 Good morning, everybody. Welcome to Barcelona. Welcome to our summer school. I'm Bach Benens, one of the organizers, together with Mathieu de Crane and Jérôme Noïe. What you will see is that this is the first summer school that we organize together with the VPH Institute and especially Cardio Function, which is a European project that we having here and which we're training students. The students are here also, so you can interact later on. You all have the program, so you see in the mornings we will have talks here, mainly in the afternoons we have either some visits, so today we will go to the Barcelona Supercomputing Center and on Friday we will go to the Synchrotron out of Barcelona and the other days we will do hands-on later after lunch. You will get a little bit of explanation of this. If you have any questions, practical administrative questions, so you have Joana out here, the one that you met with the registration, or if there's other things, just come to me and just ask. Unfortunately, there's also a strike of the metro these days in Barcelona, so it's a little bit more difficult to get around, but at least you manage to get here and some of your colleagues will come later, I assume. Okay, I think we can start with the program. Maybe you can switch the slides. When you look in the program, the ID that we have is like, okay, it is VPH, so it's like modeling, it's engineering, but what is quite important when you do this type of modeling, when you use this type of technologies, is that this is a constant interaction between medicine and biology and engineering and physics and mathematics. It's intrinsically interdisciplinary, and that's why I think that whoever is working in this field should at least have a little bit of knowledge of each of these, and then of course, depending on your own interests, you choose a little bit more to go into more like the computational part, the theoretical part, the biological part, but it's really important that you have at least the vague knowledge about everything that's going on in the different fields, and at least find that some point when you do this type of work, you need connections to people which have thorough knowledge of each of these. I think that's really crucial in order to advance, because unfortunately we have seen a lot like in this field also, especially from the VPH, but also everything which is modeling and a little bit also biomedical engineering, especially computational, is that kind of technical people stay within their field and try to do something which looks maybe nice, but not necessarily has some clinical impact or can help the people for biomedical research. So that's why I think it's important to go back and forth to what's the basics, what we really want to do, and keep on going on with this discussion. So we'll see that the speakers that we have during this week are from these different backgrounds. What we chose now is to do mainly about cardiovascular kind of pathology, but we also have a little bit of musculoskeletal, so we will go on these two parts. Also to show you that of course there's like a lot of interaction between these, all the methodologies, ways of thinking are very very similar. Obviously we chose cardiovascular because that's what we do here, or one of the things that we do here, it's also within this project, this European project, it's also about cardiovascular. So what I'll start to do is I'll start with kind of an introduction which is very brief in a way because we don't have too much time on cardiovascular pathophysiology, of course you can talk days or weeks about this, but what I want to show you with here is like that that sometimes things are not that simple also as people say and there's a lot of aspects to do. And also in this field what you will see is like of course obviously you have to talk to biologists and to medical doctors, but on the other hand sometimes and especially in clinical medicine people try to kind of simplify things because of course medicine is extremely complex, you have to make decisions on a patient, so you try to make it as easy as possible. But sometimes you need to go deeper, you need to talk more, you need to find out more and I think that's quite important. So let's just very briefly talk about the cardiovascular system, some of the basic backgrounds. So obviously we know we're talking about a heart, a heart is located in your chest, a heart has four chambers, I think most of you will know that, there is a big pipe coming from the what we call the left heart from the left ventricle which is called the aorta and the right heart is connected to the lungs in order to get a double circulation where the left side of the heart pumps the blood throughout the body, the right side of the heart pumps the blood throughout the lungs in order to get them oxygenated. One thing that you see Pashi in this drawing is that actually it's a biological system in the sense that okay the heart is in principle a pump that has to pump around the blood but of course it interacts with the whole system, it interacts with the blood and there's a lot of mechanisms going from molecular to macro the whole kind of system of the organ which interact in a way in order to adapt for example to a situation because it's a pump that is able to when you sleep has some kind of blood circulating but the same time when you do kind of heavy exercise it can still cope with that and it's regulated with that and also of course the blood itself has important properties so it's the whole biology which might be important depending on what you're looking at and that's actually the integrated part where we need to look at. When we look at the structure of the heart itself it's like although you will see that also in the in the practical hands on later on we have several parts which are also modeling vasculature but I will talk now mainly about the heart itself. When you look at the structure of the heart it's actually relatively complex although in what I said before it's like it is a pump intrinsically so what you have is like you have the two sides of the pump you have the left side which as I said before is pumping the blood throughout the body since that is the longest circulation obviously the pressures have to be much higher in that side so you'll see that the muscle is also much thicker and the right ventricle so which is connected to the lungs you will see is kind of attached to the left ventricle in such a way actually that the whole heart forms a certain kind of volume which is actually of course the total volume is not changing too much in your chest so your heart is in your chest but of course the heart cannot deform from the outside because then the lungs need to be deformed or you would create a vacuum within your thorax which is of course not possible so we have a relatively smooth outside and everything is actually happening within and so you see this right ventricle is connected to this left it's much thinner because it's working of course on the lower pressure at least in normal ways. What you have is that the chambers are separated by valves in order to make sure that of course the direction of the blood is only unidirectional so you will see that some problems of course can arise from that and then of course what we need is we need a regular heartbeat and we need a regular heartbeat where the rhythm of the heartbeat is of course also depending on the situation whether you need a lot of exercise or not depending on the amount of oxygen being asked by your body you will see and that is actually arranged by what we call the activation system and I'll come back to that in a minute. What's also important is like when you look at the structure of the heart so intrinsically of course all our organs our whole body are made of cells so at some point you have to go to the cellular level and try to understand what's going on there obviously. Similarly what you see is the heart is made out of what we call cardiomyocytes so heart muscle cells in a way and these are like very elongated cells and what you will see is these cells they can contract by about 10%. When we look at with every heartbeat what actually happens is that the heart ejects about 60% of its volume so in order to get this translation from cells which can shorten only a little bit to a heart which is a very efficient pump and total what you will see is actually that the myocytes are arranged in a very complex architecture within the heart where you see that the cells form more or less fibrous structures so they kind of aligned in a longitudinal way where you see that at the outside of the muscle of the left ventricle you see there in this direction and the more you go towards the inner side throughout the thickness of the muscle what you see is actually that this direction is changing gradually and then actually the inner layer is totally in the opposite direction so it's like a kind of a figure eight that is that is being made by the myocytes and here is a little bit of an illustration of this so where you see this is like going through a heart from the top to the bottom and so you see here this kind of these fiber orientations you see actually how it's different so you see here it spirals in this direction here it spirals in the other direction so you see there's a very complex arrangements of fibers where you nicely see here at the point of the heart what we call the apex all these fibers kind of form like a kind of a whirl in order to make the contraction as efficient as possible here you see that also this is a slice across section where you see that at the outside actually the the muscles the the fibers are perpendicular to the screen here you see they're nicely following in the mid layer and here they're kind of perpendicular again so these are things which are important when you want to understand the heart of course this architecture is important and as you see we need actually complex imaging this is actually images made with a synchrotron it's like face contrast CT where you try to get and capture this information now when you also look at the heart and you especially look at this inner structure so not only is this fiber structure quite quite kind of complex but you see that even the inner architecture of the wall is quite complex and here you see a video of a beating heart and you see all these strands and all this kind of what we call trabiculations and then power point questions so you see this complex structure which has actually two main purposes one is that it acts as a sponge you saw because a sponge is very efficient to take up volume to take up liquid and eject it and on the other hand all these strands that you see are actually electrical shortcuts so they contain what we call pochini cells which are very fast activating cells in order to make sure that every with every heartbeat the electrical activation is as efficient as fast as possible so we're full of these shortcuts to do that fast and so trying to quantify this and trying to also kind of compare different individuals is also one of the research projects which we're doing here which is important to try to understand what's going on now given this fiber structure where we said that when you look at the heart so when you have the top and you have the bottom some are more longitudinal oriented some are more towards the circumference of course based on that when they contract they will make sure that the whole ventricle can deform in different ways and what you will see actually is that your heart as we said before the total heart in your chest the volume is not changing so if we take we have the atria we have the ventricles so what's actually happening during the ejection is that this valve plane is actually moving towards the bottom towards the apex and actually the apex the point of the heart is kind of fixed within the thorax it's not connected to anything but kind of the balance of forces around it make sure that it stays stable and so we really see that this we have this kind of longitudinal contraction where you see that this top the base as we say moves towards the apex at the same time the circumference of the ventricle is changing by contraction of the circumferential fibers and of course because muscle is non compressible what you will see is that we need conservation of volume and you see that you actually get also thickening of the muscle and by these components this longitudinal shortening the circumferential shortening and the radial thickening we get as much volume out with every heartbeat as possible now when we look at the activation understanding the electric electric activation is of course quite important and what you will see there is that what we have is like we have like a natural pacemaker which is what we call our sinus node which is actually on the roof of the right atrium and there we have a bunch of cells which kind of spontaneously generate spikes and that's controlled by some nervous system by the autonomic nervous system which should be the rate of this firing of these cells and what you see then is that this activation is spread out towards the two atria which then of course contract so they contract they fill the heart with blood so they fill the ventricles further with blood and we have an electrical insulation between the two atria and the two ventricles so that when this is activated no electricity is going towards the ventricles and the only electrical connection is through what we call here so that's the AV node the atria ventricular node and it acts as a delay line for electricity so electricity starts here it comes here and is then delayed for a while and is then further conducted towards the ventricles so that we have like the sequence of first atrial contraction and then a little bit later we have the ventricular contraction which then does the ejection of the blood and within the ventricles what we see is so the electricity starts to come from here then is split into what we call a right bundle going to the right ventricle a left bundle going to the left ventricle and into this pukinia system which is actually on top of this trabiculations and in these strands which go from one side to the other in order to get very fast conduction so that the inner layer of the whole ventricle is activated almost instantaneously and then electricity can propagate towards the outside through the tissue in order to have all the cells activated and of course this sequence of activations when we look at that and we would measure it with electrodes on the torex will give in the anti ecg that we use and having the ecg and comparing everything towards the ecgs for timing and cardiology is extremely important so when we do imaging or whatever we always refer to the ecg in order to define the cardiac cycle and this pukinia system which is the fast activation is actually quite complex as we said before so here is a drawing of the left ventricular here you see an injection with ink in some of this pukinia system because these pukinia system really are cables so we have really kind of sheets of collagen which are non-conducting and within these are cells which are connected to each other and these are pukinia cells which have which do not contract but very fastly conduct the activation now this thing is complex and in order to study this it's a very important to incorporate this for example in simulations what you will see is that actually in reality in vivo even in vitro it's extremely difficult to visualize and measure these so in a lot of cases you will see we will discuss that later we just need models even in order to describe them okay when you look at cardiac function as i said before so we have two circulations and within each of these circulations we have actually like the the different systems also which are important so what is of course very important is blood going through your brain a big important part of the blood goes through to your brain actually a lot of blood about 10 percent which is i think is quite a lot goes to the heart itself because of course the heart needs a lot of energy and then we have different systems also within the body and so depending on what you want to study these are things that we need to model need to take into account when you only study the heart and function sometimes you take these together when you want to do it separately when you want to kind of study whatever is going on you might want to split these but we'll show that later on so when you ask a clinician and they said like okay you need to look at a patient that you need to define like is this heart functioning well in a way like then you ask yourself yeah okay what is cardiac function what is the functioning of the heart well intrinsically obviously it's what's happening at the cellular level because each of these cells need to do their work and we know that if we add all these cells up then we have the the the total organ function so knowing what's going on with these cells is probably the most interesting but obviously the most difficult to study also in clinical practice what we do in clinical practice is we try to look at the whole heart and try to infer kind of problems at the cellular level from what we see at the macroscopical level and when you look at the functional itself so of course the heart has to pump around the blood and in order to do that well we know there's two things which are important one is first of all we need to have pressure development because it needs to work at the right amount of pressure in order to get the flow and secondly of course we need to volume output so we need to have that there's enough volume going through because that's what we need we need to volume because that contains the oxygen and the and the nutrition but in order to get that volume through the system with a certain resistance with a certain compliance we of course need this pressure and the force so what you will see then is that when the heart is activated what you will see is first you start to see force development which is building up pressure within the cavity and then when pressure is high enough what we see is we start to see deformation we start to start to see kind of shortening of the muscle in order to do the ejection and when you summarize the little bit to look at the the output of the heart so what you see is we start from a single cell this is an image of a single cardiomyoside with contractile property so we have contractile proteins in there when there's activation these start to first of all develop force this force of in each of the single myosides depending on their orientation of course is translated into pressure perpendicular to the inner side of the myocardium and then this pressure is being built up when the pressure is high enough what you will see is that the valve towards the aorta if it's the left side starts to open and once the valve is open then of course the muscle can shorten and deform in order to do the output but it's already clear from this kind of working principle that first of all the orientations of the cells within the wall are quite important because that determines how force of the individual cells is translated into the pressure in the cavity and what you will see then is like not only the orientation but of course also the whole shape of the ventricle because what we'll see is that when you have diseased hearts you might have hearts which are smaller thicker thinner bigger rounder more oval so even intrinsically the shape will determine how the force of the cells is being translated into pressure next obviously the pressure that we need in order to do the ejection is important and we see with several diseases when for example there's a problem with the valve when there's an obstruction of the valve we of course need higher pressures what we know is a big problem especially in the elderly population is high is hypertension so high blood pressure because of the fact that when you age your vessels become a bit stiffer and then of course when you have stiffer vessels when they're less elastic you need higher pressure in order to get a certain amount of volume through them but not only is this important but the tissue itself is quite important because you can already imagine you have a heart you need to deform it you need to deform the tissue in order to do the ejection if tissue properties change if for some reason this tissue becomes stiffer then we start to get problems and there's several diseases of course the most common in it is that we get a heart attack and we get an infarction of course we get scar there which is much stiffer but there's actually some diseases also which are reasonably rare but still common enough in order to be important which is what we call deposition diseases but for example within the cell because of the fact that some metabolical pathways are interrupted we have for example the accumulation of starch which is like what we call amyloid or iron for example or other kind of crystals which can really get into the heart and then what you see is that of course the the tissue properties are changing already told about the fiber orientation now when you start to look at a lot of different things when you look at the local deformation of the heart because we look at a heart as a or as a ventricle because when we talk about a heart we often talk about a single ventricle what we say is like we look at the ventricle as a pump and everything works together in order to make the pump as efficient as possible but what you will see is that within cardiology there's nothing that affects the whole ventricle as a whole there's always some regional differences and i'll show you later exactly what's going on but what is most important is that when you try to understand what's going on even when you want to simulate it and things like that especially when you want to analyze it is that you have to keep in mind that different segments are actually interacting because what you will see is of course you have a certain segment which is developing force which is contracting which is deforming with a certain amount determined by for example the blood that can go there or the tissue properties but it's connected to another piece of course of myocardium which again starts to contract starts to deform and might have local properties in normal cases there is no interaction because everything is the same within the tissue but of course if one of these segments starts to be dysfunctional what you will see is that the other segments start to of course interact with it and starts to for example stretch it and that's quite important and obviously the time of activation how it's activated how much perfusion is there that will determine also what's going on and then when we study cardiac function as a whole of a whole organ what you will see is that you have different phases during the cardiac cycle where when the heart starts to be activated so what you see there that's the activation then you get atrial contraction in reality within clinical cardiology people start to when the ventricle is activated when the ventricle is activated is like within this QRS complex as we say so the big peak on the ECG that's where you get the electrical activation of the ventricle and what you see there is if it starts to get activated what you see is that the pressure rises if the pressure is high enough compared to the pressure in the aorta of course the aortic valve opens and then you start to see that the volume goes down and that the pressure first increases and then later decreases if then the pressure totally drops because of relaxation of the tissue of course first the aortic valve closes and then a little bit later the mitral valve opens so that blood can come from the atrium and then you first have what we say this early filling a lot of blood coming in and then a little bit later again we give an atrial contraction which gets a little bit more blood within the ventricle and then everything starts again and so you will see it's like when you want to look at cardiac function and you want to study it the electric activation is important the timing with electric activation the pressures are crucial because the pressures determine when we start to get opening and closing of the valves and then based on this we have ejection so we have volume changes and it's all these relations that we need to study in the different periods and so you will see like that in in traditionally for example in laboratory situations what people often do is put a relation between the volume and the pressure it's what we call pressure volume loops because both pressure is important and of course the resulting volume is important and so we can draw a diagram where we see like okay we have filling of the ventricle then we have the pressure increase during what we call the isofalumic contraction period when all the valves are closed and the pressure is being built up then we get a volume decrease during the ejection and then later on the pressure drops again and so you can go around in these circles and what you very often see is that this is what people concentrate on for example in the animal laboratory the cardiologists are looking at this but in a lot of cases also modelers are trying to say like okay this is what we need to do because this is the functioning of the heart and indeed it describes the functioning of the heart but keep in mind it describes the functioning of the heart as a pump in itself from the outside what you will see is when you really look at the tissue there's different ways to get these volumes as we said before you can have very kind of elliptical hearts you can have spherical hearts you can have big hearts you can have small hearts so you can have sometimes quite similar kind of overall function while regionally you have huge differences so it's important to also understand the regional functioning in order to look at that and when you see like what do we have available in order to study this in clinical practice or within research it's like as we said before what we want is intrinsic function we want intrinsic active force development by the myocytes we want to look at the shortening by the myocytes but of course this we cannot study in vivo because you need almost an individual myocyte or a piece of tissue so you can only do that in very invasive setup so this is what we want but we cannot do we have no tools for it what we in reality have is some tools in the clinic where we can try to look at regional macroscopic changes or of course obviously at global changes global function is relatively easy in brackets because we can look at the volume being ejected with every heartbeat so measuring volumes is relatively easy with every imaging technology we can measure volumes in principle we also need pressures then in order to look at the force component and then it becomes tricky already because measuring pressures of the heart it's like in in in kind of a non-invasive way we cannot do it there's no way to really accurately measure pressures non-invasively the only way what we can do is put a catheter inside the heart and measure the pressure locally of course when you go to your doctor they measure the blood pressure on your arm with a cuff and things like that that's easy to measure the problem is you don't know what the pressures within the heart will be because you have all the vasculature in between where depending on the vascular properties of course the transfer function of your vasculature will be different and everybody has a different vasculature and whether it's normal or disease whether you're younger whether you're older it will be different so this this blood pressure that you measure outside is not really accurate so this already is a little bit of a problem now if we want to look regionally what you will see is actually to measure regional deformation of the myocardium we start to have tools based based on echocardiography or based on on magnetic resonance imaging so this we can do but again local wall stresses the only way to do that is by putting a needle there with a force transducer and obviously that's also very very invasive so again these things we cannot do in order to get better estimates from that for example we will need models in order to look at that now the other thing is of course we you can start to look at modeling in different ways like one thing is for example you know that if you have a ventricle with a certain size a certain amount of deformation that will determine how much volume comes in so there's a geometrical relation between the size of a ventricle the deformation of a ventricle and the output performance of the ventricle and you can make models like this and then you start to get an idea that for example with bigger hearts with the same amount of deformation you can do eject much more volume so that's why you see like when you have leaking valves for example you see that for example these hearts are growing and so this is an interesting thing in order to look at and then try to study what's going on with some patients similarly when you try to understand with the forces and especially when you have a certain pressure in the ventricle how does that translate to stresses on individual myocytes or how is the contractile force of individual myocytes transferred into pressure of the ventricle then obviously the kind of the shape of the ventricle is important because we know from even a very simple and kind of a large simplification of the relation between pressures and stresses within an object we know from Laplace law that the more the kind of the more stretched the more flat the large so the larger the radius of curvature of your object the higher the wall stress will be with the same amount of pressure and so you will see that actually elongated ventricles which are very very elliptic have intrinsically higher wall stresses for the same pressure than spherical ventricles and this is important to look at at kind of the shape of the heart but of course when you do like the simple modeling you say okay my left ventricle is in ellipsoid or half an ellipsoid or something like that and you can actually do a lot of calculations and simulations with that but in reality of course it's not so looking at a personalized shape of a patient of an individual in order to understand what's going on is actually quite important and this is where imaging of course helps a lot so that from the individual we can really look at the shape and what you then see that for example is like when you take an ellipsoid actually the stress distribution within this ellipsoid is actually quite heterogeneous so at different places you have a lot of different stresses well when you go to a realistic shape you see that actually it it's much more homogeneous so you see which is actually also in a way logical because all the individual myocytes are very very similar and what we know is that because it's an active biological system if the stress on one myocyte would be higher than what it normally likes to work in you will see that there's releases of growth factors there which will make that the shape is changing or that we get more contractile material and things like that in order to homogenize things and so you will see in reality that you always go to there I think this is this this is maybe also quite important message for for everything is like what you see when you look in the body and you try to understand the system you know that actually everything is working in a local minimum nothing is maybe potentially the best ever but given what we have in the the cells in the different system in the metabolism you know that it always goes to some kind of local minima in order to make it as efficient as possible we get thousands and hundred thousands of years of evolution in order to go there now one other thing is also that while I said that this the more elliptical the ventricle is the higher the wall stresses intrinsically so the ideal would be to have low wall stresses to have a sphere but of course we don't have spherical hearts and the reason is actually is that the elliptical ventricle is more efficient in ejection so with an elliptical ventricle you can eject more blood with the same amount of deformation in a single heartbeat but at the cost of higher wall stresses and so you will see that actually patients can move on this curve it's like when you have a problem with wall stress you start to get a little bit more spherical but when you want to do as efficient as possible as low energetically as possible to do your ejection you go to this more elliptical ventricles now what's also important is that again you look at this relation with shape and the deformation and the the pressures but also like to look at the whole timing of the events is very important it's like what is happening when because that will of course determine first of all how we function at baseline but also whether we have adaptations in order to to look at problems with the heart and what you will see is that actually when we look at the force development within the myosites this force development is not during the whole period of the ejection this force development is actually just at the start of ejection and then we start to get like an increase in the force but what we see is that about half of the time of ejection what we call sisterly what you see is that actually the force development is breaking down and what we see is that most of the ejection then later is actually purely inertial so we first accelerate the blood going out and then we stop the force development but there's still outflow of course because of inertia inertia from the blood itself inertia from the tissue itself so we see that force development is very early actually there's several reasons for this so because one of the things that you will see and I'll show that later is that this gives us a way to adapt to some changing conditions but also what you see is like when you start to think again about how contraction is taking place and actually within our myosite the force development is because of the interaction of actin and myosin and what you see is like with actin and myosin the thing that needs energy is actually the breakdown of the forces so you need time in order to break down the forces so that means that you cannot suddenly stop your force development and then be able to kind of elastically recoil in order to get filling that doesn't work unfortunately so you need to stop really your active contraction earlier and this is the reason like why there's a difference in timing and looking at this difference in timing and how this timing is changing with diseases is actually quite important if we now want to understand the relation between also the force development by piece of tissue by the myosites in there and what we can measure as deformation because as I said before deformation local deformation we can measure with our imaging techniques but unfortunately local force development we cannot so we have to try to infer it or we have to make models in order to calculate it and so then of course you have to look at this intrinsic relation and of course when we know the relation the simplest relation between kind of force and deformation is of course Hooke's law which says that if we have a certain amount of force the amount of deformation will be of course proportional to the force or the stress on the object and the elastic properties the elasticity of the object and so the more elastic the object is the more we can deform it with a certain amount of force now when we look at the heart actually the force development of course of the tissue is inside the tissue not at the outside of the tissue so we would think that there's this relation between the contractile force and the deformation through the elasticity which again is true because this is a universal law you can say like okay whether this is a tensor or not but what is important is that you that this part of the equation is of course all the forces that act up on the myocardium and only contractile force is only one force because when you look at this piece of myocardium which is contracting of course it's embedded in a ventricle and inside this ventricle there's pressure which is of course made by all the segments so if something is wrong with this segment it still feels the big pressure that's being developed by the other so pressure is actually one of these forces and of course that's translated through the geometry into the local wall stress but what is also important is what we said before is this interaction with the environment because you have to take the force from the neighboring segments into account when you want to look at deformation and it's only when you make this kind of relationship where you have the contractile force the active contraction as we say and what you can call the passive loading which is mostly the influence of the other segments then you can start to look at this relationship and here you see what I said before so your active contraction which acts in this direction for this segment is of course has a certain timing in the beginning your pressure will be perpendicular to the endocardial wall so to the inner wall and is translated into stress we have the interaction with the segments and then of course we have the elastic properties of the tissue which is of course hyper elastic as we know with most of the material which means that the more you stress it or the more you press it the more force you will need in order to deform it further so this is a nonlinear relationship now one of the things when you look at the formation which also is very particular to the heart is that because of this fiber orientation that we said before it's like where at the outside of the muscle you have fibers in this direction in the middle you have fibers in this direction in the inside you have it in the other direction so that means that at the outside and at the inside you have actually fibers which are actually obliquely oriented from this base towards the apex and of course when they're oblique when they contract what they will do is they will induce a rotation so there will be a momentum of rotation between the base and the apex and what you see is the outside layer does it in one direction the inner layer does it in the other direction for several reasons being the both the geometry and of course the distance from the center of gravity what you will see is that in normal hearts this outside layer is the one which is dominant to do the rotation and what you see is that during contraction what actually happens is that the heart is not like a piston pump but it's really like screwing down so the ventricles screwing down and in this way can do do the most of the ejection now what you see there is that actually because of also this this kind of difference in this kind of the difference in the angle that these fibers are oriented what we said before is like the outside one is dominating for the rotation but the inner layers in the other direction is of course counteracting but what you will see is that most of the diseases in cardiology actually affect the inner layer of the heart first there's several reasons for it first of all because the wall stress will be a bit higher there with the pressure but what is also very important is that when we look at the perfusion the coronary circulation so the arteries that bring the blood to the tissue they're actually at the outside of the heart so they are at the outside and then penetrate towards the inside that means that the endocardial layer is the furthest away from the blood circulation so whenever something happens with the blood circulation it's always this first these inner layer which is affected most and so what you will see is that for example when we age our vessels get a little bit stiffer you get a little bit more wall stress you start to lose a little bit of this initial so of this inner layer function and what happens now is that when you look at this rotation you start to lose some of these inner ones and then you start to get more rotation for example when you start aging and at one hand you get more rotation on the other hand you lose some of your myocytes which would drag down your heart so that means that this kind of contribution of the function will diminish and it's actually taken over in a lot of cases by this circumferential deformation so even when aging like a normal process you see that this is changing this also brings you to for example what is normality what you see is that that medical doctors when they do a study they have like a control population they have another population and they say like these are normals these are abnormal and you try to compare it or you have an individual patient coming to you you do a measurement you ask yourself is this measurement normal yes or no what you will see is that in most of the guidelines there's a number and that says like okay if it's below this it's normal it's above that it's abnormal but of course that's a huge simplification because normality doesn't exist there is no normal person there's just a range of possibilities which are considered to be normal so you actually have a distribution and that depends also on the age so you should compare it to ages it depends even on the gender so women and men they will have different measurements at different ages so things are complex in reality unfortunately in clinical practice this cannot be done again I think in the future more and more tools that we can provide towards the clinicians can simplify these processes so that we can take this to into account that we have a normality distribution which is dependent on individual patients now what you see in the literature if if you look at this torsion there's some cardiologists that say like yeah this increase in torsion with aging helps in order to get the ejection better what we also see is in some other diseases you get an increase so distortion is a really important component but what you see then on the other hand is that well what I said before normally your heart is towards the left side so everybody has the left heart towards the left side however there's some people born which are actually totally mirrored inside so everything so when normally your liver is at the right side your heart at the left side what they have is there everything is just the opposite it's what we call site is in versus totalis so they're just mirrored inside and what you will see is that when you then look at these hearts actually these hearts are not total mirrored because mirroring is a thing which happens genetically but some of the things of your heart for example are during the development because of hemodynamic forces and of course while genetically they have mirrored hearts their hemodynamics so the flows inside the forces the hemodynamic stresses are not mirrored because they are just whatever it is and so you'll see that they end up with a bit of a hybrid heart where you see that actually the fiber orientation is in a little bit totally messed up instead of this change from the outside to the inside you see that there's like a crossover in changes and what you see is that they don't have a lot of rotation but when you look at their cardiac function where you see that they're functioning they're actually normal they don't have cardiac problems so you will see that this torsion actually in reality is more like the result of the combination of the geometry together with the contraction rather than an intrinsic component so we cannot isolate anything without looking at the whole and especially with looking at different ways let's quickly go over some diseases that you start to see well the biggest thing is like when you look in cardiology I think about 90 95 percent of the patients are actually patients that have problems with coronary arteries so your coronary arteries as we said before are providing the blood through the heart muscle itself and one of the things that you see is that specifically with the coronary arteries so what you see is so this one would go to a piece of tissue and so you would have a piece of tissue here which receives the blood from this artery and what you see that in the heart of most people actually this perfusion territory as we say so this tissue is getting blood only from this artery and you see actually a very sharp demarcation that this piece of blood here would receive blood from this artery and the one really next to it like one millimeter further is actually getting the blood from the other this of course makes the heart rather vulnerable for problems with this coronary arteries because what you will see is if there's a blockage here which you can have what you see here is like accumulation of cholesterol and then calcification and things like that if you get a blockage here all this piece of muscle is going to be really a problem and unless we can restore the flow there very quickly if it's totally occluded we will start to get an infarction if you compare that to the cerebral circulation in the cerebral circulation there's a lot of redundancy because we have four vessels going to our brain and internally they're connected to the circle of willis so that means that even if you lose one of these vessels the other one can take over so you don't see brain in fact so often as you see heart in fact because of the fact that this coronary circulation is actually very very demarcated in most of the patient and so the problem of course arises when you start to get a kind of slow kind of obstruction of of these vessels so what we call atrosclerosis and what you see is then when this totally blocks or when some of these what we call this kind of atrosclerotic plaques when they rupture what you start to see is that you get an obstruction of the vessels and then you start to get a heart attack and currently what what they are doing they try to with a balloon with a stand for example reopen your vessels as quickly as possible and if you do it very very fast then you can salvage the heart the muscle is going to survive if you do this for example more than three to four hours after the occlusion what you start to get is that this piece of muscle will die and you get really like what we call an infarct here's like what you see is like as I said before so the the the coronary circulation is at the outside of the heart and then goes towards the inside so that means that like the dying of the tissue with a blockage starts from the inside and then gradually spreads to the outside and so if you have a long time of occlusion what you see is that all the tissue which is being perfused by this coronary artery will die at some point you will see at the same time changes in the ecg at the same time of course what you see is if cells are dying they actually release some kind of chemicals into the blood pool which you can try to measure also and you can try to look at now luckily we do have nowadays some imaging tools in order to look at this this is for example delayed enhancement magnetic resonance so this is kind of information that we can take is like you see perfusion defects or you can see scar tissue we nowadays also with some kind of different sequences can look at water content because of course if we have if you start to occlude and release vessels and things like that you change the osmotic balance locally and you get actually water accumulation and you can try to measure these also now first of all looking at this perfusion is important but what you want to do is like okay what are the functional consequences in some ways and what we can do is we can use imaging in this case it's like ultrasound imaging where you see that when you have an infarct or when you have an occlusion let's say that way of a coronary artery what you see is instead of normal like inward-outward motion inward-outward with every heartbeat you see that you actually start to get this double motion and when you start looking at timing with regard to the ECG you have like contraction of the myocardium while actually your aortic valve which should do the outflow is already close so this is very very inefficient and studying these things is actually very very important and to understand this which is called post-astolic deformation what you have to do is you have to actually look at the mechanical interaction between segments because what you will have is like when you have a normal segment next to an abnormal segment what you will see is like during contraction normal segment kind of tickens or shortens depending on how you look at it and if there's no perfusion to the abnormal segment it will not be able to tick in because there's a high pressure within the cavity so you will see that actually at the end of the ejection period you see that there's differential deformation of two segments and this differential deformation where the abnormal segment couldn't deform so much as the normal segment is kind of being maintained by this high pressure in the cavity but obviously beside the high pressure you have the interaction forces because you have differential deformation in different segments if then your pressure drops when you start to have the relaxation what you will see is that you're only left with these interaction forces and these interaction forces of course try to get an equilibrium between the two tissues and what you see is that then like so you have the systolic the ejection kind of normal deformation less deformation in the abnormal segment and at the moment that the pressure drops what you see is they start to go towards each other and you see this what looks like kind of again deformation active looks like active deformation is actually the result of passive interaction of different segments and so looking at this trying to understand this is actually quite important because this is something that you can clinically observe but also in order to try to like the first time that we notice this when you look at the older literature what you will see is like the cardiologists say like ah there's active this late active contraction because of some late activation or some late force development or whatever and then we say like as engineers we say like no no no let's look at this let's model this and after we model this then you can say like look this really is passive interaction so it's really important to try to use models for example in order to explain these things but on the other hand what you also need to do is you need to of course make sure that your models can include this because in a lot of models we cannot do this so you really have to go back and forth from okay you see something strange in reality do we see that in our models or do we make special models in order to explain that and so there's very close interaction this close loop because what you observe whether it's in patient and animal models and cellular models or whatever with what we see in computational models is I think very very important and then especially when you look at for example what's happening when we change things like I'm not going to go in detail here but what we can do is we can give drugs to a patient which would increase the contractile function of the heart and then trying to see which are the changes and whether we can relate these changes we can really find underlying differences like for example what you see is like here what you see is that if a vessel was occluded for a long time what you see is that that you measure actually abnormal deformation so when a patient comes in had like this heart attack you reopen this vessel what you see is that actually the heart doesn't start to contract normal immediately it takes a couple of weeks in order to recover while you say like yeah but there's nothing wrong with it because we have blood going there but what actually happens is that by the fact that we had at some point this osmotic imbalance within the cells what you see is that contractile material because of water getting into the cells what you see is that actually contractile material can spread a little bit and this work less efficient and then you see the heart cannot contract as it needs to so taking this into account this kind of you see something trying to explain it take all the biological parts into account going to the cellular level and try to integrate all these things is the only way in way how we can explain all the findings that we have some of the other things that you can see is like for example when you look at valvular diseases but in regular also when you look at other things it's like what you will see is that the heart tries to adapt to an abnormal situation and what you see is that sometimes what you see is you get a very thickening of the heart with a small cavity sometimes you start to get an enlargement of the heart and it becomes thinner and you see in all of these maybe a pressure development can be the same the output can be very similar but it's done in a totally different way and so we have to look at these and here are just two examples of patients this is a patient with an aortic stenosis so this is an echo of the left ventricle you see here this is a very bright valve which is almost not moving so it's totally calcified and what you see is that this heart has like a small cavity and looks like almost doing anything well we know that because this thick muscle this is like full of myocytes so there's a lot of contractile material in there so this is a heart that intrinsically can develop a huge amount of force but still its deformation is kind of limited but that's of course because this thing is like a large obstruction which makes that the pressures in order to get blood through need to be very very high so this interaction of deformation with pressures is quite important and this is a heart which is totally opposite what you see there is now this valve which is the mitral valve between the atrium and the ventricle is leaking so you see a lot of blood going through you see it already like this is like bulging inside what you will see is this is a heart which doesn't have high pressures because of a stenosis but which has high volume because of the fact that there's a leak which does shows the pushes the blood in the wrong direction and this looks like a hyper dynamic heart because it needs to display so much volume but it can be that there's still a problem with the tissue it's just this relation between again the deformation and either the pressure or the volume that is needed might be totally disturbed and this is what we need to try to investigate and then you see that when you start to look at remodeling for example when we have pressure overload what we see is that of course our stresses are changing and then we have to try to understand what's changing there and so what you see there is that when pressures are changing what you see is that actually your wall stresses during the ejection are increasing and what you see there is that what you see is that then growth factors are released in order to increase the amount of force that you can develop similarly when you have volume overload what you see is that when you have volume overload that means that with every heartbeat you need to displace a huge amount of volume that means that you have a lot of volume coming into the heart because it's the volume that you have to eject the next time and what we see is that actually for the filling we see that the pressures during this filling are actually going up normally you hope that pressures during filling are extremely low because that's the most efficient way of course to get blood into your ventricle but if you need to get a lot more blood in there what you need actually is that your atrium it starts to contract a lot and that increases pressures there and the myocytes are feeling that of course because they're being stretched and what you see is when they're stretched what happens is that they get different growth factors so that you actually get parallel serial replication of sarcomeres and every cell is elongated and of course if every cell elongates your whole heart is growing and this way you can adapt so looking at the stimuli and the adaptation that you get is important in order to understand and when you then look at a bunch of patients with this kind of diseases with for example this is with a leaking valve and with more and more leaking volume what you will see is that these hearts grow indeed so you see that's clinically what we know is that the more leakage you have the bigger your heart becomes but what you then also see is that with a certain amount of leakage some hearts are huge and some hearts are not that big actually and currently the only way that they have in clinical reality to look at these hearts is saying like okay your heart is big so we need to do surgery in order to replace your valve but we know that replacing a valve and especially doing kind of open surgery if you need to do that means it's not without risks but also when you have a valve inside of course you need to for example if you have a metal valve inside you need to take red poison for the rest of your life because red poison is a blood thinner you have to make sure you don't get clots in there or if you have what we call a biological valve you know that after 10 years the valve is just kind of yeah is wasted so every 10 years you need a new valve so all of these things are not without risk so trying to predict when it really is needed that you do these these kind of surgery that's important and if you just take a cut off of the size of the of the heart you don't know what's going on actually because we see that there's this really big difference between some of these patients but in general in medicine what they do is they work with a kind of linear fit through the data rather than try to understand it sometimes and what you start to see is if you look for example at the local deformation as a function of the size that we see is that there's actually this kind of non-linear relationship where in the beginning whenever the heart is growing it's still deforming with the same amount so it gets bigger and bigger but you still see it deforming normally but what you then see is that with some of the really big hearts there's some patients but not all of the patients but some of the patients which actually start to deform less and less and less locally and trying to do this trying to understand this seems to be important because when you start looking at this data and you start to see like if I have a patient which had a normal deformation irrespectively of the size of the heart then we know that that patient after surgery will do well if we have a patient even with a relatively small heart is not deforming as much as it should be then we see that actually in reality these patients are not doing very well afterwards and so what you see there is that you need to try to incorporate integrate understand and at some point of course model what we would say is like the physiological and the abnormal adaptation to changes and in this case what you see is like the more blood we need so the more kind of volume we need because of a leakage what we see is like we need to get a bigger and bigger heart because when we have a bigger and bigger heart with the same amount of deformation of course we can eject more volume because when you look at the volume being ejected is of course always like the outer rim and the bigger your heart the more volume will be at the outside so as long as the cells can have their normal deformation they're happy and they can withstand it but when you get a bigger and bigger heart of course your local wall stresses will increase because your radius of curvature becomes bigger and bigger and so if the local wall stress on a certain cell is getting too high the cell will die if you have a cell that dies well then the problem is that you cannot deform so much anymore and if you deform less but you still need to generate this large amount of volume the only way to generate that with less deformation is increasing the size of your heart but increasing the size will increase the wall stresses so you get more cells dying so very very rapidly and that's what you see actually with these patients is these patients for years they can do well and with a time period of three months they really start to get into problems but that's of course because you get this vicious circle between the amount of deformation that you can do your local wall stresses how this generates the stroke volume and so again making models that will include the geometry together with trying to estimate local wall stresses and then trying to estimate the local deformation they can be very very useful in order to predict what's going on but the most important is that you have to understand this relationship and if you start to go to a cardiologist and they say like okay what do we need to do we want to do a study of predicting whether we need valve replacement in this patient yes or no then the cardiologist says like okay i want you to calculate the volumes of the heart as good as possible so we take the best imaging technique with the most 3d information the nicest segmentation tool and we give that to the cardiologist and they're happy but in reality we're giving the wrong thing because what we really need to give is maybe even with a rough imaging technique more like an estimation of the wall stress because that's what's going to change but this cardiologist not necessarily knows that or doesn't tell you because they're not used in clinical practice so again this this continuous interaction between what are they asking you and you asking yourself why are they asking this to me and which is the best way to answer that is is that translating whatever they ask directly into some kind of computational tool or image processing or is it more like okay let's go into an interaction try to understand what's going on and then together come to the best conclusion what we can offer them and maybe we can make their life easier even with a relatively easy tool but they just haven't thought about it so this interaction is really really important now here's the example of when we have the the problems with with the valve that becomes stenotic so typically it's an aortic valve where we look at so you see a normal valve opening nicely an abnormal valve like most of the people which are 80 years old have evolved like this it's like the normal aging process in some way and nowadays we also have techniques in order to replace these valves without doing surgery so trying to estimate what's going on what actually the influence of this valve is on the function is important and here again when you go to a cardiologist and they ask you like look I have a problem with a valve which becomes stenotic and I need ways in order to calculate the severity what they do or what they try in clinical practice is they try to measure what is the area which is here or what is the area there and if they say if this area is less than one square centimeter then we need to do surgery but again when you start talking about it and thinking about it like I mean I don't care if this valve is large or big what I care about if if my heart muscle can withstand that if my heart muscle is going to get damaged or not because a damaged valve you don't care a damaged heart that will give you trouble so you need to do something about this abnormal valve when the muscle is starting to get in problems but of course they used to in clinical practice to look at this because there are ways to measure that and it's much more difficult to look at the intrinsic functioning of the heart so trying to find ways to look at the functioning of the heart is much more important and then what we said before is like when you start to get pressure loading you start to get this very very specific remodeling and we try to understand when remodeling is normal or abnormal and then try to see what's going on and one of the things that you also see is like in order to cope with pressures what you will see is that actually shape changes can help them as I showed you before it's like if you have a very elliptical heart an elliptical heart is very efficient for volume output but of course an elliptical heart because of the fact that the walls are more flat so with a bigger radius of curvature has intrinsically higher wall stresses so a normal heart has a certain shape which is most optimal in order to work but by the fact that this is like flattened what you can do is like if you have a sudden increase in pressure you can actually partially compensate that by changing your local geometry but on another thing what you have to see is like keep in mind as I said before the whole heart is like in a sack it's like doesn't change its volume there really is effectively actually a sack around the heart which we call the pericardium which is non-elastic in principle so that means also like when we have a heart the pressure increases it wants to become spherical what we see is of course can only become spherical what we say at the septal side because you have to mention at this side there's a right ventricle where there's of course a right ventricle can be pushed in and by doing this you can calculate actually that you see a release in wall stresses by shape changes and you can actually see that when you have more elliptical hearts they have the ability to adapt towards wall stresses much better so not only looking at for example a valve for the change but also like how this reflects or what will be the influence given a certain geometry of the ventricle is actually quite important and when you then start looking at the deformation locally for example so we have the certain amount of deformation so this is actually the shortening during the cardiac cycle of this part the lateral wall and here of the septum you see that shortening is more or less the same everywhere and normal if we suddenly increase the pressure actually this happens regular times during the day because when you go to the toilet and you press you increase of course your blood pressure when it would be cold outside like it is now in Barcelona it's far too cold when you go outside you kind of also get an increase in pressures and the way that you cope with that is actually by making your heart slightly more spherical and what you see there is that then because of this change in this ferricity your septum can actually maintain its deformation but what you see is that there because here you have this constraint of this sac around the heart you see actually that you get a decrease so although overall your function in brackets will decrease because of this increase sudden increase in pressure you partially can compensate with that for example by shape changes and one of the things that I also said before is like because of the fact that you have longitudinal fibers and you have the circumferential fibers more or less longitudinal fibers intrinsically of course much flatter than the circumferential fibers and so intrinsically longitudinal fibers have higher wall stresses with a given pressure than the circumferential fibers so that means that if the pressure increases proportionally these longitudinal fibers are much more affected and that's what you actually see is if you would just measure this is actually measuring how much displacement you have of this ring what you see is that if you have this pressure change what happens is that this longitudinal displacement is actually being diminished because of the fact that it has higher stresses and is actually being compensated by getting more in this direction so now again although you have a heart with the same size and there's the same amount of possibly pressure being developed the same amount of volume you see that it's done in a different way you can either reject blood in this way or you can eject it in that way and for example this kind of just overall pressure volume analysis that even a lot of us will refer to when we do computational modeling it's not good enough we really have to go towards okay how is this relation between deformation the loading which parts of the muscle are contracting and by using also imaging information we can get extra information from this and even then is what when again when you talk to cardiologists and they say like okay we have pressure overloading we have hypertension that means that your whole heart is affected because of course the pressure increases so that means that everywhere you see a change now of course maybe this is not completely true because when we look at the heart the heart is not a sphere if it would be a sphere then of course every part would have the same wall stresses but it's not it's like a little bit like elliptical where you see that at this point of the heart you see actually that the local radius of curvature is of course much smaller so that means that intrinsically wall stresses will be the lowest there and actually when you start to look at the heart you would take out the heart what you see is that the wall here is much much thinner than it would be anywhere else people are actually using this cardiologist are using this because if they need entry to the heart from the outside in an easy way what they will do is they put a needle this way through the point because the point is the thinnest they will never ever put a needle in this way because then you start to get in big trouble so either when you do for example an intervention or you need to do like a pump for example a patient which goes in really hard failure needs like an outside pump in order to at least keep alive for a while they always put it like this and the reason why it's thin is actually just because of this curvature and if you then start to look for example at this wall you see of course the curvature is much much higher so intrinsically your wall stresses will be higher and that's being compensated actually by having thicker muscle there because when you look at Laplace Laplace says okay the stress increases with the radius of curvature but of course decreases with the thickness of the muscle so we get thicker muscle there the septum is actually the flattest structure so has the biggest radius of curvature but keep in mind that of course at the side of the septum we have this right ventricle so again when you do modeling you can never isolate one part of the heart well even also in clinical practices like what you see is that several cardiologists they would totally independently would describe okay this is what's going on with the left ventricle and potentially this is going on with the right ventricle but even right ventricle is still ignored while all the cases but there is intrinsic interaction and even at the low level there's an interaction with although pressures at the right side are very low compared to the left side of course they still will generate forces at the left side and so you will see that the normal heart has the same thickness everywhere but of course when you start to get an increase in pressure here you will get a disproportional higher increase in pressure in the flattest regions so it means that the pressure here or the wall stress here will increase much much more and so when you then start to look at clinical images what you start to see that the patient with hypertension with high blood pressure you see you start to get this thickening there so a normal heart is the same thickness everywhere and you see a hypertensive heart you start to see this bulge and this is of course because locally the wall stresses are higher you start to get locally a response for what we say like hypertrophy so you get locally growth factors which make like okay we need more contractile material in order to withstand this pressure and so you see a thickening there locally and that by looking at the thickening and looking at where thickening is taking place we can try to look at different types of diseases and also still even with the thickening in mostly because this can be a rapid onset of high pressure for example what you see is that it doesn't fully compensate so when you start to look at deformation normally deformation is very very homogeneous within the heart you see it's the same everywhere but here what you see is like because of this higher wall stress there what you see is that actually tissue is first being stretched has less deformation and then again has disposed of deformation so looking at this and trying to understand what is happening when deformation is happening although if you now would go like for example when you do would they take MRI imaging they have like tagging MRI where you can measure deformation what they say is like okay deformation here is this and in this segment is that you said okay it's more or less the same so deformation is normal but when you look at the timing of deformation it's actually totally different and also when you look at here this is happening really really fast so you need an imaging modality which has also enough temporal resolution in order to do that also to do the timing here what we know here is that this is actually after the closure of the aortic valve so after the ejection so you need timing information and although you have the ECG ECG might not be enough in order to time opening enclosure or false so again you cannot isolate one thing and then do one measurement and say like okay this is going on you really have to try to understand the whole process and then see okay for specific changes specific diseases what is physiologically going on and how can we actually most efficiently look at this in clinical practice and you see it's like it's not only like sudden changes and seeing how the heart reacts to that but it actually can happen that you have to look at the whole again the whole picture the whole situation because when as a fetus you have problems with loading and that's mostly for example when your placenta is not sufficient this for example too small what you will get is that the fetus has pressure overload because of this high resistance of the placenta and what you see is that actually these fetal hearts become more spherical because of that but that's logical that is what we said it's like you have an elliptical heart you have a pressure increase you try to become spherical in order to decrease your wall stresses however when this happens when you're in the belly of your mother the thing is like this is happening while your heart is being formed and what you will see is actually that although this might be of course this pressure will be relieved at the moment you get born because then you don't have the placenta anymore which causes the problems of course once you have this heart which is formed in this way you will always have this heart what you will see is that actually these babies are born with much more spherical hearts compared to others but of course if you have a spherical heart and then later on you go outside you go to the toilet you cannot anymore become more spherical in order to partially compensate for that so you see that actually these people have more risk factors because the heart is more vulnerable to some kind of changes in conditions and so looking at why this is happening is actually quite important and understanding it and for example one of the practical sessions will be in order to try to simulate this whole kind of circulation and see like okay what's the influence of the placenta on the pressure distributions that will happen within the heart and so looking at this is something which is interesting and similarly is like this kind of insults is also it doesn't come alone so because we have this higher pressure and what you will see is that actually because of this higher pressure and then actually also because we have some problems potentially with the placenta what you see is that the heart itself needs more blood and what you then can see is that actually the vessels of these babies also are much much much bigger so looking at this then again we know that actually it's not only the pressure but even the perfusion even the tissue distribution where you have more space for vasculature compared to muscle can be quite important than we have to integrate that information and so what is actually quite interesting is to try to combine our techniques so we say like okay we can do a computational model in order to try to calculate the pressures but what we say is like okay what we see is that because of that the shape is changing and so we can actually do shape analysis and so this is some work of one of the phd students here also where we say like okay we took in this case the adolescent so these were babies these were now children well about 12 years old 10 to 12 years old which were born with this abnormality in the placenta and what you do is you can really try to recover the shapes and do a shape analysis and what you then see is that indeed even at 12 years old you see that their sphericity might be different and there might be also changes in like how this shape is being distributed and so combining shape analysis with other tools of computational analysis will again both first of all help you in the understanding of what's going on so this is actually for a research project that we do there but actually by trying to understand this and making tools you can actually also try to look at an individual and try to see how an individual would be affected so it's both for research and in the future for clinical practice for diagnosis you can try to use a combination of these tools and try to look at it and then also when you start to understand then you say like okay but we see this shape change this is likely due to pressure and then you say like yeah but from the adults we know that if we have pressure loading we start to see abnormal deformation in this basal septum let's start to look at this in these babies and what we saw indeed is that you see this kind of postastolic deformation there also so in this case it's like when you look at medical research a lot is kind of done okay you have it you have a new nice machine you do a measurement you do statistic you see what's going on but sometimes you can say also nobody taught about doing this before because what you see is like you understand something you see one change you say what is causing this and then you say like is this maybe causing other things also and this way for example we found that this is actually happening and actually quite interestingly what we saw is like when you start to look then for example at the 12 year old patients what you see now is that they also might have this but strangely enough they now don't have it in the basal septum where you expect it when you have pressure loading but they have it at the other side this is very strange because when you look at them they have normal pressures we know also from the law of Laplace it cannot be that there with pressure overload we will have the highest wall stresses because we need to have it there because of geometry so the only way that it can be there is of course when geometry would change and this is exactly what we said before it's like what you see is these babies are born with differently shaped hearts and apparently indeed the shape is different enough in order to cause these kind of abnormalities and telling this to the cardiologists because they might sometimes associate this for example with problems with coronary artery disease but it might be caused by something else so again trying to understand what's the underlying change what are the conditions can this be related yes or no and then using the right models and the right tools in order to understand that we can actually get more information which can be quite useful clinically now one of the things that you also see is like what I said before it's like normal contraction is very early in the cycle and then we have kind of more inertial deformation that's what you see here this green curve is a normal kind of force curve within the myocardium keep in mind that in order to get these force curves of course as I said before we cannot measure them unless we put needles within the heart but what you can do is you can try to measure the pressure in this way of course with a catheter which is still invasive but less invasive than putting a needle in there we can measure the deformation and then we can actually try to put a computational model and then we can estimate this force development and that's actually what's done in this curve now what you see is if you have the sudden loading so say for example you go to the to the colt or something like that or in this case if you for example have a problem with a sudden constriction of your large arteries or your aorta what you will see is that of course you get a sudden pressure rise and you have to cope with that one thing that I said before is like you cope with the pressure rise by trying to become more spherical that protects in brackets your myocytes sometimes but still even if your wall stresses are kind of reasonable you still have to do the ejection obviously and the ejection now will need a lot a lot more power in total you need to do a lot more work in order to get the blood at a higher pressure out and actually what is now happening is that there is no way that you can develop more force because the force development is what can be done by your myocytes if you have a sudden increase in the pressure that is needed it's like you cannot have more myocytes all of a sudden so the amount of force you can develop is remains the same the only thing that you can do is of course you can develop this much much longer so that in total your force development remains high up to the end of ejection so that of course the area under the curve which is the work that you do is much higher and you can actually do the ejection against a higher pressure so that means that having this kind of shape of a normal curve gives you again an adaptive mechanism in order to cope with problems later on the problem might be here as I said before that you still have kind of cross bridges which are bound which means that you have very stiff myocardium which means that your next filling is hampered so that's but that's another problem that you can look at and actually it's like okay we can look at this from the engineering point of view and we can say like okay we know that you need to do this force development longer and with our model we see okay we can do this force development but to calculate this force curve you need you need a pressure you need a nice geometry you need to deformation you need a computational model you need a lot of time to calculate it and then you can nicely say okay this is my curve this is what we need to do but of course you cannot do that with every patient but then if you say like okay we know this mechanism is taking place aren't there easy ways in order to look at that and actually there is and that's very often the case it's like what what you see is like with the models we try to understand what's going on and then we try to translate that into a much simpler parameter that you can see in clinical practice once you know what to look for and what you can look at this here is actually this is what we call the Doppler trace of the aortic outflow so that's actually the velocity as a function of time through the aortic valve and what you see that with a normal velocity you see that the normal velocity rises quickly in the beginning of the ejection and then slowly goes down and the more pressure loading you have so in this case this is actually an aortic stenosis which becomes narrower and narrower and narrower what you see is of course first of all the amount so the the speed of the blood going through it becomes higher and higher that's because it becomes narrower and narrower so that's what we say like okay the pressure drop over a valve this is what clinicians mostly look at is like okay what is this maximum but if you start looking at it what you see is that here for example although the maximum is the same you see that the shape is actually starting to change you see while this is very triangular early peak and then slow going down you see that this is much much more rounded and much more symmetrical so this already tells you that if the velocities stay high for a longer time of course we know that there's force development for much longer and so you know that once this gets more and more rounded we know that the heart or the myocardium has to use this mechanism of too long contraction and then probably gets into problems so here again translating the knowledge that we found into something which is a maybe a much more easy measurement where for example what you can do is you can look at for example the symmetry of the of these curves once you do a segmentation so this contains a huge amount of information but you need to know what it means in order to look at it now let's briefly talk about what's happening with athletes heart because that's also quite interesting so what you see is that we know that exercise is very beneficial for the heart and that's what we know you need to do a little bit of exercise in order to kind of so we say live longer live healthier but what you see is actually there seems to be a cutoff where at some point we start to get in trouble and actually the heart cannot follow anymore and one of the things is that you see is when you look at these athletes regularly they would come in with problems when they're for example 40 or 50 years old and you start to see that actually mainly that there's problems with arrhythmias and with ECG changes and mainly there's problems at the right side of the heart and here is an example of two athletes before and after doing some kind of heavy running and what you see is that when you look at this right ventricle what you see here for example also is this looks much more rounded much more spherical and you see even here after the race this looks even worse and so you see some people have like nice contraction and some people have very bad contraction so the question is what's going on this is what you see in clinical practice but you need to try to understand and what you see is that actually during the fact that you do exercise what you need you need much more volume going through your heart and because you need to have like five times almost more oxygen going through your muscles so you need much more volume through your heart and what you will see now is like when you look at the left side in order to get more volumes through the left side of course you have to increase your heart rate and maybe increase the amount of contraction with every heartbeat but what you have to keep in mind is that the blood from the left side goes into the aorta and the aorta is a compliant vessel so that means you push blood out the aorta really kind of captures quite a lot of blood and that means that actually the aorta acts as a buffer for the blood and means that you don't need very very high pressures in order to increase the volume through your heart because of the fact that you have this kind of wind cancel like effect of your aorta however when we look at the right heart right heart is connected to the lungs and although intrinsically the lung vessels are more compliant than the systemic vessels of course the lung circulation is very short because there's no place so that means that in reality the only way to get more volume through the lungs is actually do it at much higher pressure and so what you see is that in individuals you see that the pressure when you increase the cardiac output your pressure is going to increase a lot and you see in some people this even comes to pressures which are the same as as your systemic side normally your right ventricular pressures are not much more than 20 millimeter mercury but in some patients you see that this becomes very very very high but in other patients not so there's a big difference and that's why you see that some people doing professional sports will never have problems with their heart but these people will almost for sure have problems with their heart because what you start to see is that actually you start to get damage you can start to get fibrosis you can start to get like little scars because of the fact that these high pressures are there every time that you need to do exercise and of course we know that scar that is present will potentially lead to problems with with arrhythmias so with with what we call sudden cardiac death and one other thing is also like here again to show the complexity of the heart is that you see in some of these athletes you saw see actually that you get a lot a lot of what we call this trabeculations but these become thicker and thicker and you start to see that actually your heart starts to get filled with tissue instead of filled with blood of course that's also very inefficient and so trying to understand this relationship between the geometry and now you cannot of course use an ellipsoid or whatever kind of intersection of ellipsoids in order to describe it but you need to have a really detailed geometry and even here so we see it here on ultrasound but if you take like a ct image or an mr image which shows the geometry well what we mostly do is we totally ignore what's going on there but actually it has a profound effect in some diseases or you can discuss whether this kind of professional athletes are diseased or not but clearly this changes what's going on and we have to take that into account when going on okay one of the things that you also see is that when you start to talk with clinicians what they mostly say is like okay what I need is this ejection fraction I need to see how much the volume that is being pumped out with every heartbeat now what you see is that what I said before is that actually it's like it's not the volume which is important but it's actually partially how the ejection is taking place is ejection taking place by this kind of component this longitudinal component or is it with this circumferential component it might be different and what you see is that in reality as I said this longitudinal component is more more vulnerable to changes because of the fact that it's done by longitudinal fibers what you see is that this change from one to the other can actually for a long time compensate our and so again when we do our modeling when we do it like we don't want to necessarily model the pressures and the volumes but we want to see okay what's going on with these different components and how to integrate that in clinical practice okay for the sake of time I think I have to finish now so what I wanted to try to explain you is that actually in reality we need to understand better physiology as engineers because only when trying to understand it we can try to get the right tools in order to give the right answer to the clinicians and also the right answer is not necessarily what was the first question to of what was being brought to you what you say is you do a constant interaction with the clinicians or with the biomedical researchers where you try to ask yourself okay which is important and this important start especially for something which is complex like the heart where we have a combination of geometry function and especially mechanics where we also have hemodynamics but we need to know as we need to know the structure we need to know what's underlying we need to know the anatomy but we need to know also how the cells are individually working in order to go there and especially trying to understand the interaction also with the environment is important because whenever you model something you cannot isolate and this is also another problem that a lot of people do is they say like okay we take some kind of an image we extract the geometry from it and then we let this heart beat but it's really important to see what's the environment how is it connecting with the rest how is for example the nutrition going there how is the perfusion going there because all of these things are intrinsically related at least you have to keep it in mind obviously in a lot of cases you can simplify it but you have to explicitly know your simplifications and you have to discuss and think whether these simplifications are relevant or not for what you're studying especially when we talk about a heart which is like a kind of a mechanical organ in some way is looking at the force development the relation with the geometry the local wall stresses whatever is happening there that's important and again you cannot translate what is current clinical practice to what might be future tools which can help because current clinical practice has come from simplifications which came mainly from technology and knowledge so there is a technology that can measure something of course it's simplified but it's like implicitly simplified by the technology when you do your models you can much more explicitly simplify whatever you want to study and whatnot and then again of course it's like as I said normality doesn't exist everybody is a little bit different and it's actually this changes this deviation from normality which is induced by changes in the environment mostly or changing in the conditions it's how far in which way and how much this deviation is taking place that is what's really important these these are the things that we need to study with our tools okay thank you very much any questions before coffee most of us will be around here also so you can keep on discussing things or try to make it as informal as possible I don't know if you have a question now so wait wait just for the microphone that's easier than everybody can hear you I'm not from this field so I don't know anything about cardiology heart it's just a curiosity we had a very nice overview about the part of physiology of the heart how it adapts how it's capable to adapt its shape and structure to different environment okay but does our heart change its shape in an with aging yes just maybe I understood that wall stress it's an important thing you know so maybe just with aging it's acquiring a more spherical shape to reduce the wall it is actually because what you see is the main thing with aging is that our vessels will age so what you will see is like even if you don't have atrosclerosis and so so we know the biggest problem in in cardiology or with aging is atrosclerosis so that you get plaque deposition well first of all in your coronary arteries because that can lead to a heart attack but actually if you have plaque deposition in your coronary arteries it's likely going to be everywhere in your body and what you see is that for example also the aorta in elderly people you often see like plaques there some calcifications so vessels become stiffer and even if you don't have atrosclerosis mostly vessels become stiffer they just like because you're aging they become less elastic which means that always your blood pressures are rising a little bit and in order to cope with rising blood pressures what you see is you will get slightly more spherical heart or what you see is then it depends if you for example do then a huge amount of sports what might happen is that your right side is becoming more spherical because of problems there so it really depends on the normal aging would be that your left heart becomes a bit more spherical depending on some conditions it might be the right heart but in general what you see is you become more spherical mostly a bit more smaller and also your atria become bigger and bigger because when you see like when you look at the way that that filling is taking place because most of the research actually goes by how the blood is being ejected but as important as like how does it fill again and what you will see is a normal heart when it's very elastic fills rapidly sucks in blood in some way and then you have like a little bit of atrial contraction but of course when you get older you age you become stiffer you don't have this kind of sudden kind of early increase in filling anymore your atrium has to kind of kick much much harder and you see actually atrial enlargement also with with age so you get a little bit more spherical a little bit bigger atria that's mostly a normal adaptation other questions um thank you again for the very nice presentation um my question is something i didn't really understand maybe um when you said that um the heart might grow because of increasing loading right um how does it work with the pericardium because i said pericardium is very stiff and it doesn't really deform so yeah well everything depends on the time scale so if you have a sudden change in the volume what happens is like first of all so you have the pericardial constraint but pericardial constraint is around your whole heart so that means still if you have a problem at one side what can happen is that one side can become bigger at the expense of the other side so that means that what what can happen is for example if you have a left-sided problem it can actually push away a little bit the right ventricle that's on the short term but actually of course mean the pericardium is something which is stiff but it's still alive so actually the pericardium if it goes slow enough can actually also increase its size so it can grow with the heart everything depends a bit on the time scale so that means for example if you have sudden volume overload a typical thing is when you take for example endocarditis which is a bacterial infection of the valves and the bacteria actually literally eat away the valve so you really get a very very rapid kind of change then it tries to grow but it cannot and then you have a big problem while when for example you have a valve which is slowly deteriorating over years and years and years then you see that actually also the pericardium can can kind of accommodate and starts to grow okay so when we are modeling the biomechanical forces is important to take into account the pressure that the pericardium is causing on the heart it's essential so it really is important because what you see is that otherwise also when you don't take that into account what you will see is that with every heartbeat the heart would become spherical while in reality you have this longitudinal contraction so the only way to get a realistic kind of deformation and simulations is if you put a pericardial constraint and actually what it means is that you don't have any normal displacement you don't have any normal outward motion you have sliding so in reality the heart slides in the pericardial side so that's the kind of the boundary condition that you need to put in your simulations okay thank you which is actually also interesting and now that you talk about that because what you see is that when a patient undergoes cardiac surgery what you they need to do is they need to open the pericardium of course in order to access the heart and a lot of surgeons kind of later on don't close it again so that means that if you have a patient after pericardial opening they don't have this pericardial constraint anymore or not as much and then you see that the motion changes so sometimes also if you model surgery you have to take into account whether this is changing or not and that's also not what some people do and extremely rarely you find a patient which is born without a pericardium and when you look at these hearts they're like very oddly shaped they're in different kind of positions they have extremely strange deformations so it makes a big difference other questions there is coffee time coffee is served here outside in the hall