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Cardiac quest: Insights from simulating the heart’s geometry and function

By Shane Huntington

Computational biologist Prof Edmund Crampin examines the challenges of creating a computational model of the human heart, and discusses what scientists have learned about the actual organ from this enterprise.

SHANE HUNTINGTON
I’m Dr Shane Huntington. Thanks for joining us. Human beings are prolific in their use of pumps to move fluids, from large water pumps used in irrigation systems, to hand operated pumps to draw water from an underground well, pumps are an efficient way to move materials. But the most critical pump is the one brought to us by nature, the human heart.
Understanding the human heart requires more than just viewing it as a simple pump. The heart is a complex bioelectrical device that arguably exceeds the complexity of every other organ in the body except for the brain. Not only does it pump, but it requires the complexity to increase or decrease its pump speed at a moment's notice and to work in perfect harmony with its surrounding environment.
Today on Up Close, we will discuss the challenges of creating a computational model of the human heart with an expert in computational biology. Edmund Crampin is Professor of Systems and Computational Biology at the Melbourne School of Engineering at the University of Melbourne, where he also holds appointments in the Faculties of Science, and Medicine, Dentistry and Health Sciences. Welcome to Up Close, Edmund.

EDMUND CRAMPIN
Thank you.

SHANE HUNTINGTON
You didn't exactly start out in biology in your career, you primarily work in the School of Engineering. What does engineering offer to the biological community?

EDMUND CRAMPIN
Engineering is a way of thinking about and solving problems, and problems that life sciences researchers, in this case people interested in how the heart works, or perhaps how the heart doesn't work efficiently or properly in disease. Engineers can bring an approach to those sorts of questions and those sorts of problems, which we're finding to be very valuable and very useful.

SHANE HUNTINGTON
Let's talk about the modelling of the heart. Why is it important to do this in a computational sense?

EDMUND CRAMPIN
It's a useful approach to take a computational modelling view of the heart, because it allows us to integrate different pieces of information, different bits of knowledge, different data sets that we have about how the heart functions. Computer models can allow you bring those sorts of data sets together and to see how different components of the heart interact, different aspects of the heart work together to generate the pumping of blood around the body. In particular, to see how, if there is a problem with a certain component of the heart, so something going wrong in a heart cell for example, how does that impact the heart's ability to pump blood? And what are the kinds of ways, the kinds of approaches that we might think about taking in order to try to fix that, in order to try to overcome that problem.

SHANE HUNTINGTON
We're talking about a very complex item of the body here. It has muscles, electrical impulses are involved that stimulate each beat, and blood is flowing through its various chambers. Where do you start in terms of developing some sort of computational model that brings in all these elements together?

EDMUND CRAMPIN
That's a very good question, it's one that one could answer from a historical point of view. One of the first things that people were able to do from a computational point of view was to understand the electrical properties of the heart. So the heart pumps in a coordinated fashion because a wave of electrical activity moves through the muscle - moves through the heart muscle. Fairly early on in the development of computational modelling of the heart, Denis Noble, who is now an emeritus professor at the University of Oxford, was at the time at University College London, developed some mathematical equations which he solved on really a very early computer to describe the electrical properties of the heart. So how heart cells generate this kind of electrical activity.
From those very early days of modelling the electrical properties of the heart, people have, over time, developed descriptions of the mechanical properties of the heart, the three dimensional geometry of the heart, the chambers, and how that geometry contributes to the function of the heart. And now, looking at a whole host of other aspects of this biological system, so the metabolism, how the heart gets energy and converts energy from the chemical energy in foods, into the mechanical energy of pumping blood around the body, signalling pathways, a whole host of other aspects of the heart. So we're really building, if you like, layers of complexity to get a more and more detailed picture of how the heart really functions.

SHANE HUNTINGTON
When you talk about electrical stimulation of these muscles, is this the same as what we find in other parts of the body, like muscles in our arms, our legs? Is it essentially the same mechanical principles that are operating?

EDMUND CRAMPIN
Certainly very similar principles. The heart muscle is very similar to skeletal muscle, there are some differences but it operates in a very similar way. So some of the underlying biochemistry, if you like, is the same. Interestingly, the first models that were constructed to describe the electrical properties of the heart are really based on work that was done to describe the properties of nerve cells. So the very first work that gave us a mathematical understanding of how nerve cells work led to the understanding of how heart cells work.

SHANE HUNTINGTON
And when we pull all these elements together, are we able to construct a single model, or do you have to have a range of models looking at different elements of the heart? It seems like a lot of parameters to deal with in one model, but I suppose when we think of things like weather modelling and other sorts of significant modelling or supercomputing, it seems to be well within the range of those levels of complexity.

EDMUND CRAMPIN
So you're asking absolutely a critical question for this kind of research area. The approach that is being taken is what we call a multi-scale approach, so we can look at the heart at a number of different levels of magnification or different levels of biological organisation. So we can look at what's happening inside heart cells and describe the biochemistry of what's happening inside heart cells. We can look at the properties of those cells, how they interact with each other to generate, for example, the wave of electrical activity that moves through the tissue. We can look at the organisation of that tissue, so the heart cells line up in a sheet structure within the heart muscle, and then we can look at how the heart muscle is arranged in a three dimensional geometry.
So looking at each of those different levels, some of the major computational challenges are how to connect them efficiently together. So we do not at the moment have the computational scope or power to be able to have a mathematical model sitting on a computer which represents, for example, every single cell in the heart. That's really way beyond the scope of what's possible, and one might argue it's beyond the scope of what we'd actually like to achieve. A computational model, a computational simulation is really very useful in trying to simplify, trying to pull out some simplifications of what is a very complex system, to allow us to understand how it's really working.

SHANE HUNTINGTON
Presumably, when you have these multiple models, you would be taking the outputs of one model and using them partially as the inputs to another model. So as you suggested, the biochemistry information surely would form an input of some type to the electrical modelling or the pumping modelling. Is that the way it works at the moment?

EDMUND CRAMPIN
Yes, that's right. So if you take a model of, say the electrical properties of a heart cell, you might describe that with a set of different equations - so this is the kind of mathematics that's used to describe the electrical properties of the heart cell. You may have tens of variables describing how ions - sodium ions, potassium ions, et cetera - are crossing the cell membrane to generate the electrical properties of the membrane, describing the proteins, the ion channels which are controlling those ionic currents, looking at other aspects of the cell which are contributing to controlling those currents.
And then to put that into, for example, a model of cardiac tissue, so the next scale of organisation up from the single cell, we might simplify that down into a model which only has a small number of variables, describing some average properties which we think describe, in enough detail to be relevant but no more detail than we need, what's happening at the level of the tissue. So there's always this process of trying to go from the smaller scales to the larger scales, both in terms of spatial scales and also in terms of temporal scales. We don't necessarily need to represent all of the very detailed molecular processes going on in cells when we're trying to describe the beating of the whole heart on a timescale, which is relevant, for example, in the clinic.

SHANE HUNTINGTON
I'm Shane Huntington and you're listening to Up Close. Today we're speaking with computational biologist Edmund Crampin about modelling the human heart. Edmund, when we consider the computational programs that you're working on, what sort of information do we expect to get out of these about the heart that we don't currently know?

EDMUND CRAMPIN
There are some basic questions that we still don't really understand about the heart, and in particular in heart disease. I think that a good example of this would be to say, what we would like to be able to achieve with these models is to be able to predict the outcome of a genetic mutation in a protein which affects the heart. So for example there are ion channels in heart cells which control the electrical properties of those cells. The electrical properties of the cells determine the coordination of the beating of the heart. And we know that in heart disease, for example in fibrillation, we know that during a heart attack, the electrical patterns of beating of the heart are disturbed. But what we can't do reliably at the moment is to say, well, what would be the effect of a mutation in a protein which is involved in that process? Or even to reliably predict what would be the effect of somebody having a drug which interacted with one of those proteins.
So the models are helping us to understand the basic properties, the basic physiology of the heart, but are also moving us towards an era where we can actually predict the effect of a change, a change in a protein for example, the effect of a drug, without having to do the experiment first to see what actually happens in the real system. The models should be able to predict that ahead of time.

SHANE HUNTINGTON
We also have this understanding, of course, that the heart is our mechanism for essentially distributing energy around the body. How well do we understand the way energy actually propagates through the heart, the input and output and what happens? Do we have a good feeling for that from these models?

EDMUND CRAMPIN
That's actually something that we're very interested in. At the moment we are looking at questions around the mechanical efficiency of heart muscle. What we know, of course, is that chemical energy that's taken into the body in the way of the foods that we eat, that chemical energy is converted into a form that our cells can use, and this is not just cells in the heart, this is cells in all of the tissues of the body. And in the mitochondria, organelles inside all of our cells, that chemical energy is used to produce ATP. ATP is known as the energy currency of the cell. It's a molecule which subsequently breaks down to form products and energy is released or coupled to other processes.
Now, we're trying to understand that process, partly because it's essential to how the heart functions and we don't understand enough about it, but also because it's thought to be a major contributor to heart disease, in particular heart failure. And so a better understanding of what's happening in heart metabolism and how that impacts on the heart's ability to pump is potentially useful to us in understanding that disease better.

SHANE HUNTINGTON
Now, this is a question that I can't ask a biologist, I need to ask an engineer, but what is that efficiency of the heart like? Is it an efficient pump or is it a relatively poor pump?

EDMUND CRAMPIN
It depends on what you compare it to. Often we find that when we compare biological systems to manmade systems, biological systems are very slow, are a little bit more efficient, perhaps. I think a good example here would be to compare the conversion of energy - chemical energy in the foods that we eat to the pumping work that the heart does, compare that to what happens in a car engine, for example. In the heart we have a very constant temperature, body temperature, we have a very slow conversion of chemical energy in foods to the mechanical energy of contracting the heart. Compare that to what happens in an engine where we set fire to something, we have an explosion which we try to control. So the heart is more efficient in that sense, but much slower and much more controlled.

SHANE HUNTINGTON
Now, the traditional biological approach to answering many of these questions that we're talking about would be to use some sort of animal model, do some sort of animal experimentation. How well can animal models, in the case of the human heart, actually provide information for us?

EDMUND CRAMPIN
Animal models, in particular of heart disease, are really critical to research, and not just to traditional or conventional approaches where the animal model is used to try to understand disease, but also critical to the kinds of things we're doing. So those sorts of animal models and the experiments that are done generate the parameters that we need for our computational models. There isn't a sense in which the computational models are trying to replace animal experiments and animal-based models of disease. The computational models are really an extra tool that can work in parallel with those animal models to help us to interpret what they're telling us, by having a computational model which in some ways can be easier to investigate. We can really look inside it much more easily than may be the case in traditional wet lab experiments.

SHANE HUNTINGTON
When we think of these animal experimentation scenarios, the more typical one these days is to use mice or rat models. Is there a size problem in terms of the way the heart is operating there? Can you extrapolate from those pumping mechanisms how our heart will work, for example, or is that size differential too great?

EDMUND CRAMPIN
It's not too great. We certainly can learn a lot about how the human heart works from studying rats, from studying mice. And of course, we can manipulate rats and mice in ways that we couldn't possibly do with human cells or human tissues, for ethical reasons and for other practical reasons.

SHANE HUNTINGTON
Edmund, can you give us an understanding of how the pumping action of the heart actually works? Because there's an electrical impulse of some type and then that muscle is forced to do something very specific. Can you talk us through the mechanics of that process?

EDMUND CRAMPIN
The electrical impulse moves through the heart, and that electrical impulse depolarises the membrane of the heart cells. So the electrical depolarisation triggers calcium ions to enter the heart cells. What those calcium ions do is they trigger a larger release of calcium from internal stores. So calcium is a signalling molecule in the cell, it's coupling this electrical activation to mechanical contraction. The way it does that is by the calcium then flooding into the cell and binding to other proteins which then allow contraction to take place. So contraction takes place by other proteins sliding past each other and causing cells to shorten.
So if you think about a cell that is electrically stimulated, calcium ions enter the cell, causing a larger release of calcium ions inside the cell, which bind to proteins in the contractile apparatus of the cell and cause the cell to shorten. The cells are lined up in particular ways in fibre and sheet structures within the muscle, the cardiac muscle, which means that there is a directionality to how that muscle shortens. The consequence of that, with the arrangement of the cells within the sheet structure, within the three dimensional geometry of the heart, is actually that the outside of the heart really just twists a little bit. If you watch a movie of a heart beating, the outside of the heart really just twists a little bit, and it's the inside chamber which decreases in volume.
So if you think about what this pump is doing, the pump is actually producing pressure in the blood in the chambers to pump it around the body by thickening the muscle. The outside stays about the same, the inside gets smaller, the muscle itself actually thickens. It's quite counterintuitive, and it's actually very elegant and very beautiful to understand that from an engineering perspective, from a mechanical perspective.

SHANE HUNTINGTON
Now, when we talk about someone who has a heart that's not necessarily operating properly or is damaged, what sort of parameters within that concept you just described are changed for that person's heart so that their heart is not performing at its optimum?

EDMUND CRAMPIN
Really, there can be changes in a lot of these parameters, and in lots of different aspects of the heart. So there can be changes in the electrical properties of heart cells, so mutations in particular ion channels, for example, as I mentioned earlier. There can also be geometric changes to the heart, so the normal coordinated movement of the electrical activity through the muscle depends on the geometry of the heart. If the heart is not formed in quite the right way, it is possible that that electrical activity can be sustained, which means that when it's triggered, through the normal pace-making activity of the heart, it doesn't just last for one heartbeat, but it's self-sustained in a constant cycling. That can generate what we call an arrhythmia, and that is something which is very strongly associated with heart disease and reduced efficiency of the heart to pump blood.
There can also be disturbances in the mechanical properties of these cells, in the metabolic properties of the cells. We know, for example, that there can be changes in the movement of blood. We think about the heart as being the thing that pumps blood around the body, but of course, the heart muscle itself has to be provided with blood in order to provide oxygen, to provide fuel for the heart. Of course, when that blood supply to the heart, the blood vessels, get blocked, then of course that can lead to heart attack, to ischemia, which is when the region of muscle of the heart itself isn't getting the oxygen it needs, isn't getting the blood supply it needs. So pretty much any part of the heart that you look at is potentially susceptible to things going wrong, leading to disease.

SHANE HUNTINGTON
You mentioned before a requirement for multiple models to look at the heart. What specifically have you been looking at, and what sort of outcomes have those models given you?

EDMUND CRAMPIN
So a lot of the work that my group has been pursuing is at the level of the biochemistry of what's happening in heart cells, signalling processes going on inside heart cells, and then trying to couple that molecular, that biochemical level through to what the cells themselves are doing. So we have been interested in calcium signalling in the heart, the signalling that couples the electrical excitation of the heart muscle to its mechanical contraction. We've been interested in the mechanical properties of heart cells themselves. We work on aspects of metabolism, in particular related to disease. All of this work is done in collaboration with other groups, collaboration with experimental groups.
So my group is primarily doing computational modelling, the models are developed with parameters that come from experiments. We work with colleagues to design the experiments and to do the experiments to generate the parameters we need. Work with other colleagues to take the results or the outcomes of some of these cell models and to use those to parameterise or to inform computational descriptions of the heart muscle, the three dimensional geometry of the heart, to see how changes at the cellular level then result in changes at the level of the whole organ. So this is a big collaborative activity, we're part of several very large collaborations, some which are through colleagues at the University of Auckland – the Bioengineering Institute where we were based for 10 years. There we have colleagues, collaborators with expertise right across the different spatial scales from the molecular through to the whole organ and clinical scales, both in terms of the computational modelling and in terms of the experiments.
We're also part of some international collaborations, again looking at different aspects of heart function and cardiovascular disease, again spanning across these scales from the molecular through to the whole organ, and the clinically relevant scale of whole organ function.

SHANE HUNTINGTON
You're listening to Up Close. We're speaking with computational biologist Edmund Crampin about the possibility of modelling the human heart. I'm Shane Huntington. Edmund, when a doctor looks at a patient and they start gathering information, perhaps, for example, on the heart, there's a variety of signals they're detecting and so forth, and therefore interpret it in a certain clinical way. Are we getting all the information out of that data at the moment we possibly can, or is there the chance that some of this modelling will enable us to really draw out more data about the heart that we're perhaps not seeing at the moment?

EDMUND CRAMPIN
The short answer to that is, at the moment the doctors, cardiologists, do an incredible job with the data that they can collect. But the hope for these kinds of models is that one can pull out more information, more data, and more information from the kinds of tests and measurements that we can currently make. Also, that the models might help us to design better tests, better ways of measuring what's happening in the heart, so we can actually learn more about what's happening. But certainly my experience so far is that our medical colleagues do an extraordinary job with the technologies that are currently available.

SHANE HUNTINGTON
The heart itself is what you would essentially call a multi-scale problem, you described the various elements of it. But it also sits within a very complex environment. Are there currently models being put forward to see how that works, how the immersion of this one very sophisticated and multi-scale object actually fits into this much broader, more complex human body as a whole, and what should we expect to get from that sort of modelling?

EDMUND CRAMPIN
Yes, indeed, there are models at yet a higher level of organisation, looking at the cardiovascular system, looking at all the different inputs which control, for example, blood pressure. And so one might think of the output of a model of the heart as really just feeding into another model at a higher level of organisation. Some of the things which are coming out of that kind of thinking are really how these different systems interact with each other. If you study the heart in isolation, you will learn a great deal about how the heart functions. But of course there are other systems which are feeding back into the heart which are helping to control what the heart is doing.
So really, the whole approach of multi-scale modelling is trying to think of systems as a whole, how the systems function, how the different components of those systems interact with each other to give rise to the properties that we measure on the organism as a whole. So this is really part of what is becoming known as systems biology, the approach of trying to think of biological systems as a whole, as a collection of interacting components which give rise to the properties of the system. So this kind of multi-scale modelling is one approach to trying to do that.

SHANE HUNTINGTON
One of the hopes, I suspect, with this sort of modelling is that when a person goes into surgery, the specific problems with their heart, the special issues they have are somehow modelled before that process and the surgeon's actual work is in some sense dictated, but certainly modified as a result of the information from the models. Is that what we're getting towards here, and what sorts of problems do you think the modelling will have an impact on?

EDMUND CRAMPIN
Yes, so we are now getting to a point where the models are sophisticated enough, are well enough developed that we can start to ask those kinds of clinical questions. One example would be arrhythmia, if somebody has a re-entrant arrhythmia, so they have an accessory pathway, they have a region of the heart where the electrical activation has been continuously restarting itself in one of these loops where it goes around and around and around. What surgeons will do is they will ablate, effectively burn off a little region of the heart muscle in the hope that they can cut that pathway, they can stop that happening. At the moment, the way that that is done is through knowing, from experience, really, from the years of experience that the surgeons have, they will be able to say, well, for this patient, I think that this is the right place to go and do that procedure. The hope is that the models can be used to better guide that process.

SHANE HUNTINGTON
This, presumably, is an incredibly hard process, though. When you described the heart earlier, you talked about entire sheets of cells working collectively. Presumably when they cut into any of these sheets, they have the potential to affect the entire region of the heart that's still working effectively.

EDMUND CRAMPIN
Yes, but, I mean, really what they're doing is they're trying to ablate, they're trying to kill off small areas just to prevent that re-entrant circuit, that electrical circuit. I mean, I guess we know that that works because this is a procedure which is in common use. A question from the modelling perspective is, can we use these models, can we think about using these models to help to design that procedure? So for a particular patient, can we look at the particular three dimensional geometry of their heart, and looking at the particular patterns of electrical activation for their heart, can we give any indications to the surgeons which might make them choose to take this approach in one particular region of the heart rather than another.
There is a sense in which we don't yet have models - well, a very real sense in which we don't yet have models which can extremely reliably predict exactly what will happen. In fact, quite far from it. But the hope is that the models will give some more clues and some more indications which will really help procedures to be more accurate.

SHANE HUNTINGTON
You very elegantly described before the operation of the heart and how so much of it is internal to the outer surface and the outside volume is not really changing that much when it pumps, which would be a surprise to many of our listeners. What does this mean in terms of the possibility of designing an artificial heart? This is something that's been a promise for a long time, but it sounds like the level of complexity we're talking about here, something we have to replace, is just so sophisticated, can we get there?

EDMUND CRAMPIN
It depends what you mean by an artificial heart. This is really not an area that we've contributed very much to, of course, it's a really fascinating area. It seems to me that the developments now are towards heart assist rather than heart replace. So looking at technologies where, instead of taking out a heart and replacing it with something engineered, something made out of metal or plastic, rather the approach is to try to develop devices which can assist a failing heart to pump blood. So there are such devices, of course, currently available. Pace-makers which help the heart to coordinate the electrical activity, again, not replacing the heart but helping it in its function. Those are very engineered approaches.
Of course, there is a huge amount of work going on in terms of trying to understand the biology of heart cells to the point at which we can actually look to regenerative medicines, cell-based approaches, to actually try to help the heart to repair itself. Again, not something that we've worked in, but a very active area of research in Australia and elsewhere.

SHANE HUNTINGTON
Edmund, are there currently any efforts to draw all of these different models together into one big system model of the entire human body?

EDMUND CRAMPIN
Yes, there is an international effort, a collaborative effort called the Virtual Physiological Human, the VPH, which has been funded by the European Union through their FP7 funding program. This is an effort to get the community of people around the world, researchers who are building these kinds of models, to agree to adhere to a set of standards and approaches for modelling so that a team in one part of the world developing a model can get that model to interact with something which was developed in another part of the world, developed by another team. It's also part of the Physiome Project, again an international effort to try to model the different organ systems of the body and how they interact with each other. So a number of these kinds of coordinating activities which are trying to bring all of this activity together.

SHANE HUNTINGTON
Edmund, a pleasure talking to you. Thank you very much for being our guest on Up Close today.

EDMUND CRAMPIN
Thank you.

SHANE HUNTINGTON
Professor Edmund Crampin is the Rowden White Chair of Systems and Computational Biology at the Melbourne School of Engineering, and Adjunct Professor in the Faculties of Science, and Medicine, Dentistry and Health Sciences at the University of Melbourne.