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Mathematical models in cardiac electrophysiology research: implications for the 3Rs
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Martin Fink, Penelope J Noble & Denis Noble FRS, Department of Physiology, Anatomy, and Genetics, University of Oxford
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Abstract
Cardiac disease is one of the main causes of death in the western world; consequently substantial effort is put into researching new drug compounds that could reduce mortality. Understanding the underlying mechanisms of these and other diseases is essential to developing new treatments and to improving quality of life by providing better low cost patient-specific health care. Achieving this will require bringing together information about gene and protein expression, and whole organ function, so that the interaction and effects of multiple factors -from genetic inheritance to environmental influences - can all be assessed. Mathematical modelling and computer simulations of the heart have played an important role in driving progress in cardiac physiology research. This article describes the use of these computer models from the early 1960s to the latest scientific findings, and discusses how this technology can be harnessed to reduce and replace the use of animals in cardiac research.
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Introduction
Every beat of the heart is preceded by an electrical wave that travels across the heart, triggering heart muscle contractions. These muscle contractions are necessary to pump blood through the heart and around the body. It is these electrical waves that are altered in heart conditions such as arrhythmias (see Glossary) and fibrillation (see Glossary), and are a few of the phenomena under investigation by experimental and theoretical physiologists. A range of animal and non-animal models have historically been used to study the electrical properties of the cells and tissues (the electrophysiology) of the heart. However, in the early 1960s, the first mathematical models of heart function were developed (1). Since then, advances in computer technology have made it possible to increase the complexity of these mathematical representations of heart cells while decreasing the time to calculate this information, and it is likely that the complexity of these models will increase with time as the technology allows more features to be incorporated into the models. This article describes how this technology can be harnessed to contribute to the 3Rs.

Computer models of cardiac electrophysiology

The first computer models of heart function were used to provide information on the ion channels in the membranes of heart muscle cells. Ion channels are protein structures responsible for regulating the flow of ions (charged particles) into and out of a cell in order to create the electrical wave that results in heart muscle contraction. There are a number of different proteins in the cell membrane that regulate this ion flow. Ion channels open and close due to the voltage difference across the membrane to allow the passive flow of ions when open, whereas ion pumps and exchangers are dependent on the ion concentrations both inside and outside the cell and work to balance the different ion concentrations (potassium [K+], sodium [Na+], calcium [Ca2+] etc.) both within cellular compartments and between cells. The flow of ions into and out of the cell creates a change in electrical potential across the cell membrane - this is termed an "action potential". In cardiac muscle cells, calcium influx into the cell through calcium channels in the cell membrane triggers the release of calcium ions stored in compartments (e.g. the sarcoplasmic reticulum) within the cell. This phenomenon is called "calciuminduced calcium release" and results in an increased concentration of free calcium ions (Ca2+) in the fluid component of the cell cytoplasm (the cytosol). The calcium ions in the cytosol then bind to a receptor on the actin filament part of the contractile apparatus of muscle cells causing contraction. Shortly after this contraction, the potassium ion (K+) channels reopen and the resulting flow of K+ ions out of the cell restores the ion balance causing the membranes to repolarise to the resting state. Mathematical models of cardiac electrophysiology can illustrate the flow of ions into and out of a cell or even the compartments within a cell, and can provide large amounts of information not only about the ion channels themselves, but also about the interaction between these channels and the electrical waves they produce. The latest computer models can provide information on the elaborate dynamics of more than 15 different ion channels at the same time (2). The models can also be used to predict responses to changes in heart beat rates (e.g. during exercise), ion concentrations in the plasma (e.g. to investigate the effects of low potassium levels in the blood), or even to study the effects of diabetes on the heart. These simulations are also valuable in investigating the effect of drug treatments on the normal functioning of the heart, not just for healthy people but also sick people. The latest models are able to deliver reliable results that have already contributed to the development of two new drugs available for treating heart disease namely: Ivabradine (Servier) and Ranolazine (CV Therapeutics, now Gilead).

Figure 1: This computer model of the canine heart shows how rhythmic waves of electrical activity excite heart muscle cells. The electrical activity is colour coded: red areas show resting muscle cells; blue areas are electrically excited. Beneath the heart is a simulated electrocardiogram (ECG), an electrical signal measured at the body surface showing the activity of the heart. Computer models such as this can be used to understand the mechanistic basis of arrhythmias. (Video provided by Professor Raimond Winslow, Institute for Computational Medicine, John Hopkins University, Baltimore, USA).

Modelling animal cardiac electrophysiology

Mathematical models can also be used to replicate the results of experiments carried out in animals, as well as investigating the mechanisms underlying heart function (see Figure 1). The models could even be used to investigate conditions that would be impossible or prohibited using animals. The action potential wave form (AP) is represented by a graph and describes the changes in electrical potential of a cell. The action potential serves two purposes: it triggers the contraction of a cell; and it interacts with the electrical potential of neighbouring cells to coordinate their contractions. APs differ between species. Figure 2 shows the APs of four different species: mouse, guinea pig, rabbit, and human (Panels A to D, respectively). The APs of the four species are very different from each other, which makes it difficult to draw conclusions from experiments carried out in one species when the results are compared with another. The different amounts of specific ion channels expressed in each species account for these apparent differences in the waveforms.

Figure 2: Electrical waveform in single muscle cells during one heart beat for various species: (A) mouse, (B) guinea pig, (C) rabbit, and (D) human. Note the different shapes and durations of the wave forms (time in milliseconds). Mathematical modelling can be used to compare these species-specific experimental results. For example, "knocking out" (eliminating) the sodium-calcium exchanger gene NCX, which prevents any active protein from being produced, did not have substantial effects in mice, but mathematical models could show that it would be much more dramatic and possibly life threatening if NCX did not function in larger animals that have a longer AP and a substantial plateau phase. Figure 2B-D shows APs that maintain positive membrane potentials for longer, producing a wave form that is a plateau (instead of a sharp peak as in Figure 2A). In mice and other small animals that have short APs, removing NCX does not change the AP waveform because other ion currents can take the place of those channelled through NCX (3). In larger animals, because NCX contributes substantially to maintaining the plateau phase, eliminating the protein would change the AP waveform dramatically by changing the balance of ions and ion currents within the heart (more on this below).

Figure 3: Blocking the sodium-calcium exchanger protein (NCX) might not be beneficial in ischemia when the main risk is intracellular calcium build up that disturbs the electrical waveform pattern (compare solid and dashed lines in Graph A). Blocking the action of NCX might help to normalise the electrical waveform in patients with "long QT syndrome" (Graph B). Solid line denotes the control (normal) case, dashed line the disease state, and the dotted line indicates the effect of blocking the action of NCX. Computer modelling can be used to investigate the effect of calcium overload on heart cells that occurs when the heart tissue is starved of oxygen (ischaemia; 4). For example, experiments and mathematical models have both demonstrated that blocking the action of the NCX protein using pharmaceutical compounds results in the accumulation of intracellular calcium causing abnormal contractions of heart muscle (arrhythmia; see Figure 3A). The same mathematical model was used to show that another type of arrhythmia is caused when repolarisation fails to occur in people with genetic mutations or in people who are taking specific pharmaceutical drugs. Many drug compounds can do this at high concentrations, creating a safety concern for the pharmaceutical industries and health authorities. The mathematical model showed that blocking the action of NCX by 50-80% in these circumstances could be beneficial and could restore the AP length to normal in these patients (5; see Figure 3). The model showed that this was mainly due to the reduced inward flow of calcium ions as a result of the blocked action of NCX, which resulted in a shorter plateau phase allowing the calcium ion levels and the resulting AP to return to normal.

Computer models of the whole ventricle

Mathematical modelling can be used to simulate a healthy heart and compare it with a model of an ischaemic one. In addition, the simulations can be used to study the effect of drugs, defibrillation and cardiac pacemakers, and to optimise drug treatments. Models exist that represent the whole ventricle of the heart (see Figure 4). In order to do this millions of cells have to be included in the simulations and high performance computers are necessary to model just 3 or 4 heart beats. It currently still takes days to do this, however improvements to computational speed will enable more complex and detailed in silico investigations of the heart.

Figure 4: This image shows a heart simulation for a patient with left bundle branch block (see Glossary), modelled using patient-specific clinical data. The image shows electrical activation in the septum and the right ventricle wall of the heart. The ribbons show the muscle microstucture orientation across the heart wall. The blue cones show compression and the red cones show elongation of ventricle motion. Data provided by Dr Reza Razavi at St Thomas Hospital and King's College London; video provided by Steven Niederer, Gernot Plank, Reza Razavi and Nic Smith of the Oxford University Computing Laboratory, Oxford, UK, funded by the EPSRC Grand Challenge project.

Using computer models for hypothesis testing

Cardiac modelling can also be used to test current hypotheses. For example, researchers used mathematical modelling to determine whether or not the changes in expression levels of four ion channels observed in experiments were sufficient to explain the changes in AP waveform and intracellular calcium dynamics observed (6). By adjusting the ion currents in the mathematical model to mimic the experimental situation, they observed a change in AP waveform equivalent to the experimental results seen (see Figure 5). If these adjustments to the model had not been sufficient to confirm the experimental results, a parameter analysis of the model would have been conducted, which might have revealed other changes in gene expression levels; this information would then have been used to influence the design of further experiments to validate the model prediction.

Figure 5: The action potential waveforms of normal cells and heart failure cells are shown in graphs A and B, respectively; intracellular calcium dynamics in these cells is shown in graphs C and D. The underlying ion currents responsible for these changes are shown in Panels E and F. Heart failure (all graphs on the right) is accompanied by changes in the amounts of specific ion channels in the heart muscle cells. Mathematical modelling shows that expression level changes of ion channel proteins are sufficient to explain the differences in electrical waveform compared with a normal heart (left panels).

Cardiac modelling and drug development

Cardiac disease and cancer are two of the main causes of death in the western world; consequently substantial effort is put into researching new drug compounds that could reduce mortality from these diseases. However, more than half of the new compounds that might be beneficial for treating cancer, diabetes, etc. have adverse side effects on the heart.

Figure 6: In a mathematical model of a pacemaker cell the hyperpolarising current (If) was shown to be the main current active during the depolarising phase that determines heart rate. Graph A shows the membrane potential and the current If, whereas Graph C shows the main underlying currents with If. Using ivabradine to block this current (shown in Graph D) slows down the heart rate (solid vs. dashed line Graph B). Electrophysiological models of heart function can be used to improve the safety and efficacy of drugs. For example, Ivabradine, a drug used to treat angina (see Glossary), was developed using computer modelling and was approved by the European Medicines Agency in 2005. Researchers studying rabbit cardiac pacemaker cells (cells that control heart rate by creating the rhythmical electrical impulses), discovered that these cells produced another, previously unknown electrical impulse current (7). When this current was programmed into a newly developed mathematical model the investigators found that it was the main current bringing sodium and potassium ions into the cell during the phase immediately following the initiation of a heart beat. As this phase is important for determining the heart rate a change in this ion current translates into a change in heart rate (see Fig. 6A; 8). Because this ion channel protein was thought to be expressed almost exclusively in pacemaker cells, it represented an excellent target for drug compounds that decrease heart rate (see Fig. 6B), and could therefore be useful for developing treatments for angina (see Glossary).

Figure 7: Mathematical modelling has been used to understand the mode of action of Ranolazine. Even though the drug blocks one of the important repolarising currents (IKr) - which on its own could lead to sudden cardiac death (dashed line) due to its action on other currents (especially the persistent sodium current) it works as an anti-arrhythmic to normalise the currents (dotted line). Mathematical modelling was also used in developing another drug used to treat angina, Ranolazine. This compound prolongs action potential (similar to the effect depicted in Figure 3B), by blocking one of the important potassium ion repolarising currents (IKr) however, due to its activity on multiple ion channels, in particular the persistent sodium current, its overall effect is actually anti-arrhythmic (see Fig. 7). Mathematical modelling could therefore be used to better understand the mode of action of Ranolazine and to gather the necessary data to convince the scientific community and the regulatory agencies that its effect of prolonging the AP does not necessarily mean that the compound will initiate arrhythmias.

The Virtual Physiological Human

Computer models of human physiological processes are not limited to heart function. The Virtual Physiological Human Initiative (VPH-I) aims to improve understanding of the human body by developing computer models that simulate human physiology and disease-related processes. The VPH-I initiative will enable clinicians and researchers in academia and industry to use the simulations to improve the diagnosis, prevention and treatment of disease, ultimately providing patientspecific predictive healthcare (9). There are at least 15 projects that have received substantial funding from the European Union to further scientific research in this area, modelling the different body organs as well as diseases ranging from cancer

and Alzheimer's disease to cardiovascular diseases and osteoporosis (see www.vph-noe.eu/vph-projects). This initiative is based on the Physiome Project, begun in 1997 by the IUPS (International Union of Physiological Sciences), which was the first worldwide effort to develop databases and models to understand the integrated function of cells, organs and systems of the human body. The project focused on compiling central databases that link information from experiments and computational models carried out in laboratories all over the world into a single resource for scientists (10).

Cardiac modelling and the 3Rs

Replacement Computational models will be able to replace animal experiments up to a certain level of complexity in the future. Some data can be gained from in vitro experiments using cultured cells. However, to validate the mathematical models and to obtain more information to increase their reliability and their abillity to accurately predict the in vivo situation, experimental data from animals is currently still necessary. Reduction The most obvious use of mathematical models is to help researchers to decide what animal experiments it would be useful to do. Because the mathematical models contain integrated information about many experiments that have already been performed, they can be used to investigate the importance of future experiments and to predict possible outcomes. Experimental protocols can be simulated before they are carried out in animals. The modelled information can then be used to optimise the protocols to predict whether or not the experiment will be able to answer the question under consideration. As the integrated knowledge represented in the models continues to increase, the number of experiments, and therefore the number of animals used, will decrease. Paradoxically, this may initially require an increase in the number of experiments performed in order to validate the mathematical models. Computer models can also help to ensure that all necessary information can be gained from in vivo experiments using the shortest and least invasive experimental protocol using "sensitivity analysis". This technique has been used in other fields (11) and is currently used in cardiac research mainly to aid in vitro experimental design. Future improvements in numerical algorithms and computer technology will allow the complex whole heart simulations that are needed to replicate the in vivo situation, enabling this method to be used in cardiac electrophysiology research. Refinement Cardiac modelling technology has limited applicability to refinement.

Conclusions
Using computer modelling to understand the heart and its functions has reached a high level of accuracy. However, biological systems are vastly more complex than any engineered artefacts and so it is extremely unlikely that we will be able to reproduce the complexity of nature faithfully within just a few decades. However, these models are becoming increasingly useful tools with an important part to play in understanding human physiology, whilst reducing and replacing animal use in cardiac electrophysiology, and possibly in the study of other diseases and organ systems in the future.

Glossary
Angina: angina pectoris, chest pain due to ischemia (lack of oxygen supply to the heart). Arrhythmias: irregular, unsynchronised beating of the heart. Electrophysiology: science of electrical properties of biological cells and tissues. Fibrillation: is the irregular, rapid contraction of muscle fibres - in this case heart (cardiac) muscle. In silico: a term used to describe research using computers or computer simulations Left bundle branch block: is a cardiac conduction abnormality where electrical activation of the left ventricle is delayed, meaning that right ventricle the contracts before the left ventricle.

Acknowledgements
The NC3Rs would like to thank Professor Raimond Winslow at the Institute for Computational Medicine, John Hopkins University, Baltimore, and Drs Steven Niederer, Gernot Plank, Reza Razavi and Nic Smith at the Oxford University Computing Laboratory, Oxford (funded the EPSRC Grand Challenge project), for the video material they provided, and Dr Steven Manos at the Centre for Computational Science, University College of London for his help in obtaining this material.

References
1. Nobel D (1962) A modification of the Hodgkin-Huxley equations applicable to Purkinje fibre action and pace-maker potentials. Journal of Physiology 160: 317-52. 2. Ten Tusscher KHWJ & Panfilov AV (2006) Alternans and spiral breakup in a human ventricular tissue model. American Journal of Physiology 291: H1088-1100. 3. Noble D et al. (2007) Resistance of Cardiac Cells to NCX Knockout: A Model Study. Annals of the New York Academy of Sciences 1099: 306-309. 4. Noble D (2002) Modelling the heart: from genes to cells to the whole organ. Science 295: 1678-1682. 5. Milberg P, Pott C et al (2008) Inhibition of the Na+/Ca2+ exchanger suppresses Torsade de pointes in an intact heart model of LQT2 and LQT3. Heart Rhythm 5: 1444-1452. 6. Winslow RL et al (1999) Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart failure, II: model studies. Circulation Research 84:571-586. 7. Brown HF, DiFRANCESCO D & NOBLE SJ (1979) How does adrenaline accelerate the heart? Nature 280:235-236.

8. DiFrancesco D (1991) The contribution of the 'pacemaker' current (if) to generation of spontaneous activity in rabbit sino-atrial node myocytes. Journal of Physiology 434: 23-40. 9. Kohl, P. & Noble, D. (2009) Systems biology and the Virtual Physiological Human. Molecular Systems Biology 5: 292 10. Hunter PJ & Borg TK (2003) Integration from Proteins to Organs: the Physiome Project. Molecular Cell Biology 4:237243. 11. Fink M, Batzel JJ & TRAN H (2008) A Respiratory System Model: Parameter Estimation and Sensitivity Analysis. Cardiovascular Engineering 8: 120-134. All views or opinions expressed in this article are those of the authors and do not necessarily reflect the views and opinions of the NC3Rs.

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