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Review articles

Modelling the heart: insights,


failures and progress
Denis Noble

Summary illustrate this interaction in biological simulation using some


Mathematical models of the heart have developed over of the cell models that I have been involved in developing.
a period of about 40 years. Cell types in all regions of
the heart have been modelled and they are now being Since my purpose is didactic, I will be highly selective. A more
incorporated into anatomically detailed models of the complete historical review of cardiac cell models can be found
whole organ. This combination is leading to the creation elsewhere(4) and the volume in which that article appeared is
of the first ‘virtual organ,’ which is being used in drug also a rich source of material on modelling the heart, since that
discovery and testing, and in simulating the action of was its focus.
devices, such as cardiac defibrillators. Simulation is a
necessary tool of analysis in attempting to understand At each stage, I will highlight the theoretical insights that
biological complexity. We often learn as much from the came from mathematical modelling as well as the experi-
failures as from the successes of mathematical models. mental basis. I will then briefly review the use of cell models in
It is the iterative interaction between experiment and tissue and organ simulations.
simulation that is important. Examples are given where
this process has been instrumental in some of the major
advances in the field. BioEssays 24:1155–1163, 2002. Energy conservation during the cardiac cycle:
ß 2002 Wiley Periodicals, Inc.
discovery of various forms of potassium
channels
Introduction
The first cardiac cell models sought insight into the most
Mathematical modelling is widely accepted as an essential
obvious difference between electrical activity in heart and
tool of analysis in the physical sciences and engineering, yet
nerve: the duration of the action potential. A nerve action
many are still sceptical about its role in biology. Why is this so?
potential may last only 1 msec. Its function is to encode infor-
A partial answer would be that many chose to work as biolo-
mation as rapidly as possible. In contrast, a human ventricular
gists precisely because they were not mathematically inclined.
action potential may last 400 msec, during which time many
But I think there is a stronger reason. There is also a wide-
events are triggered that initiate and control mechanical
spread belief in the biological sciences that, to be useful,
contraction.
theory must be correct. Failure is seen as just that, i.e. failure,
FitzHugh(5) showed that the Hodgkin–Huxley model of
rather than as an essential part of a two-way iterative process
the nerve impulse could generate slow repolarization by
between theory and experiment.
greatly reducing the amplitude and speed of activation of the
In the case of excitable cells, it could also be that the para-
delayed potassium current, IK. These changes not only slowed
digm model, the Hodgkin–Huxley(1) equations for the squid
repolarization; they also created a plateau. This result showed
nerve action potential, was so spectacularly successful that it
that there must be some property inherent in the Hodgkin–
created an unrealistic expectation for the rapid application of
Huxley formulation of the sodium current that permits a
the same principles elsewhere. In fact, modelling of the much
persistent inward current to occur. The main defect of the
more complex cardiac cell has required many years of inter-
FitzHugh model was that it was a very expensive way of
action between experiment and theory. In modelling com-
generating a plateau, with such high ionic conductances that,
plex biological phenomena, this is precisely what we should
during each action potential, the sodium and potassium ionic
expect(2,3) and it is standard for such interaction to occur over
gradients would be run down at a rate at least an order of
many years in the physical sciences and engineering. I will first
magnitude too large.
That this was not the case was already evident since
Weidmann’s(6,7) pioneering work showed that the conduc-
University Laboratory of Physiology, Parks Road, Oxford OX1 3PT, tance during the action potential is very low. The experimental
UK. E-mail: denis.noble@Physiolox.ac.uk
reason for this became clear with the discovery of the inward-
Funding agencies: The British Heart Foundation, The Medical
Research Council, The Wellcome Trust and Physiome Sciences Inc.
rectifier current, IK1(8–10) (see Fig. 1, top). The permeability of
DOI 10.1002/bies.10186 this channel falls almost to zero during strong depolarisation.
Published online in Wiley InterScience (www.interscience.wiley.com). These experiments were also the first to show that there are at
least two Kþ conductances in the heart, IK1 and IK (referred to

BioEssays 24:1155–1163, ß 2002 Wiley Periodicals, Inc. BioEssays 24.12 1155


Review articles

as IK2 in early work, but now known to consist of IKr and IKs).
The Noble 1962 model(11,12) (Fig. 1, bottom) was construct-
ed to determine whether this combination of Kþ channels,
together with a Hodgkin–Huxley type (see Box 1 in Marder and
Prinz in this issue of BioEssays) sodium channel could explain
all the classical Weidmann experiments on conductance
changes. The model not only succeeded in doing this; it also
demonstrated that an energy-conserving plateau mechanism
was an automatic consequence of the inward-rectifying pro-
perties of IK1. This has featured in all subsequent models,
and it is a very important insight. The main advantage of a low
conductance is minimising energy expenditure.
Unfortunately, however, a low conductance plateau was
achieved at the cost of making the repolarization process
fragile. Pharmaceutical companies today are struggling to deal
with evolution’s answer to this problem, which was to entrust
repolarization to the potassium channel iKr. This channel pro-
tein is one of the most promiscuous receptors known: large
ranges of drugs can enter the channel mouth to block it, and
even more interact with the G-protein-coupled receptors that
control it. The consequence can be failed repolarization, and
the triggering of fatal arrhythmias (see http://georgetowncert.
org/qtdrugs_torsades.asp). Computer simulation is now play-
ing a major role in attempting to find a way around this difficult
and seemingly intractable problem.(13)
The main defect of the 1962 model was that it included
only one voltage-gated inward current, INa. There was a good
reason for this. Calcium currents had not then been dis-
covered. There was, nevertheless, a clue in the model that
something important was missing. The only way in which
the model could be made to work was to greatly extend the
voltage range of the sodium ‘window’ current by reducing
the voltage dependence of the sodium activation process (see
Figure 1. Top: Experimental basis of the first classification Ref. 12, Figure 15). In effect, the sodium current was made to
of potassium currents. Redrawn from reference (10, Fig. 2B). serve the function of both the sodium and calcium channels so
The solid line shows the total membrane current recorded in far as the plateau is concerned. There was a clear prediction
a Purkinje fibre in a sodium-depleted solution. The inward- here: either sodium channels in the heart are quantitatively
rectifying current was identified as iK1, which is extrapolated
here as nearly zero at positive potentials. The outward-
different from those in nerve, or other inward current-carrying
rectifying current, IK, is now known to be mostly formed by channels must exist. Both predictions are correct.
the component IKr. The horizontal arrow indicates the trajectory The first successful voltage clamp measurements came in
at the beginning of the action potential, while the vertical 1964(14) and they rapidly led to the discovery of the cardiac
arrow indicates the time-dependent activation of IK which calcium current.(15) By the end of the 1960s therefore, it was
initiates repolarization. Bottom: Sodium and potassium
conductance changes computed from the 1962 model(12) of
already clear that the 1962 model needed replacing.
the Purkinje fibre. Two cycles of activity are shown. The con-
ductances are plotted on a logarithmic scale to accommodate Controversy over the ‘pacemaker’
the large changes in sodium conductance. Note the persistent current: the MNT model
level of sodium conductance during the plateau of the action In addition to the discovery of the calcium current, the early
potential, which is about 2% of the peak conductance. Note
also the rapid fall in potassium conductance at the beginning of
voltage clamp experiments also revealed multiple compo-
the action potential. This is attributable to the properties of the nents of IK. Noble & Tsien(16) labelled them Ix1 and Ix2, but they
inward rectifier iK1. are now referred to as IKr and IKs.(17) They also showed that
these slow gated currents in the plateau range of potentials
were quite distinct from those near the resting potential, i.e.
that there were two separate voltage ranges in which very slow

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conductance changes could be observed.(16,18) These experi- This is the point at which to emphasise one of the important
ments formed the basis of the MNT model.(19) points about the philosophy of modelling which I highlighted
The MNT model reconstructed a much wider range of at the beginning of this article: it is one of the functions of
experimental results, and it did so with great accuracy in some models to be wrong! (Indeed, a Popperian philosopher of
cases. A good example of this was the reconstruction of the science would say that one can only ever establish the falsity
paradoxical effect of small current pulses on the pacemaker of theories.) Of course, there are many ways of being wrong,
depolarisation in Purkinje fibres (see Fig. 2)—paradoxical and I am not talking here of failing in arbitrary or purely con-
because brief depolarisations slow the process and brief tingent ways, but in ways that advance our understanding by
hyperpolarizations greatly accelerate it. Reconstructing para- exploring possible logics of complex systems and determining
doxical or counter-intuitive results is of course a major function which are most accurate. Again, this situation is familiar to
of modelling work. This is one of the roles of modelling in those working in simulation studies in engineering or cosmol-
unravelling complexity in biological systems. ogy or in many other physical sciences. And, in fact, the failure
But the MNT model also contained the seeds of a spec- of the MNT model is one of the most instructive examples
tacular failure. Following the experimental evidence,(18) it of experiment–simulation interaction in physiology, and of
attributed the slow conductance changes near the resting subsequent successful model development. I do not have the
potential to a slow gated potassium current, IK2. In fact, what space here to review this issue in all its details. That has
became the ‘pacemaker current,’ or If, is an inward current already been done.(21,22) Here I will simply draw the conclu-
activated by hyperpolarization(20) not an outward current acti- sions relevant to modern work.
vated by depolarisation. At the time, it seemed hard to imagine First, careful analysis of the MNT model revealed that its
a more serious failure than getting both the current direction pacemaker current mechanism could not be consistent with
and the gating by voltage completely wrong. There cannot be what is known of the process of ion accumulation and depletion
much doubt therefore that this stage in the iterative interaction in the extracellular spaces between cells. The model itself
between experiment and simulation created a major problem was therefore a key tool in understanding the next stage of
of credibility. Perhaps cardiac electrophysiology was not really development.
ready for modelling work to be successful? Second, a complete and accurate mapping between the
This was how the failure was widely perceived. Yet that IK2 model and the new If model could be constructed(21)
perception was a deep misunderstanding of the significance (see Fig. 2) demonstrating how both models related to the
of what was emerging from this experience. It was no same experimental results and to each other. Such mapping
coincidence that both the current direction and the gating between different models is rare in biological work, but it can be
were wrong, as one follows from the other. And so did much very instructive.
else in the modelling! Working that out in detail was the ground Third, this spectacular turn-around was the trigger for
on which future progress could be made. the development of models that include changes in ion

Figure 2. Reconstruction of the paradoxical effect of small currents injected during pacemaker activity. Left: Computations from the MNT
model.(19) Small depolarising and hyperpolarizing currents were applied for 100 msec during the middle of the pacemaker depolarisation.
Hyperpolarizations are followed by an acceleration of the pacemaker depolarisation, while subthreshold depolarisations induce a slowing.
Middle: Experimental records from Weidmann (Ref. 6, Fig. 3). Right: Similar computations using the DiFrancesco-Noble (1985)
model.(24) Despite the fundamental differences between these two models, the feature that explains the paradoxical effects of small current
pulses survives. This kind of detailed comparison was part of the process of mapping the two models onto each other.

BioEssays 24.12 1157


Review articles

concentrations inside and outside the cell and between levels below 1 mM, i.e. at a level low enough to permit relax-
intracellular compartments. ation to occur. Switching to a stoichiometry of 3:1 readily
Finally, the MNT model was the point of departure for the allowed resting calcium to be maintained below 100 nM. This
ground-breaking work of Beeler and Reuter(23) who developed automatically led to the prediction that there must be a current
the first ventricular cell model. As they wrote of their model: carried by the Na–Ca exchanger and that, if this exchanger
‘‘in a sense, it forms a companion presentation to the recent was activated by intracellular calcium, it must also be strongly
publication of McAllister et al. (1975) on a numerical re- time-dependent since intracellular calcium varies by an order
construction of the cardiac Purkinje fibre action potential. of magnitude during each action potential. Even as the model
There are sufficiently many and important differences be- was being published, experiments demonstrating the current
tween these two types of cardiac tissue, both functionally and INaCa were being performed(27) and the variation of this current
experimentally, that a more or less complete picture of mem- during activity was being revealed either as a late compo-
brane ionic currents in the myocardium must include both nent of inward current or as a current tail on repolarization.
simulations.’’ For a recent assessment of this model and the This prediction has turned out to have very important con-
subsequent Luo-Rudy models see Ref. 4. sequences for the elucidation of some of the mechanisms of
cardiac arrhythmia in disease states in which cells accumulate
Ion concentrations, pumps and exchangers: sodium and calcium, either through loss of energy supply, as
The DiFrancesco–Noble model(24) in ischaemia, or as a consequence of reduced activity of the
The incorporation not only of ion channels (following the Na–K ATPase (Na pump) as in treatment with cardiac
Hodgkin–Huxley paradigm) but also of ion exchangers, such glycosides. At a critical level of sodium and calcium accumula-
as Na–K exchange (the sodium pump), Na–Ca exchange, tion, calcium release occurs spontaneously and becomes
the SR calcium pump and, more recently, the transporters repetitive between sodium concentrations around 13 and
involved in controlling cellular pH,(25) was a fundamental 22 mM,(28–31) a phenomenon also seen experimentally.
advance since these are essential to the study of some dis- Each calcium release activates inward current carried by
ease states such as congestive heart failure(26) and ischaemic sodium–calcium exchange which, if large enough, can trigger
heart disease. additional (ectopic) action potentials,(32) as shown in Fig. 3.
It was necessary to incorporate the Na–K exchange pump The main defect of the DiFrancesco–Noble model was
since what made If so closely resemble a potassium channel that the intracellular calcium transient was far too large, mainly
in Purkinje fibres was the depletion of Kþ ions in extracel- because the model did not represent the attachment of
lular spaces. This was a key feature enabling the accurate calcium to intracellular proteins. This signalled the need to
mapping of the IK2 model (MNT) onto the If model.(21) But, to incorporate intracellular calcium buffering.
incorporate changes in ion concentrations it became neces-
sary to represent the processes by which ion gradients can be Calcium balance: the Hilgemann-Noble model
restored and maintained. In a form of modelling ‘avalanche,’ This deficiency was tackled in the Hilgemann–Noble(33)
once changes in one cation concentration gradient (Kþ) had (1987) modelling of the atrial action potential. Although this
been introduced, the others (Naþ and Ca2þ) had also to be was directed towards atrial cells, it also provided a basis for
incorporated since the changes are all linked via the Na–K and modelling ventricular cells in species (rat, mouse) with short
Na–Ca exchange mechanisms. This ‘avalanche’ of additional ventricular action potentials, and many of its features were
processes was the basis of the DiFrancesco–Noble (1985) adopted in later ventricular cell models of species with high
Purkinje fibre model.(24) plateaus.(34–38)
The greatly increased complexity of the DiFrancesco– The Hilgemann–Noble model addressed a number of
Noble model, which for the first time also represented intra- important questions concerning calcium balance:
cellular events by incorporating a model of calcium release
from the sarcoplasmic reticulum, increased both the range of 1. When does the calcium that enters during each action
predictions and the opportunities for failure. Here I will limit potential return to the extracellular space? Does it do this
myself to one example of each. during diastole (as most people had presumed) or during
The most influential prediction was that relating to the systole itself, i.e. during, not after, the action potential?
sodium–calcium exchanger. In the early 1980s, it was still Hilgemann(39) had done experiments with tetramethylmur-
widely thought that the original electrically neutral stoichio- exide, a calcium indicator restricted to the extracellular
metry (Na:Ca ¼ 2:1) derived from early flux measurements space, showing that the recovery of extracellular calcium
was correct. The DiFrancesco-Noble model achieved two (in intercellular clefts) occurs remarkably quickly (see Fig. 4,
important conclusions. The first was that, with the experimen- inset). In fact, net calcium efflux is established as soon as
tally known Naþ gradient, there simply wasn’t enough energy 20 msec after the beginning of the action potential, which at
in a neutral exchanger to keep resting intracellular calcium that time was considered to be surprisingly soon. Calcium

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Figure 3. Left: Calcium oscillations computed in a model of the Purkinje fibre during the rise in intracellular sodium (red) following block of
the sodium-potassium ATPase. Each oscillation of intracellular calcium (blue trace below) triggers inward sodium-calcium exchange
current (brown trace top) (from Ref. 25). These computations were done under voltage clamp conditions. Right: Free-running action
potentials in the same model with intracellular sodium set at a level corresponding to the middle of the oscillation period in the left hand figure
(from Ref. 32). For a theoretical analysis of this phenomenon in the DiFrancesco–Noble model see Refs. 28,29 and for an analysis of the
more detailed Winslow–Rice–Jafri model(30) see Ref. 31.

activation of efflux via the Na–Ca exchanger achieved this needed to pump? Mitchell et al(40) had already done
in the model (see Fig. 4—compare the computed trace experiments in rat ventricle showing that replacement of
[Ca]0 with the experimental trace labelled [Ca]0) sodium with lithium removes the late plateau. This was the
2. Where was the current that this would generate and did it first experimental evidence that the late plateau in action
correspond to the quantity of calcium that the exchanger potentials with this shape might be maintained by sodium–
calcium exchange current. The Hilgemann–Noble model
showed that this is precisely what one would expect.
3. Could a model of the SR that reproduces at least the
major features of Fabiato’s experiments(41,42) showing
calcium-induced calcium release (CICR) be incorporated
into the cell models and integrate in with whatever were
the answers to questions 1 and 2. This was a major
challenge (see reference (33), pp 173–174). The model
followed as much of the Fabiato data as possible, but the
conclusions were that the modelling, while broadly con-
sistent with the Fabiato work, could not be based on that
alone. It is an important function of simulation to reveal
when experimental data needs extending.
4. Were the quantities of calcium, free and bound, at each
stage of the cycle consistent with the properties of the
cytosol buffers? The answer here was a very satisfactory
yes. The great majority of the cytosol calcium is bound so
Figure 4. The first reconstruction of calcium balance in that, although much more calcium movement was involved,
cardiac cells. The Hilgemann – Noble model (33) incor- the free calcium transients were much smaller, within the
porated complete calcium cycling, such that intracellular and
extracellular calcium levels returned to their original state after
experimental range.
each cycle and that the effects of sudden changes in frequency
could be reproduced. Left: Computed action potential (AP), There were however some gross inadequacies in the
intracellular calcium transient, contraction (represented by
cross-bridge formation) and extracellular calcium transient. calcium dynamics. An additional voltage-dependence of Ca
Inset: Experimental recording of action potential (AP), cell release was inserted to obtain a fast calcium transient. This
motion and extracellular calcium transient. was a compromise that really requires proper modelling of
the subsarcolemmal space where calcium channels and the

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ryanodine receptors interact, a problem later tackled by Jafri, triggering a spreading wave of excitation in the whole tissue
Rice & Winslow(43,44) and by Noble et al.(38) Another problem model (Fig. 5). This was an important step forward in link-
was how would the conclusions apply to action potentials with ing a subcellular mechanism of arrhythmia to multicellular
high plateaus. This was tackled both experimentally(45) and processes. However, the initiation of an ectopic beat is not,
computationally.(35,38) The answer is that the high plateau in in itself, sufficient to trigger a life-threatening arrhythmia
ventricular cells of guinea-pig, dog, human etc greatly delays (fortunately most ectopic beats are benign!) It still remains to
the reversal of the sodium calcium exchanger so that net work out how this mechanism interacts with other features of
calcium entry continues for a longer fraction of the action ischemic tissue, such as slowed conduction due to potassium
potential. This property is important in determining the force- accumulation(48–50) and action potential shortening, to trigger
frequency characteristics. re-entrant arrhythmias that may break down into full-scale
ventricular fibrillation.
Incorporation of cell models into tissue On the one hand, this example shows that both qualitative
and organ models and quantitative conclusions may be drawn from computations
Although single-cell models of the heart were first constructed based on multidimensional, uniform grid-structured cardiac
over 40 years ago, it is only relatively recently that it has models. On the other hand, the deficiencies in these models
become possible to move up to the next levels: tissue and also show that geometrical factors, tissue (in)homogeneity,
organ models into which the cell models can be incorporated. cell-to-cell coupling, etc., are critical to an understanding of
This was always one of the aims of the single cell work, but detailed physiology and pathology. Thus, while grid-structured
until the development of sufficiently powerful supercomputers cardiac tissue models clearly have their place, more sophis-
this objective was beyond reach. ticated ‘anatomical’ models are required to progress be-
One of the early examples of massive three-dimensional yond the reproduction of biophysical behaviour and towards
ionic tissue models used intracellular calcium oscillator models the provision of physiologically and clinically relevant new
of the kind shown in Fig. 3 to address the question of the insights.
minimal size of an ischaemic focus, simulated by sodium Simulating myocardial excitation in three-dimensional
overload in a defined tissue region, that would be arrhyth- anatomically detailed models of the heart began with the work
mogenic.(46) A sodium-overloaded cell group was placed in a of Panfilov and colleagues(51,52) who mapped finite difference
20-cell-diameter spherical volume in the centre of a three- models of FitzHugh–Nagumo equations to experimentally
dimensional network of 128  128  32 atrial cells using the determined cardiac geometry and fibre distribution data.(53)
Earm–Noble single cell model(47) (i.e. more than 500,000 ionic The first solutions of ionic current models used finite
cell models were used). It was shown that this relatively small difference techniques and non-deforming anatomical heart
‘ischaemic’ focus—in real terms, the tissue volume would be geometry.(54)Later, ionic current models were linked to mate-
in the order of no more than a cubic millimetre—is capable of rial points of a moving finite element mesh.(55) This allowed

Figure 5. A three-dimensional atrial model with


centrally located small sodium-overloaded ischae-
mic focus. The dimensions of the atrial tissue block
are outlined in orange, while the action potential
wavefront and plateau are colour coded (red and
magenta, respectively). The excitation begins in the
small central region of sodium overload, where a
calcium oscillation generates an action potential by
activating sodium-calcium exchange (see Fig. 3).
If the overload region (top left) is sufficiently large,
the current it generates is capable of exciting the
surrounding ‘normal’ tissue (top right), so initiating
a propagated wave (bottom left). Reprinted from
Winslow RL, Varghese A, Noble D, Adlakha C,
Hoythya A. Proc Roy Soc B 1990;240:83–96, with
permission from The Royal Society.

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simulation of the electromechanical coupling between the


activation process and the mechanically deforming finite
element model in both directions: the solution of the electro-
physiological equations described the calcium current that
initiates contraction, and the shape changes caused by
cardiac contraction influenced electrical propagation.(56)
Extensions of this work have now been made to accommodate
more-sophisticated models of cardiac ion channels(36–38) and
cellular electromechanical coupling.(57)
At the same time, other important elements of a whole-
heart model are being put in place. Modelling of the coronary
circulation(58) has advanced to the point at which it is possible
to simulate coronary occlusion and so define the areas in the
ventricle that would become ischaemic.(32) Work is also in
progress to incorporate the SA node, atrial and Purkinje
conducting network. A reasonably complete ‘virtual heart’ is
well on the way to construction. Such a project, with immense
implications for practical use in designing new therapies,(32)
would have been inconceivable until very recently.
I will finish this article with a spectacular example of this
kind of use of the ‘virtual heart’. Figure 6 (top) shows the
anatomical model of the canine ventricles(59) with a 1 mm thick
slice in which the fibre orientations are shown. The lower part
of the figure shows three frames from a simulation of arrhy-
thmia (called a tachycardia) in which a rotating spiral wave
(at the back), triggered by the collision of two stimulated
waves, is generating successive waves that propagate
through the structure of the slice. This simulation uses a
modified version of the Beeler–Reuter ventricular cell equa-
tions.(60) It is part of a major study not only of the conditions for
initiating arrhythmia but also of the mechanisms by which
electrical defibrillation may work. The model is the first to use
bi-domain simulation (in which the electrical field outside
the cells is reconstructed as well as the potentials across
the cell membranes), with detailed fibre geometry and detailed
cellular electrophysiology.(61,62)
Such simulations require enormous computing resources,
currently available only on large supercomputers (which is
the main reason why the simulation is restricted to a slice of Figure 6. Top: Diagram of the canine ventricular model(59)
showing the fibre structure of the slice in which the computa-
the ventricle—computations of the whole canine ventricle
tions shown below were carried out. The slice is represented
would, at present, be too demanding). as a full bi-domain model, i.e. the electric current flow in
the extracellular space is also computed. This enables such
Modularity in biological systems models to be used to investigate the effects of massive electric
A recurring theme in these developments is what I have shocks of the kind used in defibrillation. Bottom: Rotating
spiral wave generating successive propagated waves com-
called a modelling ‘avalanche’ in which incorporation of one
puted within the slice model using a modification of the Beeler–
new element has required incorporation of a set of related Reuter ventricular cell ionic current equations (from Refs.
processes. Biological modelling often exhibits this form of 61,62).
modularity, making it necessary to incorporate a group of
protein components together. It will be one of the major chal-
lenges of mathematical biology to use simulation work to approach. This piecemeal approach to reconstructing the
unravel the modularity of nature. Groups of proteins co- ‘logic of life,’ which is the strict meaning of the word ‘phy-
operating to generate a function and therefore being selected siology,’(63) could also be the route through which a systematic
together in the evolutionary process will be revealed by this theoretical biology could eventually emerge.(64,65)

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Future challenges and the nature 3. Bock G, Goode J. (Eds.) Novartis Foundation Symposium no 247,
of biological simulation In Silico simulation of biological processes. London: Wiley; 2002.
4. Noble D, Rudy Y. Models of cardiac ventricular action potentials: iterative
Progress in this field was slow and spasmodic in the period interaction between experiment and simulation. Phil Trans Roy Soc A
between 1960 and 1990. This reflected the lack of experi- 2001;359:1127–1142.
mental data (a problem that was overcome at the cellular level 5. FitzHugh R. Thresholds and plateaus in the Hodgkin-Huxley nerve
equations. J Gen Physiol 1960;43:867–896.
with the introduction of the patch clamp technique and its 6. Weidmann S. Effect of current flow on the membrane potential of cardiac
application to isolated cells), and the lack of computing power. muscle. J Physiol 1951;115:227–236.
But since 1990 there has been an extraordinary explosion of 7. Weidmann S. Elektrophysiologie der Herzmuskelfaser. Bern: Huber;
1956.
modelling work on the heart.(66) There are multiple models of 8. Hutter OF, Noble D. Rectifying properties of heart muscle. Nature 1960;
all the cell types, and I confidently predict that there will be 188:495.
many more to come. Why do we have so many? Couldn’t 9. Carmeliet EE. Chloride ions and the membrane potential of Purkinje
fibres. J Physiol 1961;156:375–388.
we simply ‘standardise’ the field and choose the ‘best’? To 10. Hall AE, Hutter OF, Noble D. Current-voltage relations of Purkinje fibres
some extent, that is happening. None of the historical models in sodium-deficient solutions. J Physiol 1963;166:225–240.
described in this article is now used much in its original form. 11. Noble D. Cardiac action and pacemaker potentials based on the
Hodgkin-Huxley equations. Nature 1960;188:495–497.
One of the major reasons for the multiplicity of models is 12. Noble D. A modification of the Hodgkin-Huxley equations applicable to
that there will always be a compromise between complexity Purkinje fibre action and pacemaker potentials. J Physiol 1962;160:317–
and computability. A good example here is the modelling of 352.
13. Muzikant AL, Penland RC. Models for profiling the potential QT pro-
calcium dynamics. As we understand these dynamics in ever longation risk of drugs. Current Opin Drug Disc Devel 2002;5:127–135.
greater detail,(31) models become more accurate and they 14. Deck KA, Trautwein W. Ionic currents in cardiac excitation. Pflügers
encompass more biological data, but they also become Archiv 1964;280:65–80.
15. Reuter H. The dependence of the slow inward current in Purkinje fibres
computationally demanding. This was the motivation behind on the extracellular calcium concentration. J Physiol 1967;192:479–492.
the simplified dyadic space model of Noble et al.(38) which 16. Noble D, Tsien RW. Outward membrane currents activated in the plateau
achieves many of the required features of the initiation of range of potentials in cardiac Purkinje fibres. J Physiol 1969;200:205–
231.
calcium signalling with only a modest (10%) increase in 17. Sanguinetti MC, Jurkiewicz NK. Two components of cardiac delayed
computation time, an important consideration when import- rectifier Kþ current:differential sensitivity to block by class III antiar-
ing such models into models of the whole heart. But no-one rhythmic agents. J Gen Physiol 1990;96:195–215.
18. Noble D, Tsien RW. The kinetics and rectifier properties of the slow
would use that model to study the fine properties of calcium potassium current in cardiac Purkinje fibres. J Physiol 1968;195:185–
dynamics at the subcellular level. That was not its purpose. 214.
There will probably therefore be no unique model that does 19. McAllister RE, Noble D, Tsien RW. Reconstruction of the electrical activity
of cardiac Purkinje fibres. J Physiol 1975;251:1–59.
everything at all levels. Any of the boxes at one level could be 20. DiFrancesco D. A new interpretation of the pace-maker current, iK2, in
deepened in complexity at a lower level, or fused with other Purkinje fibres. J Physiol 1981;314:359–376.
processes at a higher level. In any case, all models are only 21. DiFrancesco D, Noble D. Implications of the re-interpretation of iK2 for the
modelling of the electrical activity of pacemaker tissues in the heart.
partial representations of reality. One of the first questions to In: Bouman LN, Jongsma H.J, eds. Cardiac Rate and Rhythm. The
ask of a model therefore is what questions does it answer best. Hague, Boston, London: Martinus Nijhoff; 1982. pp. 93–128.
It is through the iterative interaction between experiment and 22. Noble D. The surprising heart: a review of recent progress in cardiac
electrophysiology. J Physiol 1984;353:1–50.
simulation that we will gain that understanding. 23. Beeler GW, Reuter H. Reconstruction of the action potential of ventricular
It is however already clear that incorporation of cell models myocardial fibres. J Physiol 1977;268:177–210.
into tissue and organ models is capable of spectacular 24. DiFrancesco D, Noble D. A model of cardiac electrical activity incorpo-
rating ionic pumps and concentration changes. Phil Trans Roy Soc B
insights. The incorporation of cell models into anatomically 1985;307:353–398.
detailed heart models, as shown in Fig. 6, has been an exciting 25. Ch’en FF-T, Vaughan-Jones RD, Clarke K, Noble D. Modelling my-
development. The goal of creating an organ model capable of ocardial ischaemia and reperfusion. Prog Biophys Mol Biol 1998;69:
515–538.
spanning the whole spectrum of levels from genes(67–71) to 26. Winslow RL, Greenstein JL, Tomaselli GF, O’Rourke B. Computational
the electrocardiogram(13,32) is within sight, and is one of the models of the failing myocyte: relating altered gene expression to cellular
challenges of the immediate future. The potential of such function. Phil Trans Roy Soc A 2001;359:1187–1200.
27. Kimura J, Noma A, Irisawa H. Na-Ca exchange current in mammalian
simulations for teaching, drug discovery, device development heart cells. Nature 1986;319:596–597.
and, of course, for pure physiological insight is only beginning 28. Varghese A, Winslow RL. Dynamics of the calcium subsystem in cardiac
to be appreciated. Purkinje fibres. Physica D 1993;68:364–386.
29. Varghese A, Winslow RL. Dynamics of abnormal pacemaking activity in
cardiac Purkinje fibres. J Theoret Biol 1994;168:407–420.
References 30. Winslow RL, Rice J, Jafri S, et al. Mechanisms of altered excitation-
1. Hodgkin AL, Huxley AF. A quantitative description of membrane current contraction coupling in canine tachycardia-induced heart failure, II Model
and its application to conduction and excitation in nerve. J Physiol 1952; studies. Circ Res 1999;84(5):571–586.
117:500–544. 31. White JA, Guckenheimer J, Winslow RL. Spontaneous calcium release
2. Bock G, Goode J. (Eds.) Novartis Foundation Symposium no 239, in ventricular myocytes: mechanisms and implications. Chaos 2002;
Complexity in Biological Information Processing, London: Wiley; 2001. (in press).

1162 BioEssays 24.12


Review articles

32. Noble D. Modelling the heart: from genes to cells to the whole organ. 50. Shaw RM, Rudy Y. Electrophysiologic effects of acute myocardial
Science 2002;295:1678–1682. ischemia: a theorectical study of altered cell excitability and action
33. Hilgemann DW, Noble D. Excitation-contraction coupling and extracel- potential duration. Cardiovasc Res 1997;35:256–272.
lular calcium transients in rabbit atrium: Reconstruction of basic cellular 51. Panfilov A, Holden A. Computer simulation of re-entry sources in
mechanisms. Proc Roy Soc B 1987;230:163–205. myocardium in two and three dimensions. J Theoret Biol 1993;161:
34. Luo CH, Rudy Y. A model of the ventricular cardiac action potential: 271–285.
Depolarization, repolarization, and their interaction. Circ Res 1991;68: 52. Panfilov A, Keener J. Re-entry generation in anisotropic twisted
1501–1526. myocardium. J Cardiovascular Electrophysiol 1993;4:412–421.
35. Noble D, Noble SJ, Bett GCL, Earm YE, Ho WK, So IS. The role of 53. Nielsen PMF, LeGrice IJ, Smaill BH, Hunter PJ. A mathematical model of
sodium-calcium exchange during the cardiac action potential. Ann NY the geometry and fibrous structure of the heart. Am J Physiol 1991;29:
Acad Sci 1991;639:334–353. H1365–H1378.
36. Luo CH, Rudy Y. A dynamic model of the cardiac ventricular action 54. Winslow RL, Scollan D. 1997; Modelling normal and abnormal
potential: I. Simulations of ionic currents and concentration changes. electrical activity in the canine ventricle: from single cells to whole heart.
Circ Res 1994;74:1071–1096. In XXXIII International Congress of the IUPS pp. L017.08. (abstract),
37. Luo CH, Rudy Y. A dynamic model of the cardiac ventricular action St. Petersburg.
potential: II. Afterdepolarizations, triggered activity and potentiation. Circ 55. Sands GB. 1998. Mathematical model of ventricular activation in an
Res 1994;74:1097–1113. anatomically accurate deforming heart. In Department of Engineering
38. Noble D, Varghese A, Kohl P, Noble PJ. Improved guinea-pig ventricular Science, University of Auckland, Auckland
cell model incorporating a diadic space, iKr & iKs, and length- & tension- 56. Hunter PJ, Nash MP, Sands GB. Computational electromechanics of
dependent processes. Can J Cardiol 1998;14:123–134. the heart. In: Panfilov A, Holden A, editors. Computational Biology of the
39. Hilgemann DW. Extracellular calcium transients and action potential Heart. Chichester: John Wiley & Sons; 1997. pp. 345–407.
configuration changes related to post-stimulatory potentiation in rabbit 57. Hunter PJ, Smaill BH. The analysis of cardiac function - a continuum
atrium. J Gen Physiol 1986;87:675–706. approach. Prog Biophys Mol Biol 1998;52:101–164.
40. Mitchell MR, Powell T, Terrar DA, Twist VA. The effects of ryanodine, 58. Smith NP, Kassab G. Analysis of coronary blood flow interaction with
EGTA and low-sodium on action potentials in rat and guinea-pig ventri- myocardial mechanics based on anatomical models. Phil Trans Roy Soc
cular myocytes: evidence for two inward currents during the plateau. Lond A 2001;359:1251–1262.
Brit J Pharmacol 1984;81:543–550. 59. LeGrice I, Hunter P, Young A, Smaill B. The architecture of the heart: a
41. Fabiato A. Calcium-induced release of calcium from the cardiac data-based model. Phil Trans Roy Soc Lond A 2001;359:1217–1232.
sarcoplasmic reticulum. Am J Physiol 1983;245:C1–C14. 60. Skouibine K, Trayanova N, Moore PA. Numerically efficient method for
42. Fabiato A. Time and calcium dependence of activation and inactivation simulation of defibrillation in an active bidomain sheet of myocardium.
of calcium-induced release of calcium from the sarcoplasmic reticulum Mathematical Biosciences 2000;166:85–100.
of a skinned canine cardiac Purkinje cell. J Gen Physiol 1985;85:247– 61. Trayanova N, Eason J. Shock-induced arrhythmogenesis in the
298. myocardium. Chaos 2002;12:962–972.
43. Jafri MS, Rice JJ, Winslow RL. Cardiac Ca2þ Dynamics: The Roles of 62. Trayanova N, Eason J, Aguel F. Computer simulations of cardiac
Ryanodine Recptor Adaptation and Sarcoplasmic Reticulum Load. defibrillation: A look inside the heart. Computing and Visualization in
Biophys J 1998;74:1149–1168. Science 2002; (in press).
44. Winslow RL, Scollan DF, Holmes A, Yung CK, Zhang J, Jafri MS. 63. Boyd CAR, Noble D. The Logic of Life. Oxford: OUP. 1993.
Electrophysiological modeling of cardiac ventricular function: from cell to 64. Noble D. Biological Computation. In Encyclopedia of Life Sciences,
organ. Ann Rev Biomed Eng 2000;2:119–155. http://www.els.net, London: Nature Publishing Group; 2002.
45. LeGuennec JY, Noble D. The effects of rapid perturbation of external 65. Noble D. The rise of computational biology. Nature Rev Mol Cell Biol
sodium concentration at different moments of the action potential in 2002;3:460–463.
guinea-pig ventricular myocytes. J Physiol 1994;478:493–504. 66. Hunter PJ, Kohl P, Noble D. Integrative models of the heart: achieve-
46. Winslow RL, Varghese A, Noble D, Adlakha C, Hoythya A. Generation ments and limitations. Phil Trans Roy Soc Lond A 2001;359:1049–1054.
and propagation of triggered activity induced by spatially localised Na-K 67. Clancy CE, Rudy Y. Linking a genetic defect to its cellular phenotype in a
pump inhibition in atrial network models. Proc Roy Soc B 1993;254: cardiac arrhythmia. Nature 1999;400:566–569.
55–61. 68. Noble D, Noble PJ. Reconstruction of cellular mechanisms of genetically-
47. Earm YE, Noble D. A model of the single atrial cell: relation between based arrhythmias. J Physiol 1999;518:2P–3P.
calcium current and calcium release. Proc Roy Soc B 1990;240: 69. Noble PJ, Noble D. Reconstruction of the cellular mechanisms of cardiac
83–96. arrhythmias triggered by early after-depolarizations. Japanese Journal of
48. Shaw RM, Rudy Y. Electrophysiologic effects of acute myocardial Electrocardiology 2000;20(suppl 3):15–19.
ischemia: a mechanistic investigation of action potential conduction and 70. Wehrens XHT, Abriel H, Cabo C, Benhorin MD, Kass RS. Arrhythmognic
conduction failure. Circ Res 1997;80:124–138. mechanism of an LQT-3 mutation of the human heart Naþ channel
49. Shaw RM, Rudy Y. Ionic mechanisms of propagation in cardiac tissue: a-subunit. Circulation 2000;102:584–590.
roles of the sodium and L-type calcium currents during reduced ex- 71. Nuyens D, Stengl M, et al. Abrupt rate accelerations or premature beats
citability and decreased gap junction coupling. Circ Res 1997;81:727– cause life-threatening arrhythmias in mice with long QT syndrome.
741. Nature Medicine 2001;7:1021–1027.

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