Feature: The virtual heart

The heart physiome team is building computer models of the heart to study arrhythmias.

The human heart’s resilience and rhythm is astounding. Every day, it beats about 100 000 times; over 70 years, it will beat 2.5 billion times. Each heartbeat is a masterpiece of choreography: a wave of electrical stimulation spreads across the heart and is turned into the mechanical movements that pump blood to the lungs and body.

The beating heart on Peter Hunter’s laptop screen animates this process in dazzling colours. But this heart is not a superficial animation: it is a computer model founded on millions of mathematical equations that describe the proteins, cells, and tissues of the heart, the product of more than 40 years of research.

And the next heart he demonstrates gives a clue to the object of such research, for it shows an arrhythmia, a disturbance in the normal rhythm that makes the heart pump less effectively. Such arrhythmias can lead to dizziness, fainting, chest pain, and kill hundreds of thousands of people every year.

“We want to model how the heart works as an integrated organ, and what processes lead to arrhythmias,” he explains. “We gather data on cells and processes in the cells, and establish mathematical models that represent these processes. We then have to figure out how to link that data to models of tissue structure.”

Complex though they are, the computer models still do not include all the processes and intricacies of the real human heart. To add these in, and build the most sophisticated virtual heart yet, is the goal of the Wellcome-funded Heart Physiome Project, a collaboration between five professors: Denis Noble, David Paterson, Mark Sansom and Richard Vaughan-Jones from the University of Oxford, and Peter Hunter from the University of Auckland in New Zealand. Their approach is described by Professor Paterson as‘heavy bioengineering’. “Each area has a bioengineer working closely with a physiologist on the modelling work and the experimental work,” he says. “Conceptually it’s a new way of doing science.”

Model building

The field of heart modelling dates back to 1960. Denis Noble, still a PhD student at the time, showed that mathematical equations could model how the electrical activity of a heart cell is influenced by the movement of sodium and potassium ions in and out, transported by pumps, channels that sit in the cell’s membrane. Over last 40 years and more, his models have become increasingly sophisticated, mimicking different types of heart cell and taking into account more of each cell’s ion transport systems.

The latest generations of the heart cell models also include the proton transport models developed by Richard Vaughan-Jones. Normally, the cell keeps careful control over its protons – hydrogen ions – to ensure a constant pH. If an artery becomes blocked and insufficient oxygen is reaching the heart tissue, the tissue can become damaged and acidic (ischaemic). Chaotic electrical activity across the whole heart and arrhythmia results. “These systems are all linked,” points out Professor Noble. “The metabolic functions of the cell are very dependent on protons; it links to the delivery of ATP to the pumps that drive ion transport.”

These ions are transported by pump and channel proteins that sit in the cell membrane. Modelling these proteins on the molecular scale is the focus of Professor Sansom’s research. Such models show the structure of a potassium ion channel, for example, and can be used to understand the effect of a mutation on this structure. “Part of the project is to link these [to Denis’s work],” says Professor Hunter. “What happens if you have a mutation in a particular protein, how that changes the electrophysiology of the cell, how does that change the function of the channel and therefore the cell.”

The pharmaceutical industry is extremely interested in these questions. Approximately 40 per cent of drugs produce cardiac arrhythmias, whether anticancer drugs, diabetes drugs, antihistamines and so on; it is one of the biggest causes of failure of drugs in clinical trials. This is because one of the channel proteins is a promiscuous receptor that responds to 40 per cent of pharmaceuticals and causes arrhythmias. At the end of September 2004, for example, Merck had to withdraw its arthritis painkiller Vioxx, losing billions of dollars in development costs and sales, because it induced heart attack and stroke in a small number of takers.

Coupling the cell models into a whole heart relies on the research of Professor Hunter’s team in Auckland. By taking detailed measurements of the geometry of the heart and the heart’s tissues, its mechanical structure can be modelled mathematically; then, he says, “you can solve physics on top of that”. Using a Wellcome Trust-funded morphometry system, they can zoom in on the heart to measure the three-dimensional structure of the heart tissue. “This is the first time this has been done,” he points out. “You can separate out the different structure in the heart and show how the cells are connected. Then you can run simulations of how electrical current runs through that structure, and produce a three-dimensional model to see how current flows around the heart in waves.”

A final level of detail is added by Professor Paterson’s research on how the nervous system affects the heart’s rhythm. Although the heart has its own pacemaker, the sino-atrial node, neural signals can quickly raise its rate, for example during exercise. “We look at the neural drive that comes to the heart, which affects its excitability,” he says. “When you have a disease, this neural state changes, and you become more prone to arrythmias. We want to understand the detailed neural network of the heart and add it to the whole heart model. It’s another part of understanding the function of the integrated heart.”

Integrated models

Fitting all the data together into a coherent model requires, Professor Noble argues, insight rather than brute force. A cardiac cell might have millions of each of 50 different types of channel in its membrane, so the models try to capture the ‘essence’ of the cell. “If you tried to reconstruct everything – all of the molecules in all of the heart’s cells – no current computer could cope,” he says. “You want to extract from the lower levels the key feature that you wish to incorporate into the higher levels with great simplicity. For example, a mutation in a channel protein that we’ve been looking at changes the electrical charge across the membrane. This shifts one of curves we represent in the equations, so in the model of the whole cell, all we need to incorporate is the voltage shift. You then do experiments to determine whether your insight or intuition is correct – and quite often it’s not!”

One of the team’s key aims is to use the models to help understand different mechanisms of arrythmias. A simple change in a computer file can replicate a mutation in a channel protein, for example, and the impact of that change can be followed in the model of the whole organ. This approach is already shedding light on a key problem facing clincians: why arrythmias that look very similar when recorded on an electrocardiogram (ECG) can have many possible underlying causes. But the opposite problem may be harder to crack: “Much the same mechanism in different people – or in the same person at different times – can give rise to different patterns on the ECG,” says Professor Noble. “This is a real headache that will take some clever unraveling.”

“The experience we have in putting the heart together is already proving transferable to other organs,” says Professor Hunter. “A model developed for an ion channel in the heart may be very applicable to an ion channel in the lung, in particular because biology reuses components in different organ systems.”

“This is a proof of principle, it’s a good model for future models,” adds Professor Paterson. “If we get some good milestones from the heart, we can start adding other systems such as the lung. The big mission is the virtual human – that’s where this project is going, even though it could take 20 years.”

The heart physiome team

New Zealand and Oxford…

Peter Hunter, University of Auckland, is using detailed measurements of the heart tissue architecture and models of cell electrophysiology to build models of the whole heart.

In Oxford…

Denis Noble, University Laboratory of Physiology, introduced the first models of cardiac action potentials in 1960 and is now producing extremely sophisticated models of the electrophysiology of cardiac cells.

Mark Sansom, Department of Biochemistry, is producing molecular models of the channels that sit in the membrane of cardiac cells and transport ions crucial to their electrical activity.

David Paterson, University Laboratory of Physiology, is studying how the nervous system control the heart’s rhythm in normal and disease states.

Richard Vaughan-Jones, University Laboratory of Physiology, is studying how hydrogen ions are regulated in the heart cell, and the damaging impact of low pH that arises when the heart becomes short of oxygen.

Photo credit: Peter Hunter