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Acta Cardiol Sin 2010;26:139-41
Computational Modeling of Inherited
Arrhythmogenic Disorders of the Heart for
Targeted Pharmacotherapy: Introducing an
Emerging Cardiac Electrophysiology
Research Tool
Ruey J. Sung,1 Chu-Pin Lo,2 Pi-Yin Hsiao3 and Hui-Chun Tien2
(RyR2). The Markov model of the I Ca,L channel has a
conducting mode (ModeV) and a non-conducting mode
(ModeCa). ModeV contains four closed states, a single
conducting state, an inactivation state into which channels move fast (IVf) following depolarization and another inactivation state into which channels move slowly
(IVs). ModeCa represents channels that are inactivated
due to Ca2+. Additionally, channels can also move into
another non-conducting Modeq as channels are activated
in the presence of isoproterenol. Transitions among these
states are affected by changes in voltage and Ca2+ concentrations. The ICa,L channel interacts with the Markov
model of ryanodine receptor (RyR2) in restricted ttubular subsarcolemal space for Ca2+ distribution. Intracellular Ca2+ cycling processes include Ca2+ uptake and
release by SR and a buffering system (e.g., calmodulin,
troponin, and calsequestrin).
We simulated various clinical scenarios of TS with
stepwise increase in the percentage of G406R-mutated
Ca v 1.2 channels, which have been shown to suppress
voltage-dependent inactivation of the channel, from 0 to
11.5 and 23%, and to 38.5 and 77%, respectively, for
heterozygous and homozygous states of TS1 and TS2.5
Progressive prolongation of action potential duration
(APD) and QT interval accompanied by amplification of
transmural dispersion of repolarization (TDR) (Figure
1), steepening of APD restitution, induction of delayed
afterdepolariztions (DADs) and both DAD- and phase3-early-afterdepolariztion-mediated triggered activities
correlated well with the extent of G406R Cav1.2 channel
mutation. BAS amplified TDR, steepened APD restitution and facilitated the inducibility of DAD-mediated
triggered activity. Systematic analysis of intracellular
Computational modeling of human diseases is an
emerging field of research interests.1-4 The methodology
applied is absolutely non-invasive, producing no harm to
the patient or animals, and information so obtained is
useful for identifying and/or confirming the underlying
pathogenetic mechanism.
In this communication, we describe how modeling
can recapitulate clinical features of inherited arrhythmogenic disorders of the heart. Taking Timothy syndrome (TS), a malignant form of long QT syndrome referred to as LQT8, in which patients seldom survive beyond three years of age, as an example, modeling was
intended to define the mechanism by which recurrent
ventricular tachyarrhythmias could be provoked by enhanced sympathetic tone (e.g., exertion and/or emotional
distress) and to search for potential targeted sites for
pharmacotherapy beyond beta-adrenergic blockers which
clinically often fail to provide complete protection.5
The study used the latest state-of-the-art Luo-Rudy
guinea pig ventricular myocyte model,1-3,6 which is formulated with various ion channels based on the Hodgkin-Huxley theme and is also incorporated with interacting structure-based Markov models (gating mechanisms)
of the L-type Ca2+ channel (ICa,L) and ryanodine receptor
Received: March 17, 2010
Accepted: May 4, 2010
1
Division of Cardiovascular Medicine, Stanford University School of
Medicine, Stanford, CA, USA; 2Institute of Applied Mathematics,
Providence University, Taichung; 3Institute of Life Sciences, National
Central University, Taoyuan, Taiwan.
Address correspondence and reprint requests to: Dr. Ruey J. Sung,
Institute of Life Sciences, National Central University, No. 300,
Jhonda Road, Jhongli, Taoyuan, Taiwan. Tel: 886-3-422-7151 ext.
65071; Fax: 886-3-422-8482; E-mail: [email protected]
139
Acta Cardiol Sin 2010;26:139-41
Ruey J. Sung et al.
Figure 1. Prolongation of action potentials and the QT interval associated with 23% G406R Cav1.2 mutation. Endo, M, and Epi = simulated
endocardial, mid-myocardial and epicardial myocytes respectively. ECG
= pseudo ECG obtained from 1-D strand model. WT = wild type. Modified from Figure 2 of Am J Physiol Heart Circ Physiol 2010;298:
H33-44 with permission.
Figure 2. Facilitation of induction of DAD-mediated triggered activity
in the 23% G406R Ca v 1.2 mutant. Under the influence of betaadrenergic stimulation (BAS), electrical pacing for 12 stimuli fails to
provoke any arrhythmia in control (the wild type) (not shown) and in
contrast, it provokes DAD-mediated triggered activity. The vertical arrow points to the last paced beat and the diagonal arrows identify those
currents initiated by transient inward currents (Inaca and Insca) in
response to store-overload-induce Ca2+ release (also indicated by a
diagonal arrow in the I rel channel at the bottom). DAD = delayed
after-depolarizations; Irel = Ca2+ release channel of the sarcoplasmic
reticulum (RyR2). Inaca and Insca = currents of the Na/Ca exchanger
and the Ca2+ sensitive nonspecific cation channel, respectively. Modified
from Figure 4 of Am J Physiol Heart Circ Physiol 2010;298:H33-44
with permission.
Ca2+ cycling revealed that SR Ca2+ ATPase (IUP) played
an essential role in BAS-induced facilitation of DADmediated triggered activity (Figure 2) and, in addition to
I Ca,L , it was essential for the facilitation of arrhythmogenesis under the influence of BAS. Thus, G406R
Cav1.2 channel mutation confers not only a trigger but
also a substrate for the development of ventricular arrhythmias which can be exaggerated by BAS. We concluded that, besides beta-adrenergic blockers and ICa,L
channel blockers, an agent aimed at reduction of IUP may
additionally provide antiarrhythmic efficacy in patients
with TS (Figure 3).
Similarly, we are currently applying this modeling
method for other inherited arrhythmogenic disorders
with adrenergically mediated ventricular arrhythmias
such as Andersen-Tawil syndrome (LQT7) 7 and catecholaminergic polymorphic ventricular tachycardia. Preliminary results suggest that, depending on the underlying mechanism, the effective targeted site of antiarrhythmic therapy beyond beta-adrenergic receptors varies
somewhat among these different forms of inherited arrhythmogenic disorders.
We anticipate that the technique of computational
modeling will be an integral part of translational research,
providing direction for basic and clinical investigations.
However, further refinement of the modeling methodology is required so as to enhance its predictive power.8
Acta Cardiol Sin 2010;26:139-41
Figure 3. Reduction of IUP suppress the inducibility of DAD-mediated
triggered activity in the 23% G406R Cav1.2 mutant. Under the influence, pacing for 12 stimuli (the last indicated by a vertical arrow)
readily provokes an onset of DAD-mediated triggered activity (top
panel). Note reduction of IUP by 20% prevents induction of the arrhythmia (lower panel). IUP = Ca2+ uptake channel (SERCA) of the sarcoplasmic reticulum. Modified from Figure 7 of Am J Physiol Heart Circ
Physiol 2010;298:H33-44 with permission.
140
Medical Modeling and Drug Discovery
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Acta Cardiol Sin 2010;26:139-41