CHIN.PHYS.LETT.

Vol. 25, No. 7 (2008) 2706

Suppression of Spiral Waves by Voltage Clamp Techniques in a Conductance-Based Cardiac Tissue Model
YU Lian-Chun(
1 2

)1 , MA Jun(

)2 , ZHANG Guo-Yong(

)1 , CHEN Yong(

)1,3

Institute of Theoretical Physics, Lanzhou University, Lanzhou 730000 Department of Physics, Lanzhou University of Technology, Lanzhou 730050 3 Key Laboratory for Magnetism and Magnetic materials of the Ministry of Education, Lanzhou University, Lanzhou 730000

(Received 19 February 2008)

A new control method is proposed to control the spatio-temporal dynamics in excitable media, which is described by the MorrisLecar cells model. It is conrmed that successful suppression of spiral waves can be obtained by spatially clamping the membrane voltage of the excitable cells. The low voltage clamping induces breakup of spiral waves and the fragments are soon absorbed by low voltage obstacles, whereas the high voltage clamping generates travel waves that annihilate spiral waves through collision with them. However, each method has its shortcomings. Furthermore, a two-step method that combines both low and high voltage clamp techniques is then presented as a possible way of out this predicament.

PACS: 87. 18. Hf, 87. 19. Hh, 05. 45. a, 05. 45. Gg Pattern formation far from equilibrium has been studied extensively in the last years (for a review, see Ref. [1]). Formation of spatial patterns such as spiral waves has been observed in a wide range of physical, chemical, and biological systems, e.g., Rayleigh Benard convection,[2] BelousovZhabotinsky (BZ) reaction,[3,4] and the cardiac muscles.[5] Spiral waves has attracted particular attention due to the fact that spiral waves in cardiac tissue are life threatening. Spiral waves act as high frequency sources of waves that induce tachycardia, an abnormal rapid heart beat that is not controlled by the natural pace maker of heart.[6] These spiral waves, under certain conditions, may become unstable and break up, giving rise to spatiotemporal chaos. This spatial extended chaotic activity causes complete loss of coordination between dierent regions of the heart, leading to rapid death of a heart within minutes unless the condition is terminated promptly.[7] Therefore, suppression of spiral waves and spatiotemporal chaos in excitable media is of much practical interest. Conventional debrillation is carried out by applying large electrical shocks to body surface or directly to cardiac muscle.[8] These large amplitude shocks may damage the cardiac tissue and cause serious pains. Therefore, in both elds of nonlinear science and cardiac physiology, there are growing experimental and theoretical eorts to develop low amplitude debrillation methods and several methods for controlling or suppressing spiral waves have been proposed.[914] Zhang et al. suggested that spiral waves could be killed by generating a target wave via local periodical signal inputting or driving.[1517] Similar method used to suppress spiral wave with travel waves was also proposed.[18] Recently, successful suppression of spiral waves in cardiac tissue by locally paced waves was also experimentally obtained.[19] Actually, the modern electrophysiological techniques like voltage clamp enable one to control the dynamic variables (for example, the transmembrane voltage) of the single cell without changing its biological properties. The spatially extended application of this technique on cardiac tissue would be of great interesting. In this Letter, we explore the feasibility of using voltage clamp technique to eliminate spiral waves in excitable cell media. We use the following equations to simulate cardiac electrical activity,[20] V Iion + I0 + D2 V, = t Cm (1)

where V denotes the transmembrane potential, Cm is the membrane capacitance. Iion is the sum of V and t-dependent currents through the various ionic channel type. I0 is the external stimulus. D is the diusion constant of cardiac tissue. For the specic function form of Iion , we use the ML action potential model, a system of two dierential equations similar to the HodgkinHuxley equations.[21] The model incorporate a V -gated Ca+ channel and a V -gated, delayed-rectier K + channel and a leakage current. The membrane ionic current is given by Iion = gCa m (V )(V VCa ) + g K (V VK ) + gL (V VL ), (2) where gCa , gK and gL are the ion channel conduc tances, respectively. VCa , VK and VL are the corresponding reversal potentials. The fraction of open K +

Supported by the National Natural Science Foundation of China under Grant Nos 10305005, 10747005 and the Fundamental Research Fund for Physics and Mathematic of Lanzhou University. Email: ychen@lzu.edu.cn c 2008 Chinese Physical Society and IOP Publishing Ltd

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channels is given by d = [ (V ) ] (V ). dt (3)

The V -dependent functions m , and are in the following form: m (V ) = 0.5 [1 + tanh{V V1 /V2 }], (V ) = 0.5 [1 + tanh{V V3 /V4 }], (V ) = 1/ cosh{(V V3 )/(2 V4 )}. (4) (5) (6)

membrane voltage of site (i, j) at time t is described by V (i, j, t), 1 i, j 500. The ML model has been extensively studied and characterized with bifurcation theory by Rinzel and Ermentrout.[21] They showed some system parameters to determine whether the excitability of the neuron model is type I or type II. The type I is related to a saddle node bifurcation on an invariant circle and type II an AndronovHopf bifurcation. As show in Fig. 1(a), with the parameters used in this study, for zero input, the nullclines intersect three times. Thus there exist three xed points: A stable xed point (R), a saddle point (T), and an unstable xed point (U). If input is increased, the V-nullcline moves upwards and the stable xed point merges with the saddle point and then disappears. Thus the ML model used in our study exhibits type-I excitability.

Fig. 2. Suppression of spiral wave by spatially extended low voltage clamp. The spatial arrangement of control is for i = 250, j = 1 250, V (i, j) = 65 mV. The snapshots are taken at t = 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000 time units after control is applied, respectively in (a)(h). Fig. 1. (a) Phase plane for the ML model with the parameters used. The solid line corresponds to the Vnullcline (dV /dt = 0) and the dashed line to the -nullcline (d/dt = 0). Nullclines intersect at three places: R: a stable xed point, T: a saddle point, and U: an unstable xed point. (b) The initiation conditions to create a spiral wave with our model. The cells in grey region are at rest. The cells in dark region are clamped to V = 50 mV and in the region lled with lines V = 65 mV. (c) The snapshot of the grown spiral wave at t = 100 ms. (d) A demonstration of the voltage clamp in the two-dimensional tissue. The spatial arrangement of control is, for i, j = 250, 251, V (i, j) = 50 mV, and for i = 350, j = 1 500, V (i, j) = 65 mV.

In the following simulations, we use the parameters V1 = 1.2 mV, V2 = 18 mV, V3 = 12 mV, V4 = 17.4 mV, gCa = 4.4 mS/cm2 , gK = 8.0 mS/cm2 , gL = 2 mS/cm2 , VK = 84 mV, VL = 60 mV, VCa = 120 mV, Cm = 1 F/cm2 , and = 0.03. The numerical simulations are performed in a twodimensional grid of 500500 elements. The numerical algorithm applied is the Euler forward dierence algorithm with no-ux boundary conditions at the edges of the simulation domain. The time step t = 0.02 ms and the diusive coecient D = 2.2 and constant current I0 = 15 A/cm2 . With such arrangement, the

The method to create a spiral wave in our model is shown in Fig. 1(b): the cell membrane voltage in a line from the boundary to the centre are set at a high value (in our case, 50 mV) so to create a travel wave. Meanwhile, at the one neighbouring side and at the tip of the line, the cell membrane voltage are set at the hyperpolarized position (below the resting potential, in our case, 65 mV) so that the travel wave could only propagate in one direction. After the transient, a spiral wave develops with a core in the centre of the simulation domain. Figure 1(c) shows the snapshot of the resulting spiral wave pattern at t = 100 ms. In the following, if not specied, all the control methods are applied at t = 100 ms, thus the pattern in Fig. 1(c) is the spiral wave to be suppressed. The voltage clamp method was rst developed by Cole and Hodgkin et al.[22,23] Its basis is simple: The experimenter decides on a command voltage that the cell should be clamped to. The voltage recorded by the intracellular recording electrode is compared to this command voltage. If these voltages dier, then current is injected into the cell (positive or negative as needed) though another intracellular electrode

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to make the membrane voltage equal the command voltage.[24] This electronic feedback circuit holds the membrane potential at the desired level, even in the face of permeability changes that would suddenly alter the membrane potential (such as those generated during the action potential). In practice, to achieve a spatially uniform potential in small cardiac tissue, a so-called space clamp technique is developed.[24,25] In this contribution, we discuss the possibility of terminating spiral waves by utilizing voltage clamp technique to spatially control membrane voltage of cardiac tissue. In our study, the control scheme is described by { V (i, j, t) if site (i, j) is not clamped, V (i, j, t) = (7) Vcmd otherwise, where Vcmd is the command voltage of the voltage clamp, which is set at 65 mV for low voltage clamp and 50 mV for high voltage clamp. According to the dierent command voltages, the spatially extended voltage clamp in a two-dimensional excitable tissue results in two dierent eects. If the command voltage is low, it will form a obstacle through which no excitable waves could pass because the clamped cell could not be excited and thus excite the neighbouring cells. If the command voltage is high, the clamped cell will excite the neighbouring cells, thus form dierent wave patterns according to the spatial arrangement of the clamp. As seen from Fig. 1(d), locally clamping the cells to a high voltage results target waves. However, those waves are unable to pass the line in which the cells are clamped to low voltage.

This conclusion is also valid in our case. As demonstrated in Fig. 2, when the cells between the boundary and the core of the spiral wave are clamped to low voltage, the spiral wave is broken into several fragments. Those fragments will move towards the boundaries and then disappear, resulting in a resting state of the tissue globally. We see that since voltage clamp is basically a feedback control and the same spatial arrangement of control is used, we obtain the similar results as reported in Ref. [26].

Fig. 4. The more sophisticated spatial arrangement of control to achieve shorter eective control time. The spatial arrangement of control is, V (i, j) = 65 mV, for i = 250, j = 1 500 in (a); i = 125, 250, 375, j = 1 500 in (b); i = 85, 170, 250, 330, 415, j = 1 500 in (c); and in (d), comparing to (c), i = 1 500, j = 150, 350 are added. All snapshots are taken at 1500 time units after control is applied. The eective control time is 78.28 ms for (a), 63.38 ms for (b), 60.90 ms for (c), and 37.78 ms for (d).

To quantitatively describe evolution of the global behaviour of the excitable medium, we introduce the mean membrane potential
N 1 (t) = V (i, j, t), N N i,j =1

(8)

where N = 500, and N N is the total number of the elements in the medium. We record the evolution of in the above process of spiral wave control. As shown in Fig. 3, as the spiral wave is growing, increases. When the spiral wave fully grows up, starts to oscillate. When control is added, as the spiral wave is broken and the fragments move outward, decreases. As soon as the last fragment disappears at the boundary, the hyperpolarization after action potential of the cells makes to achieve its minimum (see the inset in Fig. 3). Then gets back to the resting value. If we dene the time at which the control is applied as tstart and the time when is at its minimum as tend , then we have the eective control time
Fig. 3. Time evolution of in the process that the spiral wave grows up and then suppressed by low voltage clamp method. The spatial arrangement of control is the same as Fig. 2. Inset: enlarged t curve in the region marked by rectangle.

T = tstart tend .

(9)

Many studies on spatially extended control method have suggested that the key point to suppress spiral wave is to kill its tip so that the entire spiral waves could not be developed and maintained from its tip. Furthermore, to completely erase the spiral waves, the moving channel of the spiral waves should be cut.[14,26]

The eective control time for Fig. 2 is 87.12 ms. Actually, more sophisticated spatial arrangements of control could short the eective time needed to eliminate spiral waves. Figure 4 demonstrates the case studied for several spatial arrangement and the corresponding eective control time. It is seen that the key point to reduce the control time with our method is to absorb the fragments with low voltage obstacles instead of the boundary. Obviously, in principle, the eective

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control time could be zero if the low voltage clamp is applied globally.

Fig. 5. Suppression of spiral waves with the two-step method. Step 1: the low voltage clamping is applied so that most of the spiral wave is killed ((a)(c)). For i = 150, 350, j = 1500, and i = 1500, j = 150, 350, V (i, j) = 65 mV. Step 2: the command voltage is partially set to a high value so that the remaining spiral wave is eliminated by travel wave trains ((d)(h)). For i = 150, j = 150350, V (i, j) = 50 mV. The snapshots are taken at t = 500, 1500, 2500, 3500, 5000, 6000, 8000, 10000 time units after control is applied, respectively in (a)(h).

The limitation of low voltage clamp method is obvious. To completely terminate spiral waves, the control must be applied around the spiral tip, but in practice the core of the spiral wave is not always available. Therefore, we propose a two-step method that combines both low voltage and high voltage clamp techniques, with which successful control could be achieved even if the spiral core is not available beforehand. The two-step method is shown in Fig. 5. In the rst step ((a)(c) in Fig. 5), the low voltage clamp is arranged so that the whole tissue is divided into several small areas. As a result, the spiral wave is broken into many fragments. Except for those in the areas in which the spiral-wave tip falls, the fragments are then absorbed by boundaries or low voltage obstacles. From the above discussion we know that if by chance the control is applied to the centre of the spiral wave, the spiral wave will be completely erased. If not, a smaller spiral wave will be sustained in the central area, as shown in Fig. 5(c). Thus, the rst step is a hit-and-miss control. To ensure that the spiral wave could be suppressed without risk at all, we then proceed to the next step, which is to adjust part of the clamped cells command voltage to a high level. Then the resulting travel wave trains move towards both sides. As shown in Figs. 5(d)5(h), the travel wave train gradually invades into the area where the spiral wave remains and nally dominates this area. After removing the control, the whole tissue will be in a resting state. It is seen that this method could greatly reduce the risk of reentrant waves induced by travel wave itself because the possibility of appearance of the inhomogeneities in each area is lower than that in the whole tissue. Note that the travel waves

only take eects in a relatively small area and could not get across the low voltage obstacles. Thus, in the presence of several spiral waves, each could be erased in its own area and there is no interference between travel waves from dierent areas. Therefore, we argue that this method is reliable to suppress spiral waves in cardiac tissue. In summary, we have presented a novel method involving voltage clamp techniques, which is successful in terminating spiral waves in a biologically meaningful model of excitable media. Spatially clamping the cells in the excitable media at low voltage, as have demonstrated, could be eective in eliminating spiral waves. Though there are still diculties for applications of spatially extended voltage clamp clinically, our work shows the potential perspective of this technique in termination of cardiac arrhythmias. Our method, along with other approaches, though currently has practical limitations, may oer hope that low amplitude control techniques will be clinically useful in the coming years. Further work should focus on suppression spiral waves in more sophisticated models (for example, the LuoRudy model[27] ) and on the suppression of spatiotemporal chaos with the method we present here.

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