© 2005 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.
An ionic model of stretch-activated and stretch-modulated currents in rabbit ventricular myocytes
Department of Bioengineering and the Whitaker Institute for Biomedical Engineering, University of California San Diego, CA, USA
Manuscript submitted 17 January 2005. Accepted after revision 3 May 2005.
*Corresponding author. Department of Bioengineering, 9500 Gilman Drive, Mail Code 0412, La Jolla, CA 92093-0412, USA. Tel.: +1 (858) 534 2547; fax: +1 (858) 534 5722. E-mail address: amcculloch{at}ucsd.edu (A.D. McCulloch).
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Abstract |
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AIMS: To develop an ionic model of stretch-activated and stretch-modulated currents in rabbit ventricular myocytes consistent with experimental observations, that can be used to investigate the role of these currents in intact myocardium.
METHODS AND RESULTS: A non-specific cation-selective stretch-activated current Ins, was incorporated into the Puglisi–Bers ionic model of epicardial, endocardial and midmyocardial ventricular myocytes. Using the model, we predict a reduction in action potential duration at 20% repolarization (APD20) and action potential amplitude, an elevated resting transmembrane potential and either an increase or decrease in APD90, depending on the reversal potential of Ins. A stretch-induced decrease in IK1 (70%), plus a small Ins current (gns=10 pS), results in a reduction in APD20 and increase in APD90, and a reduced safety factor for conduction. Increasing IK1 (150%) plus a large Ins current (gns=40 pS), also leads to a reduction in APD20 and increase in APD90, but with a greater safety factor. Endocardial and midmyocardial cells appear to be the most sensitive to stretch-induced changes in action potential. The addition of the K+-specific stretch-activated current (SAC) IKo results in action potential shortening.
CONCLUSION: Transmural heterogeneity of IKo may reduce repolarization gradients in intact myocardium caused by intrinsic ion channel densities, nonuniform strains and electrotonic effects.
Key Words: stretch-activated channels, transmural heterogeneity, rabbit cardiomyocyte
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Introduction |
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Stretch of the heart can alter the cardiac action potential and its propagation, a phenomenon known as mechanoelectric feedback (MEF). Clinically, an elevated risk of arrhythmias is associated with increased haemodynamic loading of the heart. For example, there are reports of increased incidence of ectopic rhythms and triggered activity due to early afterdepolarizations in patients with pressure/volume overload in hypertension, aortic valve disease, and congestive heart failure [1]
. Ex vivo experimental studies have shown that transient or sustained stretch of cardiac tissue can trigger premature ventricular contractions and ventricular tachyarrhythmias [2]. It is generally thought that the cellular alterations underlying these responses to altered mechanical loading are mediated at least in part by stretch-activated currents (SACs).
Despite many experiments confirming the presence of mechanosensitive channels in cardiomyocytes [3–6], there is a large variation in reports of both their characterization, and their effects on action potential duration (APD) and morphology. APD has been shown both to increase [3,7] and decrease [8] in response to axial strain. The most predominant SAC is an instantly-activating, non-inactivating, cation-selective current, Ins, carried by K+ and Na+. The reversal potential of Ins has been reported to range from –75 to +10 mV [9], and the measured conductance ranges from 10 to 200 pS [9]. The inward rectifier K+ current IK1 has been observed both to increase [3] and decrease [10] in response to different mechanical stimuli.
In addition, previous computational models of MEF have largely ignored regional heterogeneity of channel density. A recently cloned member of the tandem pore family of K+ channels, TREK-1, is highly expressed in the cardiac tissue of rats, and has been shown to carry a mechanosensitive current with similar characteristics to the K+ selective SAC IKo. Like many cardiac K+ channels, such as HERG and KCNQ1, evidence suggests TREK-1 is heterogeneously distributed throughout the left ventricle wall (greater in the endocardium than epicardium) [11].
In this paper, we (1) use a model of a non-specific cation-selective SAC, Ins, and investigate the effects of varying the conductance and reversal potential on the APD and morphology in rabbit epicardial, endocardial and midmyocardial cells; (2) investigate the effects of altered IK1 conductance in the presence of Ins; and (3) obtain an equation for the K+ selective SAC IKo from experimental measurements and investigate the implications of regional heterogeneity of density of the IKo current.
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Methods |
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Rabbit ventricular model
We used the Puglisi-Bers ionic model, which adapts the equations of Luo and Rudy [12]
to the rabbit ventricular myocyte [13,14] and includes all major ion channels, pumps and exchangers that contribute to the action potential. We also included transmural heterogeneity of ion channel density [15] and implemented an instantly activating, non-inactivating SAC with a linear current–voltage relationship as previously suggested [5]
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Although IKo has been characterized as an outwardly rectifying K+ current, it has not yet been modelled. We fitted the experimental data of Isenberg et al. from guinea pig ventricular myocytes to a curve of the same form as IKp (Fig. 1) [3,13,15], resulting in the following equation:
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) 3]where gKo is the channel conductance. The myocyte conductances for IKo were assumed to be proportional to the measured currents of 210 pS (epicardial) and 800 pS (endocardial) [11]
. This is the first ionic model that the authors are aware of that includes a transmurally heterogeneous SAC.
Numerical experiments
Numerical experiments were carried out to investigate the individual and combined effects of the various SACs on the rabbit ventricular action potential under a range of conditions. APD was measured at 20% repolarization (APD20) and at 90% repolarization (APD90). The channel conductance, gns was increased from 0 to 30 pS in 10 pS increments with Vr=–20 mV for all three myocyte subtypes (endocardial, midmyocardial, epicardial) at two pacing frequencies (1 and 3 Hz). The reversal potential, Vr was then varied between –70 and +10 mV at 20 mV intervals with gns=10 pS for the same subtypes and pacing conditions.
The inward rectifier K+ current IK1 was altered in the presence of Ins to a degree that is observed experimentally [3]. IKo was incorporated into a model with the SAC Ins (gns=40 pS, Vr=10 mV) and increased IK1 (150%).
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Results |
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Action potential amplitude and resting Vm is dependent on gns
The inclusion of the SAC Ins, resulted in a reduction in APD20 of all three cell types at both pacing rates (Fig. 2B), which is dependent upon the magnitude of gns and hence the amount of applied stretch. However the effects on APD90 are less clear. At 1 Hz, the model predicts APD90 shortening, but at 3 Hz, very little change to APD90 occurred (Fig. 2A). Changes in resting Vm (Fig. 2C) appeared to be strongly dependent on conductance, with little variation due to rate or myocyte subtype, as did the change in amplitude (Fig. 2D), although, in the latter, there was more variation in the baseline measurements.
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) and endocardial (
) at 1 (dotted line) and 3 (solid line) Hz. The reversal potential is –20 mV.APD90 lengthening or shortening is dependent on reversal potential of Ins
While a decrease in APD20, independent of cell type and pacing rate, was observed for all reversal potentials (Fig. 3B), both lengthening and shortening of APD90 occurred with the addition of Ins (Fig. 3A). In both cases, the tendency for shortening was strongest at lower reversal potentials. However, the alteration to resting Vm was greatest at higher reversal potentials (Fig. 3C). The change in APD90 appeared to depend somewhat on the pacing rate (with larger changes at lower frequencies), and cell type (with endocardial and midmyocardial cells showing a greater sensitivity to stretch, see Figs. 3A and B). The decrease in amplitude seen with stretch does not seem to relate to the reversal potential (Fig. 3D).
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Both increasing and decreasing IK1 can result in a decrease in APD20 and increase in APD90
Decreasing IK1 (70%) plus a small Ins current (gns=10 pS) lead to a decrease in APD20 and increase in APD90 (Fig. 4), and a reduced safety factor for conduction (data not shown). Increasing IK1 (150%) plus a large Ins current (gns=40 pS), also lead to a decrease in APD20 and increase in APD90, particularly in endocardial and midmyocardial cells, but with a much greater safety factor.
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The presence of IKo results in a decrease in APD20 and may decease spatial repolarization gradients in vivo
The SAC IKo is characterized by an outward flow of K+ ions during the action potential plateau (Fig. 1), and, therefore, resulted in a decrease in APD20. When combining the previous conditions in which significant lengthening of APD90 occurred (increased IK1 and Ins), with transmural heterogeneity of IKo density (40 pS on the endocardium, 10 pS on the epicardium), the net result (Fig. 5) may decrease the spatial repolarization gradients through the ventricle wall. The increased presence of IKo on the endocardium may counteract the increased APD prolongation from Ins and altered IK1. As no values were reported for IKo conductance in the midmyocardium, we did not include the subtype in this analysis.
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Discussion |
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Conflicting experimental observations under varying protocols and in different species, combined with the paucity of specific inhibitors, have made the task of elucidating the effects of mechanosensitive currents on cardiomyocyte electrophysiology challenging. The use of mathematical models of whole cells and heterogeneous tissue based on experimental measurements may provide useful insights into the contributions of SACs to MEF in the rabbit ventricle.
The effects of Ins on action potential duration and morphology
While most investigators consistently report decreases in APD20 due to stretch, both increases [3,7,16] and decreases [8] in APD90 have been observed in various experimental preparations. Our model agrees with these data by predicting a reduction in APD20 independent of cell type, pacing rate and reversal potential, and either an increase or a decrease in APD90, depending on the reversal potential. Endocardial and midmyocardial cells appear to be more sensitive to Ins, probably due to intrinsically lower K+ repolarizing currents. Pacing at a slower rate also appeared to increase the APD changes, possible due to an indirect effect on other repolarizing currents. We also predict an experimentally consistant gns-dependent decrease in amplitude and increase in resting Vm [17].
Modulation of the IK1 current via stretch
The ventricular myocyte IK1 current appears to decrease during locally applied axial stretch and either increase or decrease as a result of cell compression [3]. Somewhat paradoxically we show here that similar effects of the action potential can be achieved with a low gns combined with a decrease in IK1, or with a larger gns combined with an increase in IK1. This is due to the competing effects of these two currents during repolarization. The main difference in the two instances is in the safety factor for conduction, with conduction block occurring at a lower level of applied strain when IK1 is reduced.
This may be clinically relevant in instances where repolarization reserve is decreased, such as with gender differences [18], inherited ion channelopathies [19], drugs inhibiting K+ currents [20], remodelling [21], or in cases where the stretch-response is amplified, such as in congestive heart failure and hypertrophy [1]. These individuals may be particularly susceptible to stretch-induced arrhythmias.
Potentially cardioprotective effects of regionally varying IKo
Endocardial and midmyocardial cells are the most vulnerable to the development of calcium-mediated early afterdepolarisations (EADs) [15,22], and our results indicate these cell types are the most affected by the SACs that may further prolong APD. This increases both the likelihood of EAD development and the transmural dispersion of repolarization (TDR), both of which may act as a substrate for reentrant arrhythmia. In addition, the endocardium experiences greater strains than the epicardium [23], potentially resulting in increased repolarization gradients. Endocardial action potentials also tend to prolong due to heterogeneity of electronic loading via wavefront curvature and stimulus effects [24]. We hypothesize that the increased density of the APD shortening current IKo in the endocardium may counteract the regional prolongation due to intrinsic ion channel densities, greater mechanical stimuli and electrotonic effects.
This is particularly important in the case of stretch, because Ins causes a decrease in the gradient of Phase 3 repolarization (as evidenced by APD90 prolongation). This may decrease the antiarrhythmic effects of electrotonic coupling since the strength of coupling depends on the action potential repolarization gradient [25].
Limitations
In this study, we have ignored changes to the intracellular ion concentrations resulting from Ins. Na+ and Ca2+ have both been shown to be elevated in stretched ventricular myocytes in mouse [26], and these species changes are likely directly or indirectly to alter ionic fluxes.
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Conclusions |
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We have developed an ionic model of stretch-activated and stretch-modulated currents in rabbit ventricular myocytes, with a novel formulation for IKo and alterations to IK1, which may be useful for investigating the electrophysiological response to stretch in heterogeneous myocardium.
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Acknowledgements |
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This work was supported by a New Zealand Government Top Achiever Doctoral Fellowship (to S.N.H), the National Biomedical Computation Resource (P41 RR08605) (to A.D.M.), and the National Science Foundation (BES-0096492 (to A.D.M).
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