Mathematical Biosciences 334 (2021) 108567

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Mathematical Biosciences
journal homepage: www.elsevier.com/locate/mbs

Review
Evolution of mathematical models of cardiomyocyte electrophysiology
Bogdan Amuzescu a,b ,∗, Razvan Airini a,b , Florin Bogdan Epureanu a,b , Stefan A. Mann c ,
Thomas Knott d , Beatrice Mihaela Radu a,b
a
Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, 91–95 Splaiul
Independentei, Bucharest 050095, Romania
b
Life, Environmental and Earth Sciences Division, Research Institute of the University of Bucharest (ICUB), 91–95 Splaiul
Independentei, Bucharest 050095, Romania
c Cytocentrics Bioscience GmbH, Nattermannallee 1, 50829 Cologne, Germany
d CytoBioScience Inc., 3463 Magic Drive, San Antonio, TX 78229, USA

ARTICLE INFO ABSTRACT

MSC: Advanced computational techniques and mathematical modeling have become more and more important to the
92-08 study of cardiac electrophysiology. In this review, we provide a brief history of the evolution of cardiomyocyte
92C30 electrophysiology models and highlight some of the most important ones that had a major impact on our
92C37
understanding of the electrical activity of the myocardium and associated transmembrane ion fluxes in normal
92C40
and pathological states. We also present the use of these models in the study of various arrhythmogenesis
92C42
92C45
mechanisms, particularly the integration of experimental pharmacology data into advanced humanized models
for in silico proarrhythmogenic risk prediction as an essential component of the Comprehensive in vitro
Keywords:
Proarrhythmia Assay (CiPA) drug safety paradigm.
Cardiac action potential
Cardiomyocyte
Cardiomyocyte electrophysiology
Mathematical models
Hodgkin–Huxley models
Markov models

Contents

1. Introduction ...................................................................................................................................................................................................... 1
2. Purkinje fiber cardiomyocyte models ................................................................................................................................................................... 6
3. Atrial cardiomyocyte models............................................................................................................................................................................... 8
4. SAN cardiomyocyte models ................................................................................................................................................................................ 10
5. AVN cardiomyocyte models ................................................................................................................................................................................ 11
6. Ventricular cardiomyocyte models....................................................................................................................................................................... 11
7. Mathematical models of stem cell-derived cardiomyocytes .................................................................................................................................... 12
8. Stability and bifurcation analysis of cardiomyocyte models ................................................................................................................................... 13
9. Use of cardiomyocyte models in arrhythmogenesis and cardiac safety pharmacology studies.................................................................................... 14
10. A note on computational methods ....................................................................................................................................................................... 15
11. Conclusions and perspectives .............................................................................................................................................................................. 16
Declaration of competing interest ........................................................................................................................................................................ 16
Acknowledgments .............................................................................................................................................................................................. 16
References......................................................................................................................................................................................................... 16

1. Introduction (Table 1), and the complexity of these models increased progres-
Starting with the 1960s an impressive number of mathematical sively since then as more and more experimental data became avail-
models of cardiomyocyte electrophysiology have been developed able. Mathematical modeling of excitatory systems featuring sustained

∗ Corresponding author at: Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, 91–95 Splaiul Independentei,
Bucharest 050095, Romania.
E-mail address: bogdan@biologie.kappa.ro (B. Amuzescu).

https://doi.org/10.1016/j.mbs.2021.108567
Received 7 October 2020; Received in revised form 10 January 2021; Accepted 4 February 2021
Available online 16 February 2021
0025-5564/© 2021 Elsevier Inc. All rights reserved.
B. Amuzescu, R. Airini, F.B. Epureanu et al. Mathematical Biosciences 334 (2021) 108567

Abbreviations hiPSC-CM Human induced pluripotent stem

cell-derived cardiomyocyte
ACh Acetylcholine
IBM-PC International Business Machines personal
AF Atrial fibrillation
computer
AGOS API Generator for ODE Solution
IP3R Inositol triphosphate receptor
ALGOL Algorithmic language
JSR Junctional sarcoplasmic reticulum
AP Action potential
LC Limit cycle
APD Action potential duration
LRd Luo–Rudy dynamic model
API Application programming interface
LQT long QT syndrome
ATP Adenosine triphosphate
M Midmyocardial ventricular cardiomyocyte
AVN Atrioventricular node
MathML Mathematics Markup language
BR Beeler–Reuter model
MDP Maximum diastolic potential
CaM Calmodulin
MNT McAllister–Noble–Tsien model
CaMKII Calcium/calmodulin-dependent protein ki-
MS-DOS Microsoft Disk Operating System
nase II
NCX Sodium-calcium exchanger
CaN Calcineurin
NSR Network sarcoplasmic reticulum
CellML Cell Markup Language
ODE Ordinary differential equation
CESE Cell Electrophysiology Simulation Environ-
PB Priebe–Beuckelmann model
ment
RDF Resource Description Framework
CICR Calcium-induced calcium release
RP Resting potential
CiPA Comprehensive in vitro Proarrhythmia As-
RV Right ventricle
say
RyR Ryanodine receptor
CMISS Continuum Mechanics, Image analysis, Sig-
nal processing and System identification SA Sinoatrial
CPVT Catecholaminergic polymorphic ventricular SAN Sinoatrial node
tachycardia SERCA Sarcoendoplasmic reticulum calcium pump
CV Conduction velocity SR Sarcoplasmic reticulum
CUDA Compute Unified Device Architecture TdP Torsades-de-pointes
CVODE Variable coefficient ODE solver written in C TEA Tetraethylammonium
DAD Delayed afterdepolarization TP Turbo Pascal (programming language)
DAE Differential algebraic equation TRPM4 Transient receptor potential melastatin-
DLSODE/DLSODA Double-precision Livermore Solver for related 4 ion channel
ODEs/with Automated method switching TTX Tetrodotoxin
for stiff/nonstiff problems XML eXtensible Markup Language
EAD Early afterdepolarization
EASE Electronic Analog and Simulation Equip-
ment
as analytically tractable simplified versions of the highly successful
ECC Excitation–contraction coupling
Hodgkin–Huxley (HH) model [7]. Unfortunately, in this group of mod-
ECG Electrocardiography
els there is no direct link between electrical activity and physiological
EGTA Ethylene glycol-bis(𝛽-aminoethyl
processes important for the generation and propagation of excitation
ether)-N,N,N′ ,N′ -tetraacetic acid
such as the opening and closing of ion channels.
EP Equilibrium point
In 1949, Hodgkin and Katz showed that the amplitude and speed of
FDA Food and Drug Administration action potential upstroke varies with extracellular Na+ concentration,
ginSODA GPU integrator for Systems of ODEs with concluding that the upward phase of the nerve impulse is produced by
Automated stiff/nonstiff switching a specific increase in membrane permeability for Na+ ions. A few years
GPU Graphics processing unit later Hodgkin and Huxley separated the total transmembrane ion flow
hERG Human ether-à-go-go related gene into the Na+ and K+ components and formulated the equations describ-
HH Hodgkin–Huxley model ing how these currents vary depending on the membrane potential and
hESC-CM Human embryonic stem cell-derived car- time. In a series of five articles published in the Journal of Physiology
diomyocyte (London) in 1952, they described a mathematical model based on
previously obtained experimental data using the equivalent electrical
circuit of the nerve cell membrane (Fig. 1A). The main relationship
underlying this mathematical model (the current equation):
oscillations similar to those involved in pacemaking begins with the 𝑑𝑉 ∑
𝐼𝑚 (𝑡) = 𝐶𝑚 𝑚 + 𝐼𝑖
studies of van der Pol and van der Mark. They published in 1928 𝑑𝑡
∑
the first mathematical description of the heartbeat as a relaxation 𝐼𝑖 = 𝐼𝑁𝑎 + 𝐼𝐾 + 𝐼𝐿 = 𝑔 𝑁𝑎 𝑚3 ℎ(𝑉𝑚 − 𝑉𝑁𝑎 ) + 𝑔 𝐾 𝑛4 (𝑉𝑚 − 𝑉𝐾 )
oscillation [1]. This study underpins the development of a group of
‘‘cell’’ models represented by a minimum number of equations and vari- +𝑔 𝐿 (𝑉𝑚 − 𝑉𝐿 )
ables and described by terms such as excitability, stimulus threshold is a first order non-linear ordinary differential equation linking the
and refractory period. The most widely used models in propagation transmembrane potential 𝑉m to the total transmembrane current sur-
studies were the FitzHugh–Nagumo [2,3], Aliev–Panfilov [4], Roger– face density 𝐼𝑚 (t ), present in all cardiomyocyte electrophysiology mod-
McCulloch [5], and Mitchell–Schaeffer [6] models, all of them derived els. I 𝑖 , I 𝑁𝑎 , I 𝐾 , I 𝐿 represent generic and specific (for Na+ , K+ and

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B. Amuzescu, R. Airini, F.B. Epureanu et al. Mathematical Biosciences 334 (2021) 108567

Table 1
Brief description of cardiomyocyte electrophysiology mathematical models of first, second and third generation, including their type, species and heart territory, main features,
explained phenomena, parent models, and AP shapes.
Name Type Main features AP shape Explained phenomena Parent
(year) model
First generation models
Monocompartmental
HH-like formulations
Based on microelectrode impalement and voltage-clamp data in multicellular preparations
Built to study the role of one or a few ion current components
Purkinje fibers
Noble 1962 HH-like Introduces delayed and inward rectifier K+ I-V relationship in Purkinje fibers Hodgkin–Huxley
generic current (𝐼K2 and 𝐼K1 ); HH regenerative repolarization 1952
model with modified gating kinetics pacemaking
McAllister–Noble–Tsien HH-like Two 𝐼K delayed rectifier components (𝐼X1 and Notched (spike-and-dome) AP Noble 1962
(MNT) 1975 generic 𝐼X2 ); slow inward (Ca2+ ), transient and effects of current pulses and [Ca2+ ]o
background currents on diastolic depolarization
Ventricular
Beeler–Reuter (BR) 1977 HH-like Slow inward Ca2+ current (𝐼CaL ); fast and slow freq.-APD; repolarization by fast MNT 1975
generic 𝐼Na recovery from inactivation (𝑚3 hj gating voltage-clamp during AP plateau;
kinetics) sustained/damped oscillations
Drouhard–Roberge 1987 HH-like Improved Na+ current model with realistic AP phase 0 maximal slope BR 1977
generic activation and inactivation kinetics comparable to experiment; fixed
firing threshold for RP-90 to-70 mV
Sino-atrial
Yanagihara 1980 HH-like Includes 𝐼f , effects of ACh, epinephrine, steady Slow inward (Ca2+ ) current plays a BR 1977
rabbit external current on pacemaking major role and K+ current almost no
role in sino-atrial pacemaking
Irisawa–Noma 1982 HH-like Includes novel experimental data for slow Simulates pacemaking well, but exp. Yanagihara 1980
rabbit inward Ca2+ current (𝐼CaL ) activation at I-V and AP fitted only with artificial
potential above-60 mV ‘‘window’’ 𝐼si (in fact 𝐼CaT )
Bristow–Clark 1982 HH-like Modification of MNT1975 model currents Mimicks well experimental data MNT 1975
rabbit (voltage dependence of gating variables) to fit reproduces free pacemaking and
exp. data effects of injected current
Reiner–Antzelevitch 1985 HH-like 𝐼K2 replacement by 𝐼f pacemaker current-less Reproduces pacemaker Bristow–Clark
rabbit important for phase 4 depolarization than for phase-resetting and annihilation to 1982
phase reset subthreshold/electrotonic stimuli
Second generation models
Monocompartmental
HH-like formulations
Based on patch-clamp/single-channel data from isolated cardiomyocytes
Include Ca2+ dynamics, some ion pumps and exchangers
Ventricular

Luo–Rudy I 1991 HH-like 6 dynamic/background currents; 𝐼Na mh kinetics Wenckebach BR 1977

generic from Ebihara–Johnson; [K+ ]o dependence of 𝐺K patterns/alternans/supernormal
and 𝐺K1 excitability (chaotic activity) at
normal/low [K+ ]o
Atrial
Rasmusson 1990 HH-like 3 dynamic+6 background currents; Role of Ca2+ buffers in the positive Hilgemann–
bullfrog internal & cleft ion concentrations; Ca2+ force–frequency relationship; NCX & Noble
dynamics without SR Na/K pump - small role in repol. 1987

(continued on next page)

leak) ion current surface densities, C 𝑚 transmembrane capacitance
surface density, 𝑔 𝑁𝑎 , 𝑔 𝐾 and 𝑔 𝐿 the maximal conductance surface
densities of the respective ion current components, m, h and n the
open probabilities of Na+ activation and inactivation and K+ activa-
tion gates, respectively, and V 𝑁𝑎 , V 𝐾 , V 𝐿 the reversal potentials of
these ion current components. HH introduced the concept of voltage-
dependent activation and inactivation gates and developed kinetic
differential equations describing the time and potential dependence of
these gates [8]. Although the authors initially regarded their work as a
partial failure to uncover the specific molecular mechanisms underlying
nerve excitability [9,10], the HH model proved highly accurate in
quantitatively reproducing a wealth of experimental data. It was also
insightful in terms of revealing structural details of transmembrane ion
transport systems, correctly predicting the four-subunit stoichiometry
of voltage-dependent Na+ and K+ ion channels, as well as easy to use,
robust and computationally effective, a fact that explains its widespread
use in systems biology approaches and modeling of complex excitable
systems at almost seven decades since its appearance [11,12].
The first models of cardiomyocytes tried to reproduce the experi-
mentally recorded shape of the action potential. Since the potentials
of a nerve fiber act to encode information as quickly as possible,
they last only a few ms. The action potential of a human ventricular
cardiomyocyte may last 400 ms. This extended duration is required
for excitation-contraction coupling (ECC), a series of molecular events
initiated by depolarization wave progression along the t tubule system,
triggering diadic Ca2+ -induced Ca2+ release necessary for actin–myosin
interaction [16]. FitzHugh (1960) showed that within the HH for-
malism repolarization can be delayed by reducing the amplitude and
speed of K+ current activation and the rate of Na+ current inacti-
vation [17], consistent with the experimental results of Tasaki and
Hagiwara on squid giant axons internally perfused with tetraethylam-
monium (TEA) [18]; these changes slowed repolarization and created a

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B. Amuzescu, R. Airini, F.B. Epureanu et al. Mathematical Biosciences 334 (2021) 108567

Table 1 (continued).
Name Type Main features AP shape Explained phenomena Parent
(year) model
sino-atrial
Rasmusson HH-like Similar to Rasmusson 1990 atrial cell model; Pacemaking cannot be attributed to a Hilgemann–
1990 bullfrog includes a diffusion-limited extracellular single current; it is due to lack of 𝐼K Noble
space (cleft) background+effect of 𝐼Ca , 𝐼K , 𝐼b 1987
Third generation models
Multicompartmental, including ion diffusion and buffering, release and reuptake from stores, exchangers, pumps, modulatory and regulatory effects (e.g.
adrenergic/cholinergic)
HH-like and/or Markov formulations
Built to study complex effects of the interplay between structural/functional features
Often include complex experimental datasets, ion microfluorimetry, pharmacological effects
Trend towards human/humanized models
Purkinje fibers
DiFrancesco– HH-like Replacement of hyperpolarization-inhibited [Na+ ]i changes by [Na+ ]o variation MNT 1975
Noble generic 𝐼K2 with 𝐼f ; NCX and Na/K pump; SR or Na/K pump block; effect of
1985 release/ uptake stores current pulses during phase 2/4
Aslanidi 2009 HH-like 𝐼NaL , 𝐼CaL , 𝐼CaT , 𝐼to , 𝐼Kr , 𝐼Ks , 𝐼K1 densities AP shape and rate dependence; too Hund–Rudy
dog and kinetics from experimental data fast or too slow conduction through 2004
validated by RP, 𝑉peak ,dV /d 𝑡max of AP P-V junction is not safe Benson 2008
Stewart 2009 HH-like Inclusion of 𝐼f and 𝐼sus and modification of Reproduces AP shape, overdrive Ten Tusscher–
human 𝐼K1 and 𝐼to in ten Tusscher–Panfilov 2004 suppression, effects of ion current Panfilov
model density changes on AP 2004
Atrial
Hilgemann– HH-like Includes exchangers and pumps, Ca2+ buffers, Reproduces [Ca2+ ]I and [Ca2+ ]o DiFrancesco–
Noble rabbit SR Ca2+ release & uptake, an electrogenic transients, Ca2+ dynamics during Noble
1987 NCX steady/non-steady stimulation 1985
Earm–Noble HH-like Explores Ca2+ -activated SR Ca2+ release and Reproduces nonlinear relation Hilgemann–
1990 rabbit NCX inflow during late plateau; uses 𝐼to between Ca2+ current and Ca2+ Noble
inactivation release, effect of Fura-2 buffering 1987
Lindblad 1996 HH-like Ion currents based on whole cell Provides accurate simulations of Demir 1994
rabbit voltage-clamp data; Na+ , K+ , Ca2+ dynamics, whole-cell voltage-clamp data; fits
SR release/uptake APs at 35 ◦ C 0.2–3.0 Hz stim. rate
Courtemanche HH-like Specific formulations of 𝐼K , 𝐼Na , 𝐼Ca based on Reproduces AP shape, APD Luo–Rudy 1994
1998 human human atrial myocytes data, pumps and rate-dependent adaptation, 𝐼CaL and
exchangers NCX inhibition, 𝐼to variations
Nygren 1998 HH-like Based on averaged voltage-clamp data Proves that the role of 𝐼sus in AP can Lindblad 1996
human recorded from isolated single be modulated by 𝐼CaL , 𝐼sus , 𝐼Kr ;
myocytes;bulk&cleft external space 𝐼sus changes in diseases like AF
Ramirez 2000 HH-like Includes 𝐼K , 𝐼Na , 𝐼Ca , 𝐼Cl based on Realistic APD rate dependency;
dog measurements in canine atrial myocytes; central role of 𝐼CaL inactivation in
junctional & network SR rate adaptation; AF remodeling
Grandi 2011 HH&Markov Redefined current densities (lower 𝐼K1 , 𝐼NCX , Chronic AF model with shorter AP, Grandi–Bers
human 𝐼NaK , removed 𝐼toslow , higher 𝐼tofast , inserted reduced APD shortening at high rate; 2009
𝐼Kur ); altered SERCA 𝐼Kur block -> adrenergic EAD
Davies 2014 HH&Markov 𝐼CaL , 𝐼tofast , 𝐼Kur , 𝐼Kss , 𝐼k1 from atrial myo- Successfully reproduces murine atrial Bondarenko–
mouse cytes experimental data; AP, RP, 𝑉peak ,dV /d 𝑡max , APD and Rasmusson
fibroblast–cardiomyocyte coupling 2D model rate dependence 2004

(continued on next page)

depolarization plateau. FitzHugh’s approach main flaw was the energy-
intensive way of generating a plateau; the ion conductances were so
large that, during each action potential, the Na+ and K+ ion gradients
would have to degrade at a rate of at least one order of magnitude
larger than the real one. In contrast to this predicted behavior, Weid-
mann’s experiments on cardiomyocytes in the 1950s [19] showed that
transmembrane conductance is very low during the action potential
plateau. Later it was discovered that this decrease in conductance was
due to the special features of the inward rectifying K+ current (𝐼K1 ).
Ronald Wilders divided the period from the first cardiomyocyte
model developed by Denis Noble in 1962 until 2007 into two stages:
early electrophysiology models of cardiomyocytes, starting in the early
‘60s and lasting until 1988, and advanced or detailed models that
emerged after 1989 [20]. The early models include: Noble, 1962 [21],
McAllister–Noble–Tsien [22], Beeler–Reuter 1977 [23], DiFrancesco–
Noble [24] and Hilgemann–Noble [25] models. These are based on
mathematical formulations of specific ion current components similar
to those of the HH model, including a few variables such as maximal
conductance surface densities, driving forces, and open probabilities of
various independent activation and inactivation gates, evolving under
kinetic equations driven by voltage-dependent rates. Despite their sim-
plicity, these early models fit surprisingly well action potentials (APs)
and voltage-clamp currents experimentally recorded via microelectrode
impalement in Purkinje fibers, ventricular or atrial cardiomyocytes.
Mathematical models developed after 1989 are more complex (Figs. 2
and 3). They include additional sets of differential equations for de-
scribing the kinetics of ion pumps and exchangers, as well as calcium
uptake and release processes in subcellular compartments [20]. Some
models that emerged after the 1990s, particularly those developed by
the group of Prof. Yoram Rudy, include more detailed ion current
kinetics based on single-channel patch-clamp recordings.
The tremendous success of HH-like models relies on a powerful
combination of fundamental simplicity in formulation and computa-
tional effectiveness, explaining why these models are still preferred
and dominate cardiomyocyte and neuronal electrophysiology modeling

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B. Amuzescu, R. Airini, F.B. Epureanu et al. Mathematical Biosciences 334 (2021) 108567

Table 1 (continued).
Name Type Main features AP shape Explained phenomena Parent
(year) model
sino-atrial
Noble 1989 HH-like Based on patch-clamp exps. on isolated cells Features pacemaking, but with 𝐼K DiFrancesco–
rabbit (Denyer&Brown 1990) scaled up 2.7-fold; 𝐼ε−NaK and 𝐼bNa Noble
new equations for 𝐼f and 𝐼K probably overestimated 1985
Wilders 1991 HH-like Current equations based on published Reproduces spontaneous pacemaking, DiFrancesco–
generic single-cell voltage-clamp data; includes 𝐼CaT AP parameters, voltage-clamp and Noble
I-V data 1985
Demir 1994 HH-like Two 𝐼Na recovery components, new 𝐼f Fits well voltage-clamp&AP data; DiFrancesco–
rabbit equations; a diffusion-limited external space assesses role of 𝐼CaT , 𝐼b , pumps, Noble
(cleft) exchangers on pacemaker rate 1985
Dokos 1996 HH-like Dynamic modulation of 𝐼f and 𝐼CaL by ACh; Strong ACh-induced Wilders 1991
rabbit improved 𝐼K(ACh) , second-order kinetics of hyperpolarization with
ACh action phase-dependent slowed-down
pacemaking
Zhang 2000 HH-like New formulations of several ion current Reproduces center/periphery AP
rabbit components; SA node center/periphery shape & pacemaking, effects of 𝐼Na ,
current differences 𝐼CaL , 𝐼CaT , 𝐼to , 𝐼Kr , 𝐼Ks , 𝐼f blockers
Sarai 2003 HH-like Includes contraction, a sustained inward Reproduces effects of [Ca2+ ]o and
(Kyoto model: rabbit & Na/K current-𝐼st ; current densities from [K+ ]o , 𝐼CaL and 𝐼st changes on AP
Matsuoka guinea pig experimental data and pacemaking rate
2003)
Lovell 2004 HH&Markov Spatial gradient model of SA node AP Reproduces a wide range of
rabbit heterogeneity;7 time-dependent currents: experimental AP waveforms from
3/4-states Markov models central & peripheral SA node
Kurata 2002 HH-like Subsarcolemmal diffusion space, new 𝐼st , 𝐼Kr Simulates 𝐼CaL , 𝐼Kr , 𝐼st voltage-clamp
rabbit activation kinetics, 𝐼CaL Ca2+ and data, AP and currents waveforms
voltage-dep. inactivation during AP-clamp
Kurata 2008 HH-like Model for central & peripheral SA node cells; Reproduces bifurcation behavior for Zhang 2000
rabbit includes internal Ca2+ dynamics, 𝐼CaL , 𝐼Kr , and steady external
vagal/adrenergic effects current, 𝐼Na peripheral pacemaking
Atrio-ventricular nodal (AVN)
Inada–Boyett HH-like Models for atrio-nodal, nodal, nodal-His cells Atrio-ventricular nodal reentry after Kurata 2002
2009 rabbit with realistic AP shapes and refractoriness premature beat; AVN block during Zhang 2000
atrial fibrillation (AF)
Ventricular
Luo–Rudy HH-like 𝐼CaL , 𝐼NaCa , 𝐼NaK ,SR Ca2+ release/ uptake, 𝐼CaL V -dependent inactivation,AP& Luo–Rudy 1991
1994 guinea pig network&junctional NSR & JSR, currents, phase 2/3EAD, DAD,
(Luo–Rudy SR&myoplasm Ca2+ buffering post-extrasystolic potentiation
dynamic)
Shaw 1995 HH-like Simulation of unidirectional propagation in a Exploration of time and voltage Luo–Rudy 1994
guinea pig 1D cardiac fiber using the Luo–Rudy 1994 vulnerable window for unidirectional
model block/reentry arrhythmias
Zeng 1995 HH-like Uses the Luo–Rudy 1994 model with Mechanisms of EAD and DAD: 𝐼CaL Luo–Rudy 1994
guinea pig modified CICR for EAD&DAD; recovery&reactivation, no matter
+ BayK8644/Cs+ /isoproterenol what current induces EAD
Jafri 1998 HH&Markov Detailed model of Ca2+ regulation: includes Simulates well Ca2+ transients during Luo–Rudy 1994
guinea pig subspace, Keizer-Levine RyR & AP, with higher peak [Ca2+ ] in
mode-switching 𝐼CaL model subspace vs. bulk myoplasm

(continued on next page)

at more that 7 decades since their introduction. Their main com-
petitors are Markov gating models, developed since the emergence
of the patch-clamp technique and the first single-channel recordings
of nicotinic acetylcholine receptors of skeletal muscle end-plates per-
formed by Bert Sakmann and Erwin Neher in the late 1970s [26,27].
Analysis of single-channel recordings, developed with the essential
contribution of Sir David Colquhoun, is comprised of a series of steps
including preprocessing, idealization, plotting dwell-time and all-points
histograms, model-dependent fitting, etc. [28,29]. Under the assump-
tions of Markov chain of random independent events, it can be shown
that the lifetimes of a certain state, corresponding to a particular con-
formation of the ion channel molecule, are exponentially distributed,
therefore mono- or multiexponential fits of dwell-time histograms of
a conductance level obtained from single-channel traces provide es-
timates of transition rates between different states such as open (O),
closed (C), inactivated (I), or blocked (B) (Fig. 1B). In addition, model-
dependent fitting algorithms of idealized single-channel recordings in
stationary or non-stationary conditions using hidden Markov modeling
and maximum log-likelihood methods allow comprehensive analysis
of entire sequences of events and search of optimal models [14,30].
Markov models and state diagrams are more accurate for simulating
complex ion channel gating behaviors such as fast and slow voltage-
dependent inactivation of Na+ and Ca2+ channels, the late bursting
mode and late I Na [31], Ca2+ -dependent inactivation of I CaL [32], mode
switching and voltage hysteresis of I f and its antiarrhythmic effects on
pacemaking [33], allosteric effects in activation of ion channel sub-
units [34], state-dependent drug binding [35], etc. Despite their high
fidelity in reproducing ion channel state transitions, Markov models
add supplementary differential equations and parameters to the car-
diomyocyte model, therefore requiring extra computational resources
and increased computation times, and sometimes not all rates of a

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B. Amuzescu, R. Airini, F.B. Epureanu et al. Mathematical Biosciences 334 (2021) 108567

Table 1 (continued).
Name Type Main features AP shape Explained phenomena Parent
(year) model
Noble 1998 HH-like Iadic space with increased Ca2+ Reproduces diadic space Ca2+ Noble 1991
guinea pig accumulation, 𝐼Kr , 𝐼Ks , length- and accumulation during AP plateau;
tension-dependent processes study of 𝐼Na and 𝐼NaK inhibitors
Priebe– HH-like 𝐼CaL , 𝐼to , 𝐼Kr , 𝐼Ks , 𝐼K1 based on human data, Cellular electric properties in heart Luo–Rudy 1994
Beuckelmann human modified Ca2+ SR release/uptake and failure:longer ventricular AP&EAD by
(PB) 1998 buffering 2+
lower 𝐼Kr & spont. Ca release
Winslow 1999 HH-like Jafri 1998 model with modified 𝐼to , 𝐼Kr , 𝐼Ks , Reproduces normal & failing AP & Jafri 1998
dog 𝐼K1 , 𝐼CaL , 𝐽up ; heart failure modeled by lower Ca2+ transient; used to estimate
𝐼to , 𝐼K1 , 𝐼NaCa , 𝐽up 𝐼NaCa &𝐽up in failing myocytes
Dumaine 1999 HH-like Endocardial, LV & RV epicardial modified Effects on AP of accelerated 𝐼Na Luo–Rudy 1994
guinea pig Luo–Rudy 1994 model with mutant T1620M inact.-rapid RV repol. explaining ST
Na+ channel elevation in V1-V3 in Brugada
Clancy–Rudy HH&Markov Wild-type and 𝛥KPQ mutant Na+ channel Arrhythmogenic consequences of Luo–Rudy 1994
1999 guinea pig Markov models included in Luo–Rudy 𝛥KPQ mutation: APD prolongation
dynamic model and EADs
Viswanathan HH-like Subepicardial/M/subendocardial models with Pause-induced EADs by 𝐼CaL recovery Luo–Rudy 1994
-Rudy 1999 guinea pig fixed 𝐼Kr & variable 𝐼Ks density; models of & 𝐼NaCa ; M cells: propen- sity for
LQT1,2,3 EADs, higher in LQT1/2/3
Faber–Rudy HH-like Luo–Rudy dynamic model with 2-phase APD shortening with rapid Luo–Rudy 1999
2000 guinea pig re-formulation of Ca2+ dynamics: 𝐼NaK , pacing, by high 𝐼Ks & [Na+ ]i with
𝐼NaCa ,CICR, 𝐼K(Na) ; high [Na+ ]i & [Ca2+ ]i high 𝐼NaCa &𝐼NaK
Viswanathan– HH-like LQT1/2 (reduced 𝐼Ks / 𝐼Kr ) & LQT3 M cells: higher EAD susceptibility in Vishwanathan-
Rudy guinea pig (increased 𝐼Na late) poorly coupled tissue; 𝐼Kr block/late Rudy 1999
2000 subepicardial/M/subendocardial models 𝐼Na increase APD differences
Greenstein HH&Markov 𝐼to fast (Kv4.3) and slow (Kv1.4) human and Effects of 𝐼to density on AP shape Winslow 1999
2000 dog canine Markov models included in Winslow and duration: bimodal relationship
1999 model between 𝐼to fast and APD
Clancy–Rudy HH&Markov Wild-type/mutant (T474I, R56Q, N629D) Arrhythmogenic consequences of Vishwanathan-
2001 guinea pig hERG1 Markov models included in Rudy hERG1 mutations: APD prolongation Rudy 1999
1999 model and EADs
Puglisi–Bers HH-like Modified conductances for 𝐼Na , 𝐼K1 , 𝐼Kr , 𝐼Ks , Reproduces AP shape and Luo–Rudy 1994
2001 rabbit 𝐼Kp , 𝐼CaT , 𝐼NaCa ; 𝐼to kinetics from Winslow voltage-clamp data for normal/failing
1999; new 𝐼Cl(Ca) rabbit ventricular myocyte
Pandit 2001 HH-like Subendocardial/subepicardial rat ventricular Reproduces AP shape, Ca2+ fluxes, Demir 1994
rat cardiomyocyte model; currents form Demir Ca2+ transient in
models subendocardial/subepicardial
myocytes
Bernus 2002 HH-like Reduced version of PB 1998 model for 6-variable model with fixed [Ca2+ ]i PB 1998
human subendocardial/subepicardial/M human reproduces APD and CV restitution
ventricular myocytes properties; 2D spiral waves

(continued on next page)

complex Markov model can be accurately estimated from experimental
data.
2. Purkinje fiber cardiomyocyte models
At the beginning of 1960s Denis Noble and Otto Hutter proved
the existence of two types of K+ channels in Purkinje cardiac fibers:
the inward rectifier current 𝐼K1 , and the delayed rectifier current 𝐼K
[36,37]. In 1962 Noble published the first cardiomyocyte electrophysi-
ology model. The Noble 1962 model was an adapted version of the HH
model created in order to reproduce the cardiac action potential and
pacemaker behavior.
For the inward rectifier K+ current 𝐼K1 Noble fitted his own equa-
tions including the dependence of this current on external K+ con-
centration [38], while for the delayed rectifier K+ current 𝐼K he used
slower versions of K+ current equations from the HH model, due to
the fact that a process that lasts a few milliseconds in the nerve
needs hundreds of milliseconds in the heart. For the Na+ current
Noble used the HH equations because Na+ current inactivation occurs
similarly in the myocardium [39]. The Noble 1962 model emphasizes
the balance imposed by evolution in the development of long APs in
cardiomyocytes; by reducing the K+ ions outflow during depolarization,
𝐼K1 allows to some small Na+ and Ca2+ inward currents to maintain
the long depolarized AP plateau with a smaller ATP consumption by
the ion pumps to restore the transmembrane gradients at the end of
the AP. Thus, metaphorically speaking, the paradoxical functioning of
𝐼K1 represents ‘‘Nature’s pact with the Devil’’, as Denis Noble himself
inspiredly described this phenomenon in a review [40], a process which
allows generating long APs with at least one thousand times less energy
waste than by using the classical Na+ and K+ currents of the HH model
with modified kinetics but without 𝐼K1 , as in the initial theoretical
approaches of FitzHugh and Noble in 1960. However, the introduction
of 𝐼K1 rendered repolarization a much more sensitive process, because
small current variations can change the delicate balance between out-
ward and inward currents during AP plateau, disturbing or completely
impeding repolarization [41]. Even though the equations of the Noble
1962 model were incomplete, by omitting (or rather incorporating in
the Na+ current equations) the L-type Ca2+ current (𝐼CaL ), important
during the plateau phase, but still unknown at that time and discovered
at the end of the ‘60s [42], and by the lack of characterization of the
late components of the Na+ current, K+ current kinetics was success-
fully reproduced. In addition, the slow decay of 𝐼K allowed the model to
reproduce the pacemaker behavior, generating transmembrane voltage
traces very similar to the experimentally recorded ones.
The McAllister–Noble–Tsien 1975 model is based on the Noble
1960 and Noble 1962 models. This model used for the first time
experimental data obtained with advanced voltage-clamp protocols to
derive rate equations. It introduced the ‘‘slow inward’’ calcium current

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B. Amuzescu, R. Airini, F.B. Epureanu et al. Mathematical Biosciences 334 (2021) 108567

Table 1 (continued).
Name Type Main features AP shape Explained phenomena Parent
(year) model
Hund–Rudy HH-like Includes subspace compartment, dynamic Reproduces APD adaptation, 𝐼CaT Luo–Rudy 1994
2004 dog effects of CaMKII on several ion currents and increase at shorter cycle length by
fluxes CaMKII phosphorylation
Shannon–Bers HH&Markov Subsarcolemmal & junctional subspace, Reproduces the nonlinear Luo–Rudy 1994
2004 rabbit realistic Ca2+ buffering, SR release and dependence of ECC gain (𝐽rel ∕𝐼CaL )
reuptake and fractional SR release on SR load
Ten Tusscher– HH-like Transmural 𝐼to , 𝐼Kr , 𝐼Ks gradients APD and CV restitution PB 1998
Panfilov human realistic Ca2+ transients and positive staircase spiral waves in 2D model Courtemanche
2004 1998
Iyer–Mazhari– HH&Markov Markov models for 𝐼Na , 𝐼CaL , 𝐼to fast and 𝐼to APD restitution, [Ca2+ ]SR -frequency,
Winslow human slow , 𝐼Kr , 𝐼Ks extrasystolic restitution and
2004 post-extrasystolic potentiation
Bondarenko– HH&Markov Markov models for 𝐼Na , 𝐼CaL , 𝐼Kr ; other Realistic simulation of AP shape from
Rasmusson mouse currents, Ca2+ transients, buffering & apex&septum, voltage-clamp data,
2004 dynamics like in experiments Ca2+ transients
Faber–Rudy HH&Markov Markov models for L-type Ca2+ and Ryr2 Realistic 𝐼CaL (whole-cell & single- Luo–Rudy 1994
2007 guinea pig channels, diadic subspace, realistic Ca2+ channel), APD & 𝐼CaT restitution,
buffering & dynamics variable gain of SR Ca2+ release
Mahajan 2008 HH&Markov Shannon–Bers 2004 model with Markov 𝐼CaL Reproduces 𝐼CaL Ca2+ and Shannon–Bers
rabbit model and [Ca2+ ]i cycling from Shiferaw et voltage-dependent inactivation, 2004
al. 2003 APD&Ca transient alternans &
restitution
Saucerman– HH&Markov Shannon–Bers 2004 model integrating Only for internal Ca2+ Predicts that CaM is highly activated Shannon–Bers
Bers rabbit kinetic models of Ca2+ binding on CaM, dynamics during AP plateau in diadic cleft 2004
2008 CaMKII, CaN &not in bulk myoplasm
Grandi–Bers HH&Markov Subsarcolemmal&diadic subspace, humanized epi&endo models reproduce AP&Ca2+ Shannon–Bers
2009 human ion channel&transporter models, transmural transients, APD adaptation and 2004
gradients restitution
Livshitz–Rudy HH-like Luo–Rudy dynamic&Hund–Rudy models with With biphasic charge-conserving Luo–Rudy1994
2009 guinea pig DAE, removed singularities, charge stimuli models reach steady-state and Hund–Rudy
dog conservation eqn. 1D propagation alternans 2004
O’Hara–Rudy HH-like Includes human ventricular myocyte data for Reproduces AP shape (subendo-, Luo–Rudy 1994
2011 human ion channels& transporters, detailed effects of subepi- and M-type), rate
CaMKII depen-dence of APD,[Na+ ]i ,[Ca2+ ]i ,
EADs
Li–Dutta– HH&Markov O’Hara–Rudy 2011 model including 𝐼Kr Introduces cqInward (integral of O’Hara–Rudy
Colatsky human Markov model and multiple ion channel 𝐼Nalate + 𝐼CaL over AP duration) as 2011
2017 inhibition data for 12 drugs torsadogenic risk predictor

All graphs of simulations for AP shape, generated with OpenCOR, CESE, MatLab® , Myokit, or C++ scripts, have a duration of 3 s (unless otherwise specified) and amplitude range
from −100 to +50 mV; the isoelectric line is marked with a dotted line.
Abbreviations: HH - Hodgkin-Huxley model; MNT - McAllister–Noble–Tsien model; BR - Beeler–Reuter model; PB- Priebe–Beuckelmann model; DAE - differential algebraic equation;
AVN - atrio-ventricular node; SA - sino-atrial (node); AP - action potential; APD - action potential duration; RP- resting potential; EAD - early afterdepolarization; DAD - delayed
afterdepolarization; AF - atrial fibrillation; CV - conduction velocity; LQT - long QT syndrome; ECC - excitation–contraction coupling; SR - sarcoplasmic reticulum; JSR - junctional
sarcoplasmic reticulum; NSR - network sarcoplasmic reticulum; CICR - calcium-induced calcium release; ACh - acetylcholine; CaMKII - calcium-calmodulin-dependent kinase II;
CaM - calmodulin; CaN - calcineurin; hERG - human ether-à-go-go related gene; RyR - ryanodine receptor; NCX - Na+ /Ca2+ exchanger; SERCA - sarcoendoplasmic reticulum Ca2+
pump; RV - right ventricle; M - midmyocardial ventricular cardiomyocyte.

(𝐼si ), based on experimental results of Harald Reuter, who provided
the first description of the cardiac calcium current [42], and the
voltage-clamp experiments of Noble and Richard Winyu Tsien, who
discovered multiple K+ current components with slow kinetics [43,44]
called 𝐼X1 and 𝐼X2 (known today as 𝐼Kr and 𝐼Ks ) [45], along with
the much faster inactivating transient outward current 𝐼qr and various
background currents [22]. Although slow diastolic depolarization and
pacemaking were explained by activation during depolarization of an
outward current instead of deactivation of an inward current [46], the
mathematical description of this current and the subsequent behavior of
the model were adequate, succeeding to accurately reproduce particu-
larly the chronotropic effects of brief current pulses applied externally
during slow diastolic depolarization (phase 4) of pacemaker Purkinje
cells. The model explained the slow changes of conductance around
the resting potential as the result of a K+ current with slow gating, 𝐼K2 .
The DiFrancesco and Noble 1985 model [24] incorporated the
𝐼f current (funny, queer, anomalous rectifier) discovered by Dario
DiFrancesco [47] to replace the role of I K2 used in the McAllister–
Noble–Tsien model [48]. This model incorporated for the first time the
changes in intracellular and extracellular ion concentrations and the
intracellular calcium signaling system. At the same time a similar 𝐼f
current contributing to slow diastolic depolarization and pacemaker ac-
tivity was identified in collagenase-dissociated isolated Purkinje fibers
of different species approached via two-microelectrode voltage-clamp
[49].
Newer Purkinje cell models included improved biophysical descrip-
tion of several ion current components, such as I f and a sustained
(plateau) 4-aminopyridine-sensitive K+ current named I sus , with a volt-
age dependence similar to I to but non-inactivatable. Thus, Stewart
et al. [50] developed a Purkinje cell model based on the ten Tusscher–
Panfilov 2006 ventricular model [51] and including experimental data
from human heart failure myocardium [52], succeeding to demonstrate
the role of I f in pacemaking, to explore all-or-nothing repolarization
and overdrive suppression, to evidence I to conductance density differ-
ences between human and canine Purkinje fibers and their effect on
AP, and to assess consequences of heart failure-induced electrical re-
modeling [50]. Other models, like Li and Rudy 2011 [53] and Trovato
et al. 2020 [54], take into account the lack of t tubules in Purkinje cells,
which renders Ca2+ diffusion the dominant process of Ca2+ cycling, and
the triple-layer spatial distribution of ryanodine receptors RyR1, RyR2,

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B. Amuzescu, R. Airini, F.B. Epureanu et al. Mathematical Biosciences 334 (2021) 108567

Fig. 1. Hodgkin–Huxley and Markov models. A. The equivalent electrical circuit of squid giant axon and the simplified set of equations of the Hodgkin–Huxley model [8]; B.
Markov models based on transitions between states with predefined rates; as an example, the state diagram of the Lu–Vandenberg 2001 model for hERG channel gating [13],
with added state-dependent drug block (C - closed states, O - open state, I - inactivated state, B - blocked states); single-channel traces simulated with the Lu–Vandenberg 2001
model with default parameters at + 40 mV (top trace - 1 s total duration, bottom trace - 0.1 s total duration); dwell time histograms of the conducting and non-conducting level
durations for a 10-s single-channel simulation with the above-mentioned model; traces and histograms were obtained with the QuB software package [14,15].

and inositol triphosphate receptors IP3R1 that induces biphasic Ca2+
transients and affects Purkinje cell electrophysiology (rate dependence)
and arrhythmic properties.
3. Atrial cardiomyocyte models
The first (rabbit) atrial cardiomyocyte model was developed in
1987 by Hilgemann and Noble [25] based on the DiFrancesco–Noble
1985 model. This model pays special attention to Ca2+ dynamics.
Built starting from experimental data, the model simulates several pro-
cesses: Ca2+ ions influx through Ca2+ channels, sarcoplasmic reticulum
(SR) Ca2+ release, Ca2+ - dependent activation of the sodium-calcium
exchanger 1 (NCX1) and Ca2+ - dependent inactivation of 𝐼CaL .
Three years later Earm and Noble developed a new rabbit atrial cell
model [55]. This was the first model based on recordings in isolated
cardiac cells rather than multicellular cardiac tissue. In the same year
Rasmusson and co. have developed the only bullfrog atrial model [56].
This model included the dynamic intracellular Ca2+ changes as ap-
proached in the Hilgemann–Noble 1987 model, although it did not
feature a functional SR. A merit of this model is represented by the ac-
curate description of extracellular Ca2+ depletion and K+ accumulation
effects due to limited diffusion.
In 1996, Lindblad et al. published a model of rabbit atrial cardiomy-
ocytes [57]. Based on the sinoatrial node (SAN) cardiomyocyte model
developed by Demir et al. [58], this model describes ion currents using
HH-type formulations and has a very complex subcellular structure
with a double SR compartment, nucleus, mitochondria and a cytoso-
lic space that contains Ca2+ buffers. The first two models of human
atrial cardiomyocytes appeared in 1998 [59,60]. Ion currents were
formulated using HH equations and incorporated for the first time the
atrial-specific ultrarapid inactivating K+ current component 𝐼Kur . The
model of Nygren et al. [60] also included the persistent plateau current
𝐼sus , deemed to regulate AP duration [61], and the Courtemanche et al.
1998 model presented formulations for Ca2+ fluxes at SR level: 𝐽SERCA ,
𝐽leak , 𝐽tr . Despite similarities, these models show differences in AP
morphology and rate dependence [62].
Later, Ramirez et al. developed the first canine atrial model with
HH formulations of major ion currents, and including realistic L-type
Ca2+ channel Ca2+ -dependent inactivation kinetics that exerts a tight
control on AP plateau level and duration in this species [63]. The model
allows simulation of the effects of atrial tachycardia on AP, such as AP
shortening and loss of adaptation rate.
Grandi et al. developed a model of human atrial cardiomyocytes in
2011 with detailed validation of rate-dependent Ca2+ dynamics based
on new experimental data [64]. This model succeeded to simulate some
electrophysiological consequences of atrial fibrillation and 𝛽-adrenergic
receptors stimulation. The Grandi et al. 2011 model showed that block-
ing 𝐼Kur increases intracellular Ca2+ and can cause arrhythmogenic
early afterdepolarizations (EAD) during adrenergic stress, reproducing
experimental observations. In 2014 Davies et al. developed a model of
atrial cardiomyocytes in mice to reproduce atrial remodeling and ar-
rhythmogenesis associated with atrial fibrillation, using Markov models
to formulate the main ion channel current equations: 𝐼Na , 𝐼CaL , 𝐼Kr , and
studied the effects of cardiomyocyte–fibroblast electrical coupling on
AP shape, conduction velocity and reentry in a 2D tissue model [65].
Other recent multicompartment mouse atrial cardiomyocyte models

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B. Amuzescu, R. Airini, F.B. Epureanu et al. Mathematical Biosciences 334 (2021) 108567

Fig. 2. Phylogenetic tree of evolution of cardiomyocyte electrophysiology models (MNT: McAllister–Noble–Tsien 1975 model; SAN: sino-atrial node).

Fig. 3. Evolution of cardiomyocyte electrophysiology mathematical models complexity, expressed by the number of model variables, parameters and constants.

including realistic t tubule system-SR coupling, Ca2+ dynamics, 𝛽- All three pioneering human atrial cardiomyocyte models (Courte-
adrenergic signaling and sometimes Markov models for certain ion manche 1998 [59], Nygren 1998 [60], and Grandi 2011 [64]) were
currents were developed by Asfaw et al. 2020 [66] and Zhang et al. subsequently developed in series of models incorporating increasing
2020 [67]. levels of structural and functional complexity [68]. The Courtemanche

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B. Amuzescu, R. Airini, F.B. Epureanu et al.
model was modified by the group of Michael Colman by incorporating
different experimental datasets to reproduce chronic atrial fibrillation
(AF)-induced remodeling with changes in ion current densities, internal
Ca2+ handling and AP shape, resulting in the Colman 2013 model [69],
and further by inclusion of realistic t tubule and dyadic architecture
in the Colman 2017 model [69]. Another contribution of the Colman
group is incorporation in the Colman 2013 and Courtemanche models
of gain-or-loss-of-function mutations in the KCNA5 gene encoding the
main subunit of K+ channels contributing I Kur to simulate different
types of familial AF [70]. The Nygren 1998 model was developed by
Mary Maleckar et al. by improvement in ion current formulations and
inclusion of the acetylcholine-activated K+ current I K(ACh) and used to
investigate effects of cardiomyocyte–fibroblast electrical coupling [71],
and subsequently by the group of Jussi Koivumäki by simulation of
heterogeneity of SR Ca2+ release and evidencing the role of internal
Na+ accumulation at faster beat rates in adaptation of cardiac electrical
activity [72]. The Grandi 2011 model was expanded by Voigt, Heijman
et al. by including a spatial representation of Ca2+ dynamics via 2 μm-
wide longitudinal and 1 μm-wide transversal divisions of the atrial
cardiomyocyte and a stochastic model of ryanodine receptors RyR2
Ca2+ release; the model was used to demonstrate the role of RyR2
disregulation and sarcoendoplasmic reticulum Ca2+ pump (SERCA2a)
activation in promoting delayed afterdepolarizations (DAD) and trig-
gered activity in paroxysmal AF [73]. Extensions of both the Colman
2013 model and Grandi 2011 model were rendered onto realistic 3-D
atrial anatomy models and could be successfully used to study cell-
level and reentry mechanisms in AF initiation and maintenance, and
the effects of electrical remodeling on atrial arrhythmogenesis [68,69,
73–78].
All these new computational approaches to atrial electrophysiology,
particularly larger-scale propagation models, provided new insights
into the reentry mechanisms of atrial arrhythmias; some of them con-
firmed pioneering studies such as atrial electrical mapping demonstrat-
ing reentry circuits in atrial tachycardia [79], or proposed spiral waves
in sleeves of ectopic atrial tissue at the origin of pulmonary veins as
a mechanism of paroxysmal atrial fibrillation [80]. A comprehensive
approach to these topics can be found in [81]. To date in excess of
300 studies have applied mathematical atrial cardiomyocyte models at
different scales to reveal intricate details of atrial electrophysiology and
arrhythmogenesis, many of them demonstrating the important roles
of internal Ca2+ dynamics in these phenomena [62]. Future efforts
in this field will focus on multi-scale approaches with tissue struc-
tural and electrical heterogeneity due to remodeling, including effects
of autonomic innervation and mechano-electrical feedback, complex
macromolecular interactions and description of signaling pathways and
modulatory effects, as well as exploring the effects of cell-to-cell vari-
ability, and will heavily rely on enhanced and extended experimental
datasets [62,82].
4. SAN cardiomyocyte models
The first model of pacemaker activity of the sino-atrial (SA) node
was developed in 1980 by Yanagihara and co. This model included
only four dynamic currents described by HH-like equations: the slow
inward Ca2+ current (𝐼si ), a time-dependent delayed rectifier K+ cur-
rent (𝐼K ), a voltage-dependent Na+ current (𝐼Na ), and the ‘‘funny’’
hyperpolarization-activated current (𝐼f ), together with a time-
independent ‘‘leak’’ current (𝐼l ) [83]. Despite its simplicity, the model
reproduced fairly well spontaneously generated APs, the effects of
acetylcholine and epinephrine on slow diastolic depolarization (phase
4) and SA node beating rate, restitution of pacemaking by a steady
externally applied hyperpolarizing current after its cessation by a
depolarizing current, as well as 𝐼K inhibition by 5 mM external Ba2+
without significant changes in pacemaking, in good agreement with ex-
perimental results of the same group [84]. In 1982, David Bristow and
John Clark generated another successful SA node mathematical model
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Mathematical Biosciences 334 (2021) 108567
by ingenious modification of the McAllister–Noble–Tsien 1975 Purkinje
fiber model, removing or adjusting the voltage-dependent properties
of some current components; their small-scale model, including only
5 ion currents, accurately reproduced AP shape [85]. A change to
the Bristow–Clark model was brought by Reiner and Antzelevitch, by
replacing the hyperpolarization-induced deactivation of the outward
K+ current 𝐼K2 with activation of 𝐼f ; the model was subsequently used
to study phase resetting and annihilation by subthreshold external
stimuli occurring via interaction of 𝐼si and 𝐼K [86]. The Irisawa–
Noma 1982 model also represents a refinement of the Yanagihara
1980 model, including new equations for 𝐼si , 𝐼K and 𝐼f [87], but
it reproduces experimental I-V plots only by artificially introducing
‘‘voltage window’’ current properties for 𝐼si by shifting in opposite
directions the voltage dependencies of activation and inactivation to
overlap over a voltage interval, and at the price of an abnormally large
background current [88]. All these early SA node electrophysiology
models rely on two-microelectrode voltage-clamp recordings in rabbit
SA node small multicellular preparations, comprised of approximately
100 pacemaker cells, performed in the 1970s by Irisawa and Noma
(reviewed by [89]).
The Noble & Noble 1984 SA node model, a modification of the
DiFrancesco–Noble 1985 Purkinje cell model, achieved the transition
to single-cell SA node models. The model was developed separately
for central (maximum diastolic potential - MDP - between −65 and
−60 mV) and peripheral (MDP −75 mV) SA node cells; like its parent
model, it incorporates Na+ /Ca2+ exchanger and Na+ /K+ pump cur-
rents, and succeeds to reproduce the smaller influence of [K+ ]o on
pacemaking rate compared to Purkinje fibers [90]. A model of similar
complexity, incorporating some ion exchanger and pump currents but
not dynamics of internal calcium was developed in 1990 in parallel
with the atrial cell model based on recordings in isolated bullfrog sinus
venosus [91].
Due to the difficulties in maintaining a normal shape and physiolog-
ical properties of isolated SA node cardiomyocytes, the first successful
experiments on dissociated rabbit SA pacemaker cells were performed
only in 1990 [92]. These results opened the door for new SA node
models based on single-cell data, the first of them being the Noble–
DiFrancesco–Denyer 1989 model [93]. A refined version of this model
was issued by Wilders et al. in 1991, incorporating single-cell size
and membrane capacitance data, as well as realistic current surface
densities and kinetics, including 𝐼CaT , 𝐼NaCa and 𝐼NaK [88].
Subsequent SA node electrophysiology mathematical models be-
came progressively more realistic and detailed, incorporating exten-
sively new experimental data obtained on isolated cellular prepara-
tions. The 1994 model of Demir, Clark, Murphey & Giles features
several subcellular compartments (bulk and cleft extracellular space,
release and uptake sarcoplasmic reticulum - SR - components), intra-
cellular and SR Ca2+ buffers and adequate calcium dynamics, new
formulations for 𝐼f , 𝐼CaT , and a dual kinetics of 𝐼Na recovery from inac-
tivation, reproducing satisfactorily instantaneous I-V plots of multiple
ion currents [58]. The model was updated in 1999 to include effects of
sympathetic and parasympathetic activation [94]. The 1993 and 1996
models of Dokos, Celler and Lovell also incorporate realistic details for
the acetylcholine-activated K+ current (𝐼K(ACh) ) and reproduce well the
vagal stimulation-triggered SA node phase resetting [95,96]. The same
group developed in 2004 a spatial gradient SA tissue model accounting
for AP heterogeneity, with smooth transition of parameters from center
to periphery [97]. The group of Mark Boyett also built an advanced
rabbit SA node model with variants for central and peripheral cells,
including new experiment-based formulations for several ion currents,
notably a 4-aminopyridine-sensitive current including a transient out-
ward and a sustained component (𝐼to and 𝐼sus ), as well as intracellular
Ca2+ , Na+ and K+ dynamics [98]. The Kyoto ventricular and SA node
cardiomyocyte model [99] uses simplified 3/4-states Markov formu-
lations for different ion currents, an excitation–contraction coupling
model, and remarkably only for SA node a ‘‘sustained inward’’ mixed
B. Amuzescu, R. Airini, F.B. Epureanu et al.
Na+ and K+ current (𝐼st ) with a reversal potential between + 10 and
+ 30 mV, identified experimentally since 1995 [100], with properties
such as selective permeability to monovalent cations and activation
by calcium overlapping those of TRPM4, shown to be present and
influence pacemaking in the SA node [101,102]. The features of the
Kyoto SA model, particularly the effects of 𝐼CaL and 𝐼st on pacemaking
rate, were further explored by the same group [103]. Kharche et al.
published in 2011 a realistic mouse SAN model based on own experi-
mental data in isolated SAN pacemaker cells, including specific kinetics
for different I Na (Nav1.5 and Nav1.1) and I CaL (Cav1.1, Cav1.2, Cav1.3)
isoforms [104].
Another remarkable set of SA node models are those developed by
Kurata et al.., a mathematics-oriented Japanese group [105,106]. Their
models incorporate accurate experiment-based estimates of different
ion current components present in rabbit SA node cells, using HH-
like formulations, including the 𝐼st component of the Kyoto model,
deemed to play an essential role in pacemaking, as well as detailed
calcium dynamics and a subsarcolemmal subspace occupying 1% of the
cell volume and featuring higher systolic Ca2+ concentrations due to
limited diffusion. A major merit of their approach is the use of stability
and bifurcation analysis methods: detection of equilibrium points (EP)
and limit cycles (LC), construction of codimension-1 and 2 bifurcation
diagrams to detect saddle–node and Hopf bifurcation points, and study-
ing EP stability by computing the eigenvalues of the Jacobian matrix
of the non-linear dynamic system of ordinary differential equations
of the model linearized around these EP. Thus, by varying different
parameters such as an externally applied steady current (𝐼bias ) or the
conductance densities of 𝐼CaL and 𝐼Kr they could identify intervals for
these parameters with positive real part of eigenvalues that correspond
to unstable EP and spontaneous pacemaking behavior [106,107].
The group of Stefano Severi also succeeded to produce a series
of comprehensive SAN pacemaker cell models for rabbit [108] and
human [109], and used them to explore effects on pacemaking of
certain factors such as I f properties [109,110], changes in external Ca2+
concentration [111,112], or mutations in caveolin gene [113].
5. AVN cardiomyocyte models
A series of models of the rabbit atrio-nodal, nodal and nodo-Hissian
cells of the atrio-ventricular node (AVN) were developed by Inada,
Hancox, Zhang and Boyett [114]. These models were incorporated into
pseudo-linear multicellular models including SAN, atrial and AVN com-
ponents, with two distinct atrio-nodal pathways (fast and slow), used to
study AVN reentry arrhythmogenesis and ventricular protection during
atrial fibrillation. A large number of subsequent AVN model studies
explored AP propagation in physiological and pathological conditions
and the effect of different ion currents on AV conduction properties:
Climent et al. 2011 [115], Inada et al. 2013 [116], Li et al. 2014 [117],
Ryzhii and Ryzhii 2015 [118], Cheng et al. 2016 [119], Jackowska-
Zduniak and Foryś 2016 [120], Temple et al. 2016 [121], Hulsmans
et al. 2017 [122], Wallman & Sandberg 2018 [123].
6. Ventricular cardiomyocyte models
In 1977, George W. Beeler Jr. and Harald Reuter published in
the Journal of Physiology the first mathematical model of ventricular
cardiomyocyte electrophysiology. The McAllister–Noble–Tsien model
was the basis for the extension to ventricular muscle cells developed
in the Beeler–Reuter (BR) model. Since not all ion current components
of a Purkinje fiber are found in ventricular cardiomyocytes, the BR
model is less complex than the McAllister–Noble–Tsien model. The
Beeler–Reuter model started from experimental voltage-clamp data that
separated four ion currents: the fast excitatory inward Na+ current
𝐼Na , a slow inward current primarily carried by calcium ions - 𝐼S , a
time-independent inward K+ current - 𝐼K1 , and a voltage- and time-
dependent outward current 𝐼X1 , primarily carried by K+ ions. All these
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Mathematical Biosciences 334 (2021) 108567
currents were mathematically expressed by HH-like equations. The
model also includes a basic equation describing intracellular calcium
concentration dynamics.
In 1991, the first two models of guinea-pig ventricular cardiomy-
ocytes were published: one developed by Ching–Hsing Luo and Yoram
Rudy [124] and the other by Noble’s group [125], included in the
HEART software package. The Luo–Rudy I model is an update of
the Beeler–Reuter 1977 model with equations adapted from other
models to describe various ion current components. This model uses
HH-like equations to describe six ion currents: three time-dependent
(Na+ , slow inward, time-dependent K+ ) and three background cur-
rents (time-independent K+ , plateau, and background). The rapid Na+
current incorporates a slow inactivation process and an adequate max-
imum conductance surface density. The activation (m) parameters and
inactivation (h and j) steady-state values are adapted from the Ebihara–
Johnson 𝐼Na model based on experimental voltage-clamp data [126],
while the slow inactivation time constant 𝜏j , as well as the slow
inward (Ca2+ ) current are from the BR model. The time-dependent K+
current (𝐼K ) is controlled by a time-dependent activation gate (X ) and a
time-independent inactivation gate (𝑋i ) with inward-rectifying proper-
ties. There are three properties that differentiate the time-independent
potassium current (𝐼K1 ) in the Luo–Rudy I model from the same current
in the BR model: the square-root conductance dependence on [K+ ]o and
the high selectivity for K+ (both discovered by [127]) and the inactiva-
tion gate K1 identified by Kurachi in single-channel experiments [128].
Since this current is completely inactivated during depolarization, the
model was supplemented with two more currents: a [K+ ]o -insensitive
plateau current simulating the single-channel properties of the plateau
current measured by Yue and Marbán [129] and a background current
(𝐼b ). Although derived from single-channel experiments, the conduc-
tances, gating kinetics and reversal potentials of these three currents
were adjusted using a parameter estimation technique to fit the time-
independent whole-cell K+ current measured by Sakmann and Trube
for different [K+ ]o values [130]. Although the Luo–Rudy I model does
not include detailed Ca2+ dynamics, it proved to be very realistic.
A subsequent model issued in 1994 by the same authors [131],
known as the Luo–Rudy II or Luo–Rudy dynamic (LRd) model, features
major improvements in internal Ca2+ handling, including a detailed
and realistic description of SR Ca2+ release and reuptake as well as
myoplasmic and SR Ca2+ buffering. The model was used to evaluate
the relative contributions of Na+ /Ca2+ exchanger and non-specific
Ca2+ -activated currents to phase-3 early afterdepolarizations (EADs), to
distinguish them from phase-2 (plateau) EADs occurring by secondary
activation of L-type Ca2+ channels (𝐼CaL ), and to study SR Ca2+ dy-
namics during postextrasystolic potentiation [132]. It also represented
the starting point for many other ventricular cardiomyocyte single-cell
and multicellular models and studies. Thus, Shaw and Rudy used the
LRd model to build homogeneous or nonhomogeneous 1D propagation
models from gap junction-coupled cell models and studied the time
and voltage vulnerable window of unidirectional block resulting from
premature stimulation [133]. Zeng and Rudy used LRd models with
modified Ca2+ -induced Ca2+ release (CICR) to demonstrate that the L-
type Ca2+ current (𝐼CaL ) exerts the main depolarizing effect during an
EAD irrespective of its triggering factor, and that Ca2+ release from
stores does not necessarily occur during EADs [134]. Dumaine et al.
studied with modified LRd models including 𝐼to to simulate subendo-
cardial, midmyocardial and subepicardial cardiomyocytes the effects of
SCN5 A T1620M point mutation, identified in patients with Brugada
syndrome, resulting in Na+ currents with shifted voltage dependence of
activation and faster inactivation kinetics, demonstrating significantly
faster subepicardial AP repolarization that may explain very well the ST
segment elevation in right ventricular ECG leads [135]. Viswanathan
and Rudy obtained modified versions of the LRd model by varying
𝐼Kr and 𝐼Ks surface densities to reproduce AP shapes and rate adap-
tations specific for subendocardial, midmyocardial and subepicardial
ventricular cardiomyocytes [136], and also used these models to study
B. Amuzescu, R. Airini, F.B. Epureanu et al.
long QT (LQT) 1, 2 and 3 syndromes [137,138]. Clancy and Rudy
also used these modified LRd model versions with Markov models of
Na+ channels to assess the consequences of mutations 𝛥KPQ associated
with LQT3 [139] and 1795insD resulting in either LQT3 or Brugada
syndrome [140], or with Markov models of hERG K+ channels to
explore congenital LQT2 [141] (reviewed in [142]). Faber and Rudy
used the LRd model with modified equations for SR Ca2+ release (𝐼rel ),
Na+ /Ca2+ exchanger (𝐼NaCa ) and Na+ -activated K+ current (𝐼K(Na) ) to
assess the effects of internal Na+ overload on APD [143]. In 2007
they built an improved guinea pig ventricular cardiomyocyte model
including realistic Markov models of L-type Ca2+ channels and RyR2
SR release channels, succeeding to reproduce important experimental
features such as the fractional SR Ca2+ release and voltage-dependent
variable gain of SR Ca2+ release [32]. Livshitz and Rudy used the up-
dated LRd models [137] and Hund–Rudy model [144] in a differential
algebraic system of equations including electrical charge conservation
with a charge-conserving current stimulus and removing singularities
due to discontinuities in function definitions to assess evolution to
steady-state in isolated and 1D propagation models [145].
Another landmark model based on LRd was the Jafri–Rice–Winslow
1998 model [146]; it included a diadic subspace, a Keizer–Levine
Markov model for RyR2, a two-tier mode-switching Markov model of
L-type Ca2+ channel with explicit Ca2+ -dependent inactivation, and
constituted the basis for a series of subsequent developments. The
Winslow 1999 canine ventricular cardiomyocyte model represents an
updated version including modified formulations of 𝐼to , 𝐼Kr , 𝐼Ks , 𝐼K1 ,
𝐼CaL , 𝐽up , used to assess effects of changed current densities in heart
failure [147]. A subsequent update was developed by Greenstein et al.
by introduction of Markov models for the human and canine variants
of I to fast (Kv4.3) and I to slow (Kv1.4) [148].
A series of successful cardiomyocyte models was developed by the
group of Donald M. Bers. Thus, the Puglisi-Bers 2001 model represents
an update of the LRd model with modified kinetics and surface con-
ductance densities for several ion current components, most notably
a HH-like 𝐼to formulation from Winslow et al. [147]; the model was
embedded in a user-friendly graphical interface, the LabHEART soft-
ware [149]. The Shannon–Bers 2004 model includes many components
from the LRd model and Puglisi-Bers 2001 update, combined with an
original SR Ca2+ release/reuptake [150]. Mahajan et al. completed in
2008 the Shannon-Bers 2004 model with an original Markov model of
the L-type Ca2+ channel and improved internal Ca2+ dynamics [151].
Saucerman and Bers issued in 2008 another update of the Shannon-
Bers 2004 model by including kinetic models of Ca2+ binding on
calmodulin (CaM), calcium/calmodulin-dependent protein kinase II
(CaMKII), and the calcium/calmodulin-dependent protein phosphatase
calcineurin (CaN) [152].
A first mouse ventricular cardiomyocyte model, with distinct ver-
sions for apical and septal cardiomyocytes, based on own experi-
mental data and including detailed subcellular compartments, Ca2+
buffers and internal dynamics, was built in 2004 by Bondarenko,
Szigeti, Bett, Kim and Rasmusson [153]. Another mouse ventricular
cardiomyocyte model, developed by Morotti et al. in 2014 based on
the Soltis and Saucerman 2010 rabbit ventricular model [154], suc-
ceeded to reproduce the internal Na+ -induced Ca2+ overload with
subsequent CaMKII activation, creating an arrhythmogenic positive
feedback loop [155]. Negroni et al. 2015 produced a rabbit ventricu-
lar cardiomyocyte electrophysiology and contractility model including
electrophysiology components from the Soltis and Saucerman 2010
model as well as 𝛽-adrenergic effects [156]. Moreno et al. [157] de-
veloped a Markov model for the differential action of ranolazine on
peak and late I Na , separately for wild-type and 𝛥KPQ inactivation-
removed mutant channels, and further explored its pharmacological
effects by inclusion of the I Na Markov models in several ventricular
cardiomyocyte models [157].
There is a trend in cardiomyocyte electrophysiology modeling to
switch from animal models of different species (guinea pig, dog, rab-
bit, rat or mouse) to human models, deemed to be more useful in
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Mathematical Biosciences 334 (2021) 108567
studying various prorrhythmogenic conditions and arrhythmias, as hu-
man experimental data are becoming more easily available. A first
attempt to generate a human ventricular cardiomyocyte model was
taken by Priebe and Beuckelmann in 1998, by adjusting the LRd model
formulations for several ion currents in agreement with parameters
derived from human ion channels and transporters experimental data,
and an internal Ca2+ dynamics modified to reproduce Ca2+ transients
recorded in isolated human cardiomyocytes from patients with terminal
heart failure [158]. The Bernus 2002 model represents a reduced ver-
sion of the Priebe–Beuckelmann 1998 model featuring a few dynamic
variables and fixed internal calcium concentration, but succeeding to
reproduce AP duration and conduction velocity (CV) restitution prop-
erties [159]; due to its computational effectiveness it was extensively
used in large-scale multicellular modeling. The Iyer–Mazhari–Winslow
2004 subepicardial ventricular model includes experimental data from
human cardiomyocytes or human ion channels in heterologous expres-
sion systems, with Markov formulations for the fast voltage-dependent
Na+ current, L-type Ca2+ current, RyR2, 𝐼to (fast and slow), 𝐼Kr , 𝐼Ks ,
and reproduces a variety of phenomena such as spiral wave genera-
tion in 2D cardiomyocyte sheets [160]. Ten Tusscher, Panfilov et al.
also developed humanized ventricular cardiomyocyte models for dif-
ferent layers (subepicardial, subendocardial, and M) using transmural
conductance density gradients for 𝐼to , 𝐼Kr , 𝐼Ks and ion current for-
mulations adapted from other models, succeeding to reproduce the
positive staircase phenomenon for internal Ca2+ transient amplitudes
with increasing pacing frequency and reentry arrhythmias such as 2D
spiral waves [161]. Grandi, Pasqualini and Bers developed a human
ventricular cardiomyocyte model [31] adapted from the Shannon-Bers
2004 rabbit ventricular model, including transmural gradients of Ca2+
handling proteins, new formulations for 𝐼to fast and slow, and Markov
models for some ion channels like RyR2 and a human 𝐼Ks model
from [162]. However, the most successful human cardiomyocyte ven-
tricular models for subendocardial, subepicardial, and midmyocardial
(M) cells are those developed by O’Hara, Virág, Varró and Rudy in
2011 starting from extensive experimental data from dissociated human
ventricular cardiomyocytes, with new formulations and inclusion of
modulatory effects of CaMKII for many ion currents [163]. Due to
its computational effectiveness resulting from exclusive use of HH-like
formulations and a variable-step numeric integration algorithm, as well
as its ability to accurately reproduce proarrhythmogenic conditions
such as EADs, the O’Hara–Rudy 2011 model became a new standard
and reference model for in silico cardiac safety drug testing.
7. Mathematical models of stem cell-derived cardiomyocytes
Human embryonic stem cell-derived cardiomyocytes (hESC-CMs)
and human induced pluripotent stem cell-derived cardiomyocytes
(hiPSC-CMs) have many applications in disease modeling, cell ther-
apy, drug screening and personalized medicine [164]. Differentiation
of hiPSCs into cardiomyocytes is an important method for in vitro
modeling of cardiac diseases such as inherited cardiomyopathies and
arrhythmias [165]; some examples include hypertrophic cardiomy-
opathies [166], dilated cardiomyopathy [167], Barth syndrome [168],
or long QT (LQT) syndromes [169,170].
Computational models can be used to interpret experimental find-
ings in iPSC-CMs, provide mechanistic insights, and translate these
findings to adult cardiomyocyte electrophysiology. In 2013 Paci M.
et al. published the first models of ventricular and atrial-like hiPSC-
CMs [171]. These models were developed by combining different hu-
man or guinea pig HH-like formulations for different ion current com-
ponents with realistic conductance surface densities and Boltzmann
distributions of voltage-dependent activation and inactivation with
parameters adjusted according to experimental data from hiPSC-CM
obtained by the group of Craig January [172]. For the ventricular
model, they also studied the effects of replacement of iPSC-CM-adapted
ion current equations with human adult ventricular HH-like equations
B. Amuzescu, R. Airini, F.B. Epureanu et al.
of the O’Hara–Rudy 2011 model on AP shape, excitability and spon-
taneous pacemaking, and reproduced by simulation the effects on AP
of some well-known ion current blockers such as tetrodotoxin (TTX),
E4031 and nifedipine, in good agreement with results of patch-clamp
experiments on hiPSC-CM [172,173]. The in silico tests of pharmaco-
logical effects of ion channel blockers were continued in a subsequent
study [174]. These encouraging results led to the idea of adjusting or
‘‘tailoring’’ default parameters of a hiPSC-CM model according to data
obtained in an individual patch-clamp experiment on hiPSC-CM to get
a better prediction of pharmacological effects on AP duration [175].
Another interesting development is automated parameter optimization
of a hiPSC-CM model using a weighted cost function algorithm to repro-
duce the experimentally recorded AP and Ca2+ transient wave [176].
This updated Paci 2018 ventricular hiPSC-CM model was used to gener-
ate by parameter variability in silico models of long QT syndromes LQT1
and LQT2, produced by loss-of-function mutations in ion channels
passing 𝐼Ks and 𝐼Kr , respectively [177]. Koivumäki et al. developed
an improved hiPSC-CM ventricular model by using the membrane ion
current equations of the Paci 2013 ventricular model combined with
the cell geometry and Ca2+ dynamics equations of a mouse embryonic
ventricular cardiomyocyte model [178]; the enhanced model was used
to simulate changes associated with Brugada syndrome, LQT syndrome
and catecholaminergic polymorphic ventricular tachycardia (CPVT),
concluding that immature Ca2+ handling in hiPSC-CM prevents accu-
rate in silico modeling of the arrhythmogenic consequences of these
diseases [179]. Another recent study comparing simulation results
using the Paci 2018 ventricular hiPSC-CM model with experimental
extracellular field potential recordings showed that the model failed
to accurately reproduce interbeat intervals and durations of repolar-
ization, presumably due to the approximate equations for the ‘‘funny’’
hyperpolarization-activated current [180].
A remarkable attempt to produce a ‘‘population’’ hiPSC-CM model
was recently performed at University of California Davis by Divya
Kernik et al.: ion current and Ca2+ dynamics equations were adapted
from previous models and several model parameters such as conduc-
tance densities, gating rates, RyR rates, SR buffering affinities and rates
were optimized relative to different experimental datasets, followed by
generation of populations of models by introducing parameter vari-
ability according to experimental distributions, thus reproducing fairly
well the experimental phenotypic variability of AP morphology [181].
The Kernik 2019 hiPSC-CM population of models was further used to
explore and classify arrhythmogenic consequences of 40 point mutants
of KCNQ1, the gene encoding the main subunit of slow delayed-rectifier
K+ channels contributing I Ks [182].
Although a number of studies have pointed out the problems posed
by the immature morphological and electrical phenotype of iPSC-CM,
most notably the low level of I K1 current density due to less developed
t tubule system [183–185] and high propensity to spontaneous pace-
making by improper SR Ca2+ reuptake and NCX activity [184,186],
our direct experience with commercial ventricular-enriched stem cell-
derived cardiomyocyte preparations like Cor.4U® or Pluricyte® CM
from Ncardia proved that when cultured in optimal conditions, at high
density to achieve spontaneously beating confluent monolayers and
allowing sufficient time (≥ 5 days since replating) for maturation results
in about 40% cardiomyocytes with adequate RP and AP shape suitable
for pharmacology studies, particularly upon externally applying faint
hyperpolarizing steady currents up to 30 pA [173,187].
8. Stability and bifurcation analysis of cardiomyocyte models
Cardiomyocyte electrophysiology models at single-cell level, to-
gether with neuronal models, represented during the past half-century a
fertile field for test and development of advanced applied mathematics
concepts and tools such as phase space analysis of non-linear (ordinary)
differential equations (ODE) systems, linear stability analysis and bi-
furcation theory of non-linear dynamic systems, theory of deterministic
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Mathematical Biosciences 334 (2021) 108567
chaotic systems, stochastic processes and Markov chains of independent
random events, a.s.o. A landmark was set in 1960 by Richard FitzHugh
via successful use of an analog electronic computer to generate phase
space portraits of the complete Hodgkin–Huxley nerve excitability
model and of reduced HH models, to plot trajectories, to find equi-
librium points at intersection of nullclines of model variables such as
transmembrane voltage (V ) and open probability of Na+ current acti-
vation gate (m) and assess their stability in different conditions [17].
This achievement led to the development of the FitzHugh–Nagumo
model [2,3], a reduced analytically tractable version of the HH model
featuring essentially the same dynamic behaviors with equilibrium
states of monostability, bistability and sustained oscillations (stable
limit cycles) depending on model parameters, and to the understanding
of the fact that any dynamic model of an excitable system, no matter
how complex, can be transformed into an equivalent FitzHugh–Nagumo
model with only two variables: the transmembrane voltage v and a slow
gating variable w [188].
As more complex and realistic models of cardiomyocyte electro-
physiology were generated, they were subjected to detailed stability
and bifurcation analysis studies. Thus, Teresa R. Chay and Young
Seek Lee performed automated bifurcation analysis via continuation
methods with the software package AUTO developed by Prof. E. Doedel
at Concordia University, Montréal [189,190] of the Beeler–Reuter 1977
ventricular cardiomyocyte model, obtaining by varying a single pa-
rameter (a steady externally applied current) a complex codimension-1
bifurcation diagram featuring multiple fold bifurcation points, as well
as Hopf bifurcation points generating branches of stable and unstable
periodic solutions (limit cycles); near the Hopf points, adequately timed
brief stimuli triggered phase resetting from quiescence to stable oscil-
lations [191]. Vinet and Roberge performed a similar stability analysis
using the AUTO software of a modified Beeler–Reuter model [192]
in conditions simulating myocardial ischemia (high extracellular K+
concentration and increased Ca2+ [slow inward] current density under
stimulatory effect of catecholamines) [193]. Gibb et al. simulated using
the Luo–Rudy 1991 model the propagation of sustained oscillations
appeared on the plateau phase of the action potential, representing re-
peated early afterdepolarizations (EAD), from one patch of ventricular
myocardium to a neighboring one, where they were able to induce
repeated action potentials in conditions of increased tissue volume
resistivity specific for myocardial ischemia or infarction; they were
able to prove using bifurcation diagrams built with the AUTO software
that phase 2 EADs represent periodic oscillatory solutions occurring
near Hopf bifurcation points, and suggested that K+ channels blocking
drugs may enhance EAD synchronization in ventricular myocardium,
exerting proarrhythmic effects [194]. Using the same Luo–Rudy 1991
ventricular cardiomyocyte model, Tran et al. identified a region in
the parameter space of the model where oscillations of a so-called
‘‘fast subsystem’’ [a simplified model with only three variables: trans-
membrane voltage V and open probabilities of ‘‘slow inward’’ Ca2+
current activation (d) and inactivation (f ) gates, but with fixed d and
f time constants] appeared when the real part of two complex conju-
gated eigenvalues of the 3 × 3 Jacobian matrix became positive; these
oscillations representing EADs increased progressively in amplitude
until a homoclinic bifurcation occurred when the trajectory reached
the middle branch of saddle points, sending the system on the lower
branch of stable node equilibrium points at resting potential [195].
In a subsequent study, the same authors demonstrated using recur-
rence plots that irregular EAD occurrence follows deterministic chaos
patterns, and EAD synchronization in myocardial tissue can generate
complex arrhythmias such as polymorphic ventricular tachycardia and
torsades-de-pointes (TdP) [196]. In a similar analysis of the Luo–Rudy
1991 model with the MATCONT software [197,198] we proved that
EADs occur near the Hopf bifurcation point on the upper branch (on V
axis) of equilibrium points when oscillations reach a homoclinic orbit
intersecting a saddle point on the middle branch; we also assessed
vector field discontinuities at singular points resulting from definition
B. Amuzescu, R. Airini, F.B. Epureanu et al.
on intervals of some functions included in the model equations, we
computed the eigenvalues of the Jacobian matrix of the complete 8-
variable linearized system and found the region in parameter space
leading to sustained oscillations due to positive real part (for vari-
able steady externally applied current), and identified the region of
sustained oscillations for a three-dimensional parameter space with
dimensions of externally applied current, calcium (slow inward) and
time-dependent K+ current conductances [199].
Stability of cardiomyocyte models should not be regarded only as
a purely mathematical property resulting from time evolution of the
dynamic differential equations system, but it needs to be interpreted in
biological terms as an emergent feature resulting from the complex in-
terplay of various membrane current components and ion concentration
changes in cellular subcompartments. Thus, phenomena like bistability
or phase resetting of ventricular cardiomyocytes are essentially a con-
sequence of the highly non-linear voltage dependence of multiple ion
currents including the inward rectifier I K1 and fast delayed rectifier I Kr
K+ currents and their role in controlling refractoriness, as proved by ex-
ploring the origin of Wenckebach periodicity and beat-to-beat alternans
of the Luo–Rudy I model [124], or the analysis of APD90 variability
of electrically coupled or uncoupled Luo–Rudy I models and stabilizing
effects of I Na inhibitor TTX and Ca2+ buffering with EGTA vs. destabiliz-
ing effects of I Kr inhibition with L-691,121 demonstrated by Zaniboni
et al. 2000 [200]. The same study highlights the relationship between
transmembrane resistance (Rm ) evolution during AP plateau (phase 2)
and repolarization variability and the importance of Rm monitoring
along this sensitive period, a technique pioneered by Silvio Weidmann
since the 1950s [19] and used recently to improve the results of model
parameter optimization programs using genetic algorithms [201] by
taking into account the all-or-nothing repolarization window during
which dynamic Rm becomes negative [202]. This negative dynamic
Rm during early repolarization resulting from an imbalance between
repolarizing currents and increased inward depolarizing currents is
one major trigger of system oscillations known as EADs, as proved
recently by Trenor et al. [203,204]. Beyond AP phase 2 EADs generated
essentially by I CaL reactivation or its disequilibrium with repolarizing
currents, another important EAD triggering mechanism is represented
by spontaneous SR Ca2+ releases due to higher Ca2+ uptake rates,
as proved recently by Kurata et al. [205]. The same phenomenon,
produced by the chaotic dynamics of SR Ca2+ sparks [206], plays
an important role in phase 3 EADs, DADs and their arrhythmogenic
effects at both ventricular and atrial level, including AF initiation
and maintenance, particularly following heart failure-induced electrical
remodeling [64,68,73,74,157,207].
9. Use of cardiomyocyte models in arrhythmogenesis and cardiac
safety pharmacology studies
The problem of EAD origin is not one of pure theoretical inter-
est. Since a large number of pharmacological compounds are able
to trigger EADs and thus to exert proarrhythmogenic effects, cardiac
safety drug testing may benefit from applying mathematical models
and computational tools to explore such effects. It was shown that TdP
represents the most frequent drug-induced arrhythmia and its occur-
rence is correlated to prolongation of QT interval on electrocardiogram
and block of hERG K+ ion channels that pass 𝐼Kr , the main ion current
component producing repolarization (phase 3) of the ventricular action
potential [208]. It is estimated that 40 to 50% of new pharmaceutical
compounds in research phases exert hERG inhibitory effects that may
result in fatal arrhythmias in humans [209]. Consequently, cardiac
safety drug testing standards adopted by regulatory agencies worldwide
rely on direct in vitro assessment of hERG inhibitory effects or QT
prolongation effects explored in clinical trials, or by in vivo or in vitro
methods. However, a key study performed in 2013 showed that hERG
blocking effects alone are not sufficient to predict the proarrhythmo-
genic (or ‘‘torsadogenic’’) risk of a compound, and propensity to EAD
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Mathematical Biosciences 334 (2021) 108567
generation results from a delicate balance between multiple inhibitory
effects on outward and inward cardiac ion currents [210]. This finding
prompted a paradigm shift in cardiac safety drug testing from the
current ‘‘hERG-centric’’ to the new ‘‘CiPA (Comprehensive in vitro
Proarrhythmia Assay)’’ paradigm [211]. CiPA proposes a three-step in-
depth mechanistic approach based on: 1. study of inhibitory effects of a
drug on multiple human cardiac ion channels expressed in heterologous
cell lines; 2. use of these specific pharmacological inhibition data
together with an advanced human cardiomyocyte electrophysiology
model to predict proarrhythmogenic effects such as EAD occurrence;
3. validation of these predictions via experiments on human induced
pluripotent stem cell-derived cardiomyocytes. Recently, our group in-
troduced enhanced methods for patch-clamp recordings on hiPSC-CM
to combine the three CiPA steps in one assay for in vitro detection of
the proarrhythmogenic liability of drug candidates [187,212].
A number of in silico studies have addressed the second step of
the CiPA paradigm. Thus, a research group at US FDA (Food and
Drug Administration) produced a modified version of the O’Hara–
Rudy 2011 human ventricular cardiomyocyte model by replacing the
standard HH-like formulation for 𝐼Kr (hERG) with a Markov hERG
model including a physiological and a pharmacological component, and
used experimental inhibition data (half-inhibitory concentrations - IC50
and Hill coefficients) for several ion currents (𝐼Na peak and late, 𝐼CaL ,
𝐼to , 𝐼K1 , 𝐼Ks ) as well as rates for the pharmacological component of
the hERG Markov model obtained by direct model-dependent fitting
of macroscopic hERG current recordings to assess computationally
the proarrhythmogenic risk for a panel of 12 compounds [35]. They
proposed as proarrhythmogenic risk predictor cqInward, the integral
over the duration of a complete pacing cycle (2 s) of two main in-
ward (depolarizing) ion currents, 𝐼CaL and 𝐼Na late. In a subsequent
study [213], the same group proposed an even better risk predictor,
𝑄net (integral over the duration of a pacing cycle of six cardiac ion
currents: 𝐼CaL + 𝐼Na late + 𝐼Kr + 𝐼Ks + 𝐼K1 + 𝐼to ), demonstrating
it is more reliable than many other predictors based on analysis of
action potential and intracellular calcium concentration waveforms.
𝑄net seems to accurately reflect the robustness of a cardiomyocyte
model against EAD generation, but an uncertainty quantification anal-
ysis showed that it provided ‘‘safe’’ predictions for the 12-compound
panel only in the range of 1x to 10x 𝐶max (maximal therapeutic free
plasma concentration) [214].
An alternative human ventricular cardiomyocyte model extensively
used for in silico proarrhythmogenic risk testing, for computation of 𝑄net
and other predictors, was developed recently by Tomek et al. starting
from the O’Hara–Rudy 2011 model by including an original Markov
model of L-type Ca2+ channels, the Lu–Vandenberg 2001 Markov model
of hERG channels [13], and updated models of 𝐼Na , 𝐼Cl(Ca) and 𝐼K1 , fol-
lowed by application of a multiobjective genetic algorithm to generate
populations of models [215]. The model was calibrated and extensively
validated by APD restitution and rate dependence, torsadogenic risk
prediction for 62 drugs, reproduction of pathological states such as hy-
perkaliemia and hypertrophic cardiomyopathy, ECG simulations using
whole-heart models. Both 𝑄net predicting models are incorporated in
the Virtual Assay® software [216].
A new idea gaining more and more momentum in computational
cardiac safety pharmacology is that individual cardiomyocyte vari-
ability, for example that induced by stochastic I Ks current fluctua-
tions [217], may exert significant effects on repolarization, AP shape
and arrhythmogenesis, and that multivariate regression analysis ap-
plied to mathematical cardiomyocyte models and construction of pop-
ulations of models can boost proarrhythmogenic risk prediction [218].
Subsequent studies, particularly those of the Mirams group at Ox-
ford, explored the extrinsic and intrinsic sources of variability and
introduced uncertainty analysis and quantification methods for im-
proving model-based predictions [219–221]. Further approaches used
experimental pharmacological effects on AP parameters recorded in
hiPSC-CM combined with multivariate regression and simulations using
B. Amuzescu, R. Airini, F.B. Epureanu et al.
populations of human adult ventricular cardiomyocytes models gen-
erated by random variability in ion conductance surface densities to
perform clinically relevant proarrhythmogenic risk predictions [222].
The population-of-models method, with parameters generated either
randomly or, better, estimated from experimental distributions, was
successfully used in recent studies for hiPSC-CM models [181], ventric-
ular [215,216], atrial [68,78], or Purkinje cell [54] models for drugs
proarrhythmogenic risk prediction, as well as for exploring arrhythmo-
genic effects of cardiac channelopathies [177,182,223].
An interesting approach is to include in cardiomyocyte models
used for proarrhythmogenic risk predictions quantitative data ob-
tained from molecular dynamics simulations. Thus, Ramasubramanian
& Rudy succeeded to correlate structural conformational changes of
a KCNQ1 + KCNE1 (subunits of slow delayed rectifier K+ channels
passing 𝐼Ks ) molecular model obtained via Monte-Carlo methods with
experimentally recorded subconductance states [224]. Xu & Rudy
introduced voltage-and-time-dependent conducting state probabilities
of such models into an O’Hara–Rudy 2011 model to simulate AP shape
at different pacing frequencies and under adrenergic stimulation [225].
Yang et al. used different protonation states of dofetilide and mox-
ifloxacin in molecular dynamics simulations with a conducting state
model of hERG1 channels (passing 𝐼Kr ) to estimate free energy barriers
and blocking/unblocking rates for a direct pore block model, and
further included these data into O’Hara–Rudy models of isolated and
unidimensional-string cardiomyocytes to assess EAD occurrence and
effects on QT interval [226].
Although some general principles for validation of proarrhyth-
mia risk prediction models based on in silico studies have been out-
lined [219,227], the problem is far from being completely solved and
new developments will certainly occur, possibly including quantitative
assessments based on dynamic systems linear stability analysis and
bifurcation theory methods.
10. A note on computational methods
Cardiac electrophysiology models have evolved not only in terms
of the number of variables (describing ion channels and transporters)
they incorporate (Fig. 1), but also in terms of the complexity of the
equations through which these variables are expressed, as more and
more experimental data became available.
Computational tools have evolved tremendously during the last
70 years. Hodgkin and Huxley (1952) had to compute APs generated
by their models ‘by hand’, using a Brunsviga mechanical computing
machine, a process that took Andrew Huxley 8 h to generate only 8 ms
of electrical activity [10]. In 1960–1961 Denis Noble also used the
famous Brunsviga Model 20 mechanical calculator to compute the rapid
upstroke phase of his model, i.e. ∼2 ms of cardiac electrical activity,
and only after long persistence he managed to get access to a Ferranti
Mercury computer at University College London, with a top speed of
10 kFlops, for his cardiac modeling work [21,228,229]. For these first
simulations performed on an electronic valve computer, Noble used di-
rectly machine code scripts on a perforated paper tape; later, he coded
his models in the ALGOL programming language before switching to
Turbo Pascal (TP) on an IBM PC running MS-DOS [48]. In the 1950s
American researchers were also using digital electronic computers for
simulations with the Hodgkin–Huxley model [230–232]. However, use
of the centralized computing facilities of that time was very incon-
venient, and often delays of one week or more occurred between
sending the code and receiving computation results. To speed up this
process, Richard FitzHugh successfully used a Berkeley EASE analog
electronic computer for running the Hodgkin–Huxley model, com-
posed of 40 operational amplifiers, 6 diode functions generators, and
5 servo-multipliers, which printed quasiinstantaneously the dynamics
of transmembrane potential and gating variables on an X-Y chart plot-
ter [17]. In spite of the elegance and simplicity of analog computing,
15
Mathematical Biosciences 334 (2021) 108567
numeric computing eventually won the race of cardiac electrophysiol-
ogy modeling, although patch-clamp amplifiers used for cardiomyocyte
recordings can be considered advanced analog computers.
Numeric integration methods evolved in parallel with the com-
puting gear used to run simulations of the models. Thus, Hodgkin
and Huxley performed numeric integration for their nerve excitability
model [8] with advanced linear multistep integration methods [10]
such as Adams [233,234] or Hartree [235]. Later, Denis Noble used
a classical Runge–Kutta method with a time step of 100 μs [21]. How-
ever, as complexity of the models and the number of ODEs increased,
these numeric integration methods became less effective. Therefore,
Rush and Larsen proposed in 1978 an alternate numeric integration
algorithm [236] applicable to first order ODEs for gating variables, of
the general type:
𝑑𝑦
= 𝛼𝑦 (1 − 𝑦) − 𝛽𝑦 𝑦
𝑑𝑡
where 𝛼𝑦 and 𝛽𝑦 are the opening and closing rates of the gate y, gener-
ally defined by exponential functions of membrane voltage representing
Boltzmann distributions for assemblies of particles with two distinct
energy levels. If these two rates are assumed to be constant during
the integration step 𝛥t, the gating variable y would follow a first-order
monoexponential relaxation kinetics towards a steady-state value:
𝛼𝑦
𝑦∞ =
𝛼𝑦 + 𝛽𝑦
with a time constant:
1
𝜏𝑦 =
𝛼𝑦 + 𝛽𝑦
and the value of y at the time t + 𝛥t could be computed starting from
the previous value at time t with the formula:
𝑦(𝑡 + 𝛥𝑡) = 𝑦∞ − (𝑦∞ − 𝑦(𝑡)) exp(−𝛥𝑡∕𝜏𝑦 )
The method was successfully tested by Rush and Larsen for the
Hodgkin–Huxley and McAllister–Noble–Tsien models with fixed inte-
gration step of 20 μs and even with adaptive integration step in the
range of 10 μs to 1 ms, according to the change in transmembrane volt-
age dV /dt. Subsequently the Rush–Larsen numeric integration method
was widely used in simulations of cardiomyocyte electrophysiology
models based on Hodgkin–Huxley-like formulations of ion channel
gating kinetics; it is still used in the O’Hara–Rudy 2011 model with
an adaptive or constant time step [163]. However, for Markov type ion
channel gating models the direct Euler tangent line method [237] is
preferred with smaller time steps, generally between 1 and 10 μs.
The first cardiac modeling software, named OXSOFT HEART, ap-
peared in 1984 [55,238]. Starting with the 1990s a lot of software pack-
ages and computational environments like LabHEART (http://www.
labheart.org/) [149], CESE (http://cese.sourceforge.net/) [239,240],
iCell (http://ssd1.bme.memphis.edu/icell/) [241], OpenCOR (http://
www.opencor.ws/) [242], Jsim (http://www.physiome.org/jsim/)
[243], AGOS (API generator for ODE Solution) (http://www.fisiocomp.
ufjf.br/) [244], Cardiac Electrophysiology Web Lab (https://travis.cs.
ox.ac.uk/FunctionalCuration/index.html) [245], a.s.o., and libraries
and applications for finite element modeling and 3D visualization like
Virtual Cell (http://vcell.org/run-vcell-software) [246] or CMISS (http:
//www.cmiss.org/) were developed and used to perform simulations
of action potentials and ion currents under a variety of relevant
conditions.
Certainly, these user-friendly tools with attractive and easy to
use graphic interfaces boosted access to cardiac electrophysiology
computations, offering even to inexperienced users the opportunity
to select models and run simulations with different combinations
of parameters, stimulus protocols and integration steps. However,
many professional researchers prefer compiling and running model
scripts written in C/C++, Python, or developed for scientific and
mathematical software platforms such as R, MatLab® , Maple™ or
B. Amuzescu, R. Airini, F.B. Epureanu et al.
Mathematica. For example, MatLab® provides effective numeric in-
tegration routines like ode45 for nonstiff ODE systems, ode15s and
ode23s for stiff systems, while the ginSODA library based on the
DLSODA and DLSODE algorithms developed by Alan Hindmarsh and
Linda Petzold at Lawrence Livermore National Laboratory detects
automatically the errors and switches between solvers for stiff and
non-stiff ODE systems. Some advanced mathematics softwares allow
automated numeric or symbolic computation of the Jacobian ma-
trix of an ODE system, accelerating speed and effectiveness of ODE
solvers. A similar method is used by the CVODE (Variable coefficient
ODE written in C) solver [247], implemented in platforms like Open-
COR and Chaste [248]. Many of these platforms use CellML (https:
//www.cellml.org/) [249], an open multiplatform standardized format
for biological ODE/DAE systems models based on XML (eXtensible
Markup Language) [250] and MathML [251], with RDF/XML (https://
www.w3.org/TR/REC-rdf-syntax/) annotations. Several platforms like
OpenCOR, Chaste, its component PyCml (https://chaste.cs.ox.ac.uk/
cellml/), Jsim and Myokit (http://myokit.org/) [252] perform auto-
mated conversion of CellML models into C/C++ or Python™ scripts.
All these flexible, open, communicating and interchangeable formats,
platforms and libraries create a favorable environment for the devel-
opment of a generous idea in complex systems computational biology,
the Human Physiome Project [48].
In addition, Myokit performs automated CellML model conversion
into MatLab, CUDA and OpenCL scripts, offering parallel computing
facilities for GPU (graphics processing unit) architectures that can be
exploited to run large-scale cardiac electrophysiology simulations at
multicompartmented cellular, tissue or organ level [253–256].
11. Conclusions and perspectives
Cardiomyocyte electrophysiology mathematical modeling evolved
steadily over 60 years, in parallel with improvement of experimental
methods and computational techniques. Looking retrospectively, it is
amazing how the earliest models [21,124] were able to predict a variety
of experimental phenomena with minimal mathematical complexity.
Extrapolating an idea formulated by Wulfram Gerstner for neuron mod-
eling [257], ‘‘toy models’’ may still be mathematically attractive and
easier to approach with analytical methods, offering profound theoret-
ical explanations for essential phenomena like spontaneous pacemaking
and arrhythmogenesis mechanisms.
Examining this long evolution of cardiomyocyte electrophysiol-
ogy models and their surprising diversity, we can identify several
trends: progressive shift from models relying on animal cardiomyocyte
experiments to humanized or completely human models, inclusion
of realistic data on internal Ca2+ dynamics and buffering, deriving
population-average models or population-of-models using large ex-
perimental datasets comprised of current-clamp, voltage-clamp and
Ca2+ microfluorimetry recordings [163,176,181], exploring the pa-
rameter space of models by applying experimental distributions of
key features like conductance surface densities [175], using advanced
human cardiomyocyte models according to the principles of the CiPA
paradigm [211] to explore in silico proarrhythmogenic effects of drugs
[35,213]. Moreover, cardiomyocyte models can be used in massively
parallel computational approaches to explore mechanisms of proar-
rhythmogenic events like EADs, DADs and ventricular arrhythmias
that they trigger [256,258–260]. They also offer a basis for exploring
functional consequences of mutations in genes encoding ion channels
and transporters subunits or associated proteins in the study of cardiac
channelopathies in combination with experiments on patient-specific
induced pluripotent stem cell-derived cardiomyocytes [177,261–263].
Declaration of competing interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
16
Mathematical Biosciences 334 (2021) 108567
Acknowledgments
This study was funded from Competitiveness Operational
Programme 2014–2020 project P_37_675 (contract no. 146/2016),
Priority Axis 1, Action 1.1.4, co-financed by the European Funds for
Regional Development and Romanian Government funds. The authors
gratefully acknowledge Prof. Yoram Rudy for insightful comments, as
well as Cornelia Dragomir and Geanina Haralambie for support.
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