An ionic model of stretch-activated and stretch-modulated currents in rabbit ventricular myocytes
Europace (2005) 7, S128eS134
An ionic model of stretch-activated and
stretch-modulated currents in rabbit ventricular
myocytes
Sarah N. Healy, Andrew D. McCulloch*
Department of Bioengineering and the Whitaker Institute for Biomedical Engineering,
University of California, San Diego, CA, USA
Submitted 17 January 2005, and accepted after revision 3 May 2005
KEYWORDS
stretch-activated
channels;
transmural
heterogeneity;
rabbit cardiomyocyte
Abstract Aims To develop an ionic model of stretch-activated and stretchmodulated 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 PuglisieBers 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 (gnsZ10 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 (gnsZ40 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 KC-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.
ª 2005 The European Society of Cardiology. Published by Elsevier Ltd. All rights
reserved.
* Corresponding author. Department of Bioengineering, 9500 Gilman Drive, Mail Code 0412, La Jolla, CA 92093-0412, USA. Tel.: C1
(858) 534 2547; fax: C1 (858) 534 5722.
E-mail address: (A.D. McCulloch).
1099-5129/$30 ª 2005 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.eupc.2005.03.019
An ionic model of stretch-activated and modulated currents in rabbit
Introduction
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 [3e6], 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, noninactivating, cation-selective current, Ins, carried
by KC and NaC. The reversal potential of Ins has
been reported to range from 75 to C10 mV [9],
and the measured conductance ranges from 10 to
200 pS [9]. The inward rectifier KC current IK1 has
S129
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 KC 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 KC selective SAC IKo. Like many cardiac KC 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 nonspecific 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 KC selective SAC IKo from
experimental measurements and investigate the
implications of regional heterogeneity of density
of the IKo current.
Methods
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, noninactivating SAC with a linear currentevoltage
relationship as previously suggested [5]:
Ins Zgns ðVm ðtÞ Vr Þ
where gns is the channel conductance, Vr is the
reversal potential and Vm the time-varying transmembrane potential.
Although IKo has been characterized as an outwardly rectifying KC 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:
Figure 1 Currentevoltage relationship of experimentally measured inwardly rectifying IKo (B) [3] and fitted
curve (solid line).
gKo
IKo Z
m ðtÞÞ
1Cexpð19:05V
29:98
S130
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.
S.N. Healy, A.D. McCulloch
The inward rectifier KC 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 (gnsZ40 pS, VrZ10 mV)
and increased IK1 (150%).
Results
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 t (...truncated)
