 8 DIR USARL 

 AMSRL CI 

 N RADHAKRISHNAN 

 AMSRL CI H 

 C NIETUBICZ 

 AMSRL CI HC 

 A MARK 

 C K ZOLTANI (5 CPS)