Cardiovascular Health & Childhood Obesity

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Okay, good morning, everyone. Thank you for joining us. I’m really excited today, because we have this, I mean, amazing webinar, which will deal with primary prevention in children with obesity with regard in particular to primary prevention of cardiovascular disease.

And we have two incredible speakers. I’m really honored to introduce the first one, which is Professor Peter Bergsten. Professor Bergsten is professor at the Department of Medical Cell Biology in Uppsala, Sweden.

And Professor Bergsten is the PI of this longitudinal course of children with obesity that is the Uppsala longitudinal study of childhood obesity. The background of Professor Bergsten is on metabolic diseases and his activities really an example, really an amazing example of translational clinical research because he moves from cell level to the patient and to the society factor that influence obesity. I have a question, Professor Bergsten for you before starting your talk.

Why? I mean, a scientist who has background in the adult health care moves is interested to the pediatric field. Yeah, yeah. First, thank you very much for inviting me to give this, shall we say little talk, which I hope will be benefiting you.

The reason was, so I come, I’m adult endocrinology type two diabetes. And then as we know, some years ago, diabetes started to appear also in children and not only type one, but also type two. And that sort of pushed me towards that and started to think, well, what is happening here? And that was very much related to obesity, as we know.

So that was my point of entry. And the prevention side, and I work together in a multidisciplinary team at the Children’s Hospital at Uppsala University. So doctors, nurses, physiotherapists, dentition psychologists, the whole forming a team around the child and family.

So that’s how we think we may do some good. Then the other motivating factor, this is a meeting with a patient. She was referred Uppsala to a tertiary level.

And she came to us, referred in the region where Uppsala is the hub. She had IE, either complicated, you referred either having developed complications, and or an age and sex adjusted BMI of 35. So 90 99th percentile.

So she was there on the latter course, she was three years old. And that was the vivid image. She came with her mother, and the mother was also big, and three years old.

And we already come too late, because we’ve seen over the years that although we I think we do good job in secondary prevention, but pushing these very sometimes very young children back to health is difficult, difficult. So that’s a little bit on my background into this. Should I continue with the presentation? Yes, please.

The floor is yours. And yes, thank you for sharing your experience. It’s always about the patients, the people you remember, that motivates you.

But as you so kindly introduced me, I have also, shall we say, oops. Yes, let’s see. I don’t know.

It’s sticking. Yes. So I’m sharing it this way.

I have to excuse myself. But I think this will be legible to most of us. Old computer.

That’s what I blame. So here’s the thing. So I trained and came into this.

And I’m now working both in shall we say basic science, it was all around insulin. So insulin is a theme that I started with. But I also teach medical students at different levels.

And I just want to remind us all. Now with this angle, because we saw obviously, also very early in these children that are referred to us, when we just do blood pressure measurements. That’s when we saw that these, shall we say, high BP’s occur also early in life, and develop into things that are not very good.

Here, just a little bit of, shall we say histology, if I may refresh our memory. And this I picked the upper graph, the upper histological image is from the vasa femoralia. So here’s the femoral artery, and the vein.

And you can see the difference in wall structure. And just the intima, the part of the wall closest to the lumen, we’ll come back to the lumen, where things happen. And then comes the media.

So the intima, I was trying to think, I was training as a cell biologist, if you if you want. So you can always think about what cells are there. And there are many cells, but obviously, the endothelial cell is of prime importance here, fibroblasts.

And then we go to the tunica media, where we have the muscle cells, the smooth muscle cells, again, a lot of fibroblasts, producing both collagen and elastin. And then lastly, the avantitia. And when I teach my students, yes, we do focus on the endothelium closest to the blood and then the media.

And then, yes, and then there’s avantitia. And then, yeah, just a little bit of connective tissue, and then we move on. But here, I would like us to really focus on the avantitia, because here there are many cells that play an important role in what happens in these children, in the vessels of these children.

Endothelial injury, that’s a handle that we can use. And that can be caused by many different things. I’m trying to keep my time here.

Another key concept is extracellular matrix, i.e., what is being deposited by, not in the least, the fibroblasts, they build the structure of the vessels. The lower picture is just a blowout. So here are these critical cells, the endothelial cells that form the barrier between lumen and tissue, sub-endothelial tissue.

So this is what we will now talk about in just a few minutes. Okay, where does it all start? Well, it depends. But in the patients that we see, who have most of them, ordinary renal function, it starts with elevated levels of lipids in the blood.

So the part of the problem is that in the lumen, there are elevated cholesterols. And as we see that this is just a sequence that we are all rather familiar with. And if we want, we can call this accumulation of fat into non-adipose tissue, in this case, macrophages, ectopic lipid deposition.

So lipid species are deposited in cells, they’re trying to, you know, take care of the surplus of triglycerides and LDR particles to such an extent that they become overloaded. And the reaction on overload, and that’s sort of a general cellular reaction that it could be endothelial cells, macrophages, hepatocytes, and also adipocytes. When they push to the limit, they start expressing chemokines, different signaling molecules that activate the inflammatory system.

In addition, and that’s sort of a sidetrack, I’m working a lot with insulin signaling. And part of the defense of not being overworked is that they downregulate insulin receptors, i.e. they are not willing to respond to insulin anymore, which is understandable, they have done their work. But the person in question have still elevated levels of lipids and glucose and so forth.

So that’s, at least in our patient group, the prime starting point of the also the cardiovascular system. Here’s just another picture. Here you can see collagen.

And here’s just one of those pictures that illustrating the aortic, the arc where, you know, the systolic blood pressure needs to be dampened. So a lot of elastin right in the picture. So you can do these beautiful things.

This is all fine, but will deteriorate with age, but also more rapidly in these children. And then just this is where the coarctation is happening just beyond the aortis. That’s one of the causes, obviously, for problems with the increased blood pressure.

So narrowing of the aorta, that’s congenital condition. I have a couple of slides now. From I think, very important documents that we should all sort of focus on and we need to consensus.

This is children. And how should we say their difficulties because there is growth, there is natural growth occurring during these years, which makes it challenging. If you have a growth pattern that is sort of deviating on top of a normal growth pattern.

So this is tricky business. And therefore, as we can see, this is from a rather recent report, which I think you are familiar with, but just getting down to the definitions. And I think this is not written in stone.

This is after some 10 odd years revising the previous one and improving it. We need to improve our guidelines because the field is moving. 10-15 years ago, this was maybe not very common, it already started to appear.

Now it’s very common. Just as an example, children, those that are referred to us, we have 72 out of three children, age three to 18, have some aspect of, shall we say, elevated blood pressure, ie it’s very common in this patient group. And we need to constantly review the criteria, how do we diagnose and then what is the treatment options.

So this should be on our radar when we discuss this. So we can discuss between colleagues, between different groups, how do we measure blood pressure in children, not trivial, the different methods that I think is also a key point, how do we do this, so we can compare different methodologies, different routines, especially when you go into the lower ages. Okay, I was asked a little bit to touch on on these three aspects.

So genetics, I’m just sitting in a conference now, where genetics of type 2 diabetes is the focus. And obviously, you can focus and put hypertension as the disease that you want to investigate. And there has recently come out yet another GWAS, I think we’re up to around 2000 loci.

So it’s a polygenic, there’s some monogenic, and I just mentioned one here, disorder, but usually small contributions, however, influencing the phenotype. We should ask about the family history of not only CVD, cardiovascular, but also the metabolic area, because as we know, these interplay with each other, we need to establish whether there is a renal aspect, and also other endocrine disorders that can be of really importance to understand and also treat the person in question. So that’s genetics.

And I want to introduce this picture, which I guess is familiar to you, in the lower corner. So I’ve done a lot, sometimes we have a figure we think three circles, and maybe a combinator in a slide or two, but pictures of three circles, horizontally placed. In the first circle, it says healthy.

In the next, it says risk. And in the third, it says sick or disease. We are activated when a person has moved all the way over to the sick circle, and we try to mitigate and prevent.

Then we accumulate knowledge, okay? Here, the inner circle as described by Dorgan and Whitehead, age, sex, constitutional factors, including nowadays, genetics, which may have the promise of a more personalized medicine approach. This is difficult, but this is the ambition to really characterize the individual in its detail. What other things affect health? Well, here they propose that this comes in different flavors, but individual lifestyle factors, and I think we will hear more about that imminently.

Eating behaviors, physical activity, sleep is an important one, not in the least with regard to hypertension, and nocturnal dip and so forth, sleep. And as of late, I think the WHO is pushing also screen time, which is very connected with both sedentary lifestyle and sleep patterns. So yes, we need to encourage good behaviors in these patients.

And then the next level, environment, and yes, these things are important and can actually have a direct effect on hypertension, the different, these metals, if you want, and these plasticides and things, they will have been shown to affect. However, and I just want to introduce the other layers, which are important, especially if we want to do prevention, we come late, and we are pretty much directed to environments where we can do these individual lifestyle pattern interventions. So either be the family as a unit, which is often the unit of our work, but it could also be school environments and so forth.

And that’s good. And we need to continue that. But considering these other levels to create sustainability, and just mentioning that it is important for a family to have a connection for the child in the family to have a family which is connected, school conditions, leisure, sports, etc.

And then take it one sector wider, it is important for the child that her his parents, they live in a housing condition, sanitation, work, etc, etc. So these things which are not under our control needs to be worked on in order to create sustainability. And then lastly, and this is the at the national level or even international levels, we need legislation.

I know the WHO has worked a lot not only on sugar, but also salt, which is relevant for this meeting. So restriction on salt, restriction on nutrition that is more caloric than nutritious, we also need to work on. Yes, so here, a couple of things that we’ve noted, I’ll show just a slide from our cohort.

But this is this is important to remember, we have a tendency that boys are more afflicted, ie we need to pay good attention to both sexes, but not in the least boys. Connection with obesity, and you can take very many anthropometric measures, and they all correlate with hypertension. And here, this graph shows this that all kind of how should we say conditions related to, to obesity, if you want, but also to elevate the blood pressure, total cholesterol, and HDL, or, or, well, nowadays, I guess it’s more LDL and non LDL.

But these are important factors to measure and follow. And if our interventions, do they manifest themselves as improvements? Because if we do things that improve these risk factors that are so connected, remember the picture, first picture, if we have blood full of lipids, then these cellular processes will drive this person into a problem of vessel unhealth with atherosclerosis and the intima media will stiffen, the fibroblast will also be lipid laden, and stop working as laying out the collagen and elastin structure and stiffening the media and following is obviously hypertension. And we have to keep track on the kidney.

And then there is also one aspect which is important, we have to ask them about the gestational period. Were they born preterm? What was their birth weight? Because this is also correlated to, to higher risk of developing, developing metabolic disease. So this is anamnestic, this is the family history.

And all these things can help us guide us to do whatever we can to lower the CVD risk in the individual. Okay, just an example from a recent we were measuring in, I think we are up around 600. Pretty traditional.

We saw, which have been seen in many different studies, that yes, there is a rise in the intima media thickness. And this was correlated with both systolic and diastolic increase in blood pressure should be remembered. And we should remember ourselves that we need to look at current charts.

It’s not trivial to do to allocate the right blood pressure for a given individual height and weight and especially if you take into account obesity. So work with our charts to get accurate measures. And this is just pointing out again, the connection to inflammation.

So keeping inflammation low, which connects to obesity as this low grade inflammatory state. Again, I’m coming back to there is so much done here in this field. And just look at disturbed body composition.

We know a lot. And yeah, maturation, I’m coming back to the blood vessel, the stiffening. So you can see arteries in very young children that should really not happen until very much later in life.

So they are old, vessel wise, they are aged and with obvious consequences. And then the left ventricle, sympathetic drive, sleep patterns come in, everything is interconnected. But we need to pick up this info from them.

So we see the starting point and then see what interventions can help them. Kidneys, yes, you see it here. So this is a very important report as well.

And I think here I give you some and this presentation can be shared. I’m just reminding us much work has been done by the community and we should take advantage of this and maybe challenge it because this is a moving field. Unfortunately, we’re going in a maybe not an optimal direction.

This highly intricate and interconnected sequence of events. And this is the last slide. Again, looking over time, childhood, into adolescence and adulthood, because if something starts early, you’re very likely to have all these conditions lingering and being accentuated in adulthood.

So we’re building up, we can do a lot of things to prevent later really severe complications. I think this is it. And I just want to this is part of the group in Uppsala and a little bit of all the different funding agencies.

So thank you very much. Thank you, Professor Bergsten for your excellent talk. And it’s now time for the next speaker who is Professor Enner Hansen.

He is Professor of Preventive Sport Medicine at the University of Basel. Professor Hansen also has a background in adult health care and particularly internal medicine and sport medicine. So before his talk, I would like to ask the same question.

Why, I mean, you moved from the adult health care to the cardiovascular prevention in the paediatric age, Professor Enner? Yes, thank you, Melania, for inviting me actually the IAASO and also for that for the introductory question. Well, my background is also in cardiovascular medicine. And we started screening children at younger age for their motor skills and realised how the prevalence of obesity in childhood A and B, we started measuring some non-invasive vascular function markers and realised that these children not only were obese, but also we found that the vascular function and partly structure was also altered.

So this is why we realised, that’s when we realised we have to do something at a childhood age when we talk about cardiovascular prevention. And this is also why in the EAPC, the European Association of Preventive Cardiology, we started a task force for childhood cardiovascular health, even though the EAPC is also an adult association, but the focus needs to lie in primary or even primordial prevention to prevent the risk trajectories actually that Peter was referring to in his last slide. Thank you.

So please go ahead with your talk, Professor Hansen. Okay. Hang on a minute.

Hang on. Okay. You should now see the presentation in full screen mode.

Is that correct? Just give me a nod. Yeah, Peter’s nodding. Okay.

Right. So now I’m grateful to present some of our data and ideas on childhood cardiovascular prevention. I was asked to look a bit into screening programmes, which is not that easy, and also management strategies, which currently are mainly driven by lifestyle, which I will go into.

And you will see that some things are actually effective and some things still have to be thought about. So the structure of my talk here is I will go into the risk trajectories of childhood obesity, which fits in nicely with what Peter showed in his last slide. And then I’ll go into vascular ageing in childhood.

So early vascular ageing as vascular structure and function are good indicators of overall cardiovascular risk, even in children. And in Switzerland, here in Basel, we are currently performing the EXAMINE youth study, which I will go into and present and will give you a short wrap up at the end of my presentation. So what is the etiology of obesity related cardiovascular risk? And we’ve heard a bit about the comorbidities already, but just a brief idea of how complex, of course, and most of you will, of course, realise how complex the etiology of obesity is.

So we have at the environmental and societal level, we have wider impacts, such as stigmatisation, policy and culture. We have closer environment and family, which allude to health behaviour, socioeconomic status, psychological factors. And we have biological factors that are modifiable or non-modifiable, non-modifiable being, for example, biological sex or genetic predisposition or biological factors that are modifiable, such as use of medication or comorbidities.

And this, in the inner circle, of course, is related to individual behaviour, which is very obvious, of course. And we will be talking about physical activity and media use and sleep. And then there’s biochemical processes such as energy, metabolism and inflammation, which has already been mentioned.

So if we need to think about screening programmes and even management strategies, really, it is so complex that you have to keep in mind the etiology. So if you think about screening, kind of most of this etiology would need to be covered if you want a clear picture of the person’s problem. And also when you think about management strategies, of course, we can increase physical activity, which I will show how effective it can be.

But there’s a lot of factors that need to be considered. So it’s a multi-component approach in the screening, but also in the treatment that you already have to realise when you look at the etiology. But before we go on into details, I think it’s important to realise the risk trajectories from childhood to adulthood that Peter alluded to.

And I think we need to have a few kind of hard facts and to realise how serious the issue is. And most of these are just quickly going to read out. So children with obesity are five times more likely to suffer from obesity as an adult.

So this is not a problem of the children, but it will evolve into a problem in adults with all the comorbidities that are associated with it. And then elevated blood pressure in childhood tracks into adulthood. We know that from the Finnish cohort study and an association of higher childhood BMI actually is given for increased risk of coronary heart disease in adulthood.

So we’re not only talking about risk factors in childhood and the trajectories into adulthood, but they even are associated with manifest cardiovascular disease. So risk factors are associated with events, even in midlife. Childhood risk factors associated with cardiovascular events in midlife and the obesity rate in adolescence will likely lead to an estimated up to 15 percent increase in the incidence of coronary heart disease in 10 years time.

So, of course, Melania, you’ve asked me why, as a someone in preventive cardiology in adults, why are we looking at childhood obesity? And this is I think the risk trajectories are the reasons why we actually realise we can’t wait for patients to develop manifest cardiovascular disease, not for the sake of the patients, but also, of course, at some point, it won’t be payable to treat patients with manifest disease. So this is the first few slides are taken from a position statement that we’ve come up with last year. And this is a concept of what we want, would like to achieve with screening programmes and after the screening programme, the initiation of management strategies.

So on the x-axis, you have lifespan in years and on the y-axis, your cumulative lifetime risk, cardiovascular focus. And if you’re healthy and you don’t have obesity in childhood, then this is the blue line here, basically. Yeah, the blue line.

So your cumulative risk during life is quite low. But if you develop childhood obesity during childhood and comorbidities, and of course, during life, you will develop a higher risk. And the red line would be individuals with obesity in childhood, but didn’t actually get the opportunity for preventive strategies.

Right. And then what we try and do is identify the risk early in life in childhood, to then be able to implement multimodal, not only screening programmes, but also interventions to reduce the risk during childhood, during adulthood. So the kind of purplish brown line here is in individuals who had suffered from childhood obesity, but were actually undergoing prevention strategies.

That’s the concept. But to be honest, so far, what we can achieve by screening and interventions seems to be quite little, in fact. So we, looking at the data that we have available, it is still unclear whether population-based screening programmes can actually counteract the burden of obesity-related cardiovascular risk in childhood.

It’s not that clear. And it’s also not clear who, when and how to screen in order to identify those children at risk of developing cardiovascular disease later in life. And also what remains critical is the cost effectiveness.

So all of this is rather not clear yet. And I can, we can give you an idea of how we approach screening and intervention in our Basel cohort in the XMU study. But that’s only one example.

And no, there’s not one solution to the problem. I think at the moment, it’s just important to raise awareness of the complexity of the situation. Of course, there is data on treating the risk trajectories in childhood.

So, I mean, we can, we can kind of be happy that lifestyle interventions can actually reduce BMI, but not only BMI, but also systolic and diastolic blood pressure. It can even have anti-inflammatory effects. And multi-component lifestyle interventions can help reduce weight during childhood in all age groups, even in puberty.

But when you look at the data, and when you focus on weight and BMI, these effects are rather small, and they are not the sole answer to the problem that we’re facing in childhood obesity. So what I think is important to realise that a lot of the data we have available is focused on weight related measures. And oftentimes, which is not ideal, of course, as you all know, we look at BMI, change in BMI, and of course, waist circumference or waist to height ratios would be much more efficient in children, but that data currently is not available in long term prospective cohort studies.

So what perhaps will make an impact in the future, and this is the research gap that also we identified, there is not that much information on overall health, cardiometabolic psychological factors, and specifically, vascular health. And this is why I think the focus on a screening programmes, but be also on infinite intervention needs to be adapted slightly. So this is the bottom line of what in our position statement, we identified for key screening, and risk factor management strategies.

So when it comes to the screening strategies, these are, I think the most important factors that we have identified. So we need to focus on a clustering of risk factors, not just look at overweight and obesity in these children, as Peter has mentioned, we need to look involved, blood pressure, glucose metabolism, lipids, etc. And we should also focus on the overall cardiovascular risk, including psychological factors.

Those children will not only suffer from obesity as as a disease per se, but also the the overall risk, which, which is a sum of risk factors, but also which can be identified quite nicely at the vasculature at on the vascular level, because the vasculature is the end organ that represents the cumulative risk of the system on the body. So this is why I will be going into a screening of vascular health in childhood and childhood obesity next. Yeah, and family and peers need to be involved, the government on a population level, of course, needs to be involved, they need to be educational campaigns, and raise awareness that also parental lifestyle and physical activity and nutrition behaviour is very important.

So this is the screening side of things. And when you when you think about risk management strategies and treatment, also here, there’s not no, you can’t only prescribe physical activity and exercise and reduce inactivity and screen time, but you have to, you have to address eating habits, and diet counselling. But even there, also, as Peter has suggested, you look at you need to look at the built environment, yeah, is accessibility of affordable infrastructure of healthy food, is that available? Is the green environment, the built environment, good enough for the children actually to be able to, to engage in enough physical activity in urban settings, and sleep hygiene also has been mentioned.

And, and of course, to develop a screening programme that touches upon all these things, and then prescribe a management, a risk management strategy that has has these main key issues involved in it is very, very difficult to organise and to go into. But I think this needs to be needs to be looked at. And I think the key barriers on a population level is sustainability of interventions and the data of it.

This is why prospective long term studies from childhood into adulthood are important. The cost effectiveness, if we at a political level want to change something, the cost effectiveness analysis will be very important. And of course, the funding, then of prevention programmes will be able will will be possible if we actually have data on cost effectiveness.

This is just to give you kind of a broad background. And some of this you will already have realised, but I think the risk trajectories, I think, were very important and the complexity of the problem problems that we’re facing. So why do I think why there is there, I would say a research area being developed in the last five to 10 years looking at vascular health at at young age already.

So this is similar to the concept that I’ve shown you. This is the concept of early vascular ageing. So if you’re healthy, and you have a healthy lifestyle, and the blue X, the blue line will actually show you that your arterial wall dysfunctional structure will be limited in that, of course, you get older and the you have vascular damage, but it’s limited since you have a healthy lifestyle.

But when you over the years develop diabetes, hypertension, or develop obesity, then of course, the vasculature will suffer. And the idea is, in children specifically, what kind of markers vascular markers can we apply early in early childhood to A, identify the individuals at risk. And these may be children with obesity, but independent, of course, of obesity, children may be at increased cardiovascular risk independent, of course, of obesity, children can have high blood pressure, or other cardiovascular risk factors independent of obesity.

And these would be picked up when you apply noninvasive vascular imaging. And then of course, if you identify these children, you can prescribe primarily lifestyle interventions to help reduce the growing burden of vascular disease here. So the kind of greenish line indicates vascular health in children that have been identified to be at risk in early, early at an early age, and have been prescribed lifestyle interventions.

So what kind of biomarkers can we use? Carotid intima media thickness has been mentioned, of course, we can look at it, it’s, it describes the structure, arterial stiffness, describes structure and function of the vasculature, flow media dilation can be measured, it’s a bit more difficult, the variability is quite high. So it’s not ideal. And then what, what can be done quite nicely, and as this is a newer approach, and this is actually my research area where we look at the diameter of the retinal vessels as a microvascular biomarker of cardiovascular risk, even in young children, I won’t go too much into detail for time reasons on how pulse wave velocity can be measured.

But it actually measures the time the wave propagates alongside the arterial wall in meters per second, basically. And we have performed a meta analysis. And this is in children, some time ago in 2013.

And it was quite clear that here systolic blood pressure was associated with higher pulse wave velocity, with a little bit of uncertainty left. But we saw this also for diastolic blood pressure, and BMI. So increased body mass index, excess weight in young children is actually already associated with increased arterial stiffness as seen in the higher pulse wave velocity.

And in children who were particularly fit, so we were doing shuttle run tests in these children, and we actually saw that those children who were fitter, actually showed lower pulse wave velocity, which indicates that very likely, with physical activity and fitness, you can improve vascular health. And this is just in brief, the method, one of the methods, the easiest method we use when we screen retinal vessels in children. So we take a fundus image of the back of the eye and further magnification, we can actually semi automatically identify the arterioles and venular diameters.

And the arterioles show an increased risk when they are narrower and the venules when they’re widened, for example, because of systemic inflammation. And they’re also associated with cardiovascular risk. So what we see in our children or in the in the meta-analysis of studies, systolic blood pressure, again, was associated with narrowing of the arterioles.

And this was also true for higher diastolic blood pressure and also for BMI. Children with an increased BMI have narrower retinal arterioles in the back of the eye. And in adults, narrow arterioles are associated with development of manifest hypertension and cardiovascular disease later in life.

Of course, we don’t have that data in children, but it’s very clear that we have that risk in adults and it and it’s likely to be a risk factor in children as well. OK, examine new study briefly, this is a prospective cohort study started in 16 and the follow up was in 2021, 1000 children, primary schools and children, 26 schools that we all screened over four years. And what we see quite nicely here is on the y-axis, you have the pulse wave velocity.

So with overweight and obesity, this is the clinical categories children have show a higher pulse wave velocity and increase in arterial stiffness and also with blood pressure. If children have high normal or high blood pressure, the pulse wave velocities actually increase. Children have increased arterial stiffness.

And this is from the pilot study of that data, of that study. So retinal vessels and childhood BMI, you can see that children with overweight already have narrower arterials and wider venules. Sorry, on the y-axis, this is the ratio of arterials and venules.

So narrow arterials and wide venules will lead to a lower AVR. And in overweight children, the AVR is already reduced and children with obesity actually have a significantly reduced AVR ratio, indicating that the microvasculature is altered. And if you just look at the retinal arterials in this cohort, even high normal blood pressure is associated.

And this is for the time being associative, is associated with narrowing of the arterials and high blood pressure even more so. So what we did in the XMNU study, we looked at children with narrowing at baseline and we followed them up over four years. And those children who had narrow arterials at baseline, otherwise healthy children, not necessarily with obesity, they developed higher blood pressure over four years.

So the retinal arteriolar diameters are actually, the narrowing is predictive for development of blood pressure over four years. And interestingly, in those patients at risk, so those children with high blood pressure and narrowing of the arterials, retinal arterials at baseline, they, if they were able to reduce their sedentary behaviour just by 10 minutes over the four years per day, of course, they improved their microvascular health considerably and had wider retinal arterioles, which is associated with lower cardiovascular risk in adults. To summarise our XMNU study for the time being, narrow arterioles are predictive for the development of blood pressure, as you can see on the left, and children with increased blood pressure and they don’t, they remain sedentary, don’t change their lifestyle, they will have narrow arterioles four years later.

But if they increase their physical activity levels or reduce their sedentary time, those children with high blood pressure can actually reach normal, healthy microvascular health after four years. And when it comes to pulse wave velocity, it is actually clear that the physical activity needs to be a bit more vigorous to improve pulse wave velocity over four years. Professor Hansen, we are running out of time, sorry.

Okay, good. So, the take-home message perhaps is, in a nutshell, lifestyle interventions are promising preventive strategies to improve vascular health in children and, most importantly, to reduce risk trajectories from childhood to adult manifestation. Thank you.

Thank you, Professor Hansen. Thank you both. We have now time for some questions.

Well, I can see, Lisa, the chat, the Q&A. I don’t know if it’s up to me. Yep, so we use the Q&A for the questions, so just a reminder to the audience, thank you again to our speakers for your excellent presentations.

I see we have some questions at the moment. Melania, please do feel free to just read from the Q&A. I can see the Q&A section on my screen.

I don’t know why, Lisa. Just in the chat section. I think we just use the chat section.

It’s just for comments and questions from the audience. The first one was on the role of insulin resistance tests and indexes. I mean, if they have any diagnostic value.

This is a question for both or, I mean, one of you can answer. Do you want to start, Hanna? Insulin? I think you are the metabolic expert. That’s a lot.

We follow children and those, very short answer. This is a very complicated and fascinating aspect of childhood obesity. In those children where we see high insulin levels, I intentionally say high insulin levels rather than insulin resistance, that is where we see more rapid development of complications.

And blood pressure, napple D, et cetera, et cetera. And then we looked into what are causes of the high insulin levels? Yes, insulin resistance, but also at least early insulin hypersecretion. But those are kids that we need to have an extra eye on and monitor progression.

High insulin is, if not, a validated biomarker. So anyway, something that you clinically connect with. Progression.

Okay, Professor Hansen? Yeah, I mean, to my experience, I would say it’s more diagnostic than therapeutic. So what you can do with it, I guess, is treatment monitoring. But the question is, is it diagnostic or therapeutic? I don’t think the latter is true, but I guess you can use it if I understand it correctly, Peter, also what you said.

It’s treatment monitoring that it can be used for. What we can do, as we do, and what we talked about, lifestyle, that can be improved, but unfortunately difficult. So we have tried both metformin and GLP-1 receptor agonists and some progress, yes.

And particularly the individual, you have to look at them one from another, whereas metformin can do very good reduction in fasting insulin in one subject. It may not have so much effect in another. Okay, thank you.

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And you are, I mean, welcome if you want to sign and attend. Another question is about the most effective prevention strategies among children in the long term, I mean, one, two years, strategies that have been implemented in Europe so far. Yeah, I can try and take this one, which I think from my presentation also perhaps indicated that this is rather difficult.

If you just look at BMI, the results are rather small. I would say the most important strategies remain diet counselling. But of course, this includes also the environment.

So you have to include the family and perhaps even schools, right? So we know that if you go to schools, you educate schools, you talk to the kids themselves, but also the family, of course, then that is more effective. And combined with education about physical activity, ideally education, physical activity programmes, which are actually in very few countries available. So, you know, the health insurances usually do not facilitate physical activity interventions or diet counselling.

But these, I would say the combination of both is most effective. If you look at BMI only, the effects are rather small, which I think it is important to highlight here that it needs to be screening that does not only focus on weight reduction, but on the overall cardiovascular health. And I think this can be very effective if you apply a multimodal approach.

So this is a very difficult question to say what is most effective. I would say diet counselling and physical activity in combination. So in most children over age five up to 16, this would mean 60 minutes of physical activity per day and a reduction of screen time below two hours per day, for example.

One of the colleague from the audience is worried because of, I mean, the risk of developing eating disorders when you put much pressure on BMI. And I think you can also, I mean, you clearly have explained that we can’t base our effort just on the BMI as outcome. Do you have any other comment? I mean, I think what I tried to touch about and then I give over to Peter, the stigmatisation is, of course, very important.

For example, you can’t advertise a screening or intervention and a risk management programme and saying, OK, every child that suffers from obesity come and join this programme. So it needs to be very subtle and included. So I think this alludes to or refers to the fact that you have to be careful with stigmatisation.

Exactly. And we also try to flip the coin, focus on health rather than on disease. So invite people to these activities.

Another aspect, yes, we are addressing individuals. However, they are not at fault of the development. Somebody said obesity is a natural reaction on an abnormal society.

I mean, we have to tell them this is not your fault. We want to help. And then the more community based approach, just maybe we give a rather gloomy picture on future prospects.

But may I just point towards I’m working very closely with people in the Netherlands. And there are conditions that give them a possibility of doing these community based interventions and I think showing promise. So maybe that’s something that could be proposed for the ASO, where even reduction in the heart parameter, BMI, childhood prevalence of BMI.

However, after six, eight years of consistent work. Before going to the final question that we have in the chat, I have a technical question. I mean, if we can perform a study of the retina vessels analysis or the pulse wave.

I mean, it is OK to perform every year, every two years. I mean, what do you suggest in the clinical practice? Well, the good thing in childhood really is that the organ system and the metabolic pathways are very, have a high plasticity, right? They adapt to when we treat. So, for example, in adults, once you have plaque and once you have a thicker intima media thickness, it will remain thick.

But in children, it can actually regress. So, you know, childhood is a window of opportunity where you can actually do something and regress the risk. So this is very important.

And within 10 weeks, we see improvement both in children, both in arterial stiffness for large arteries and widening of the retinal arterioles that actually reflects cardiovascular risk reduction. So we can, within 10 weeks, if we apply an intervention, we can see if we have responders or no responders. If we have to increase the treatment, we can use vascular biomarkers as treatment monitoring to see if the intervention needs to be adapted.

OK, thank you. We have still time for another couple of questions, Lisa. Yeah, sure.

I think maybe these will be the final questions. The speakers are happy to stay just for a minute or so to finish. But otherwise, I think we’re ready to close soon.

Thanks. OK, a session of physical activity can be prescribed as a medicine. There is any place, any country where this already is in place? I don’t know about the rest of the world.

Peter, sorry. No, in Sweden, it is done. How shall I phrase this? I think it’s important.

It is, again, prompting families, children to move in the direction. And if this can help, fine. The evidence, if you really scrutinize it, I think you understand what I’m getting at.

Yeah, I think you probably have to give it another five or 10 years for more countries to implement such things. So in Basel, this is very specific. Since we were running the examinee study, we were screening the kids, we were following them up, and we realized we have to start implementation research.

So what we do in collaboration with the Continental Office of Sports and Education, we now offer children identified at being at risk, but offering them physical activity and health interventions. Now, this is not a focus. We identified them, but this is, of course, not a group for children with obesity, but we actually approach them.

And together with the Continental Office, in the different areas of the city of Basel, we offer once a week sessions for these children, if they’re interested. And we’re currently working on reaching more children, because out of like 400 children and families that we approached, only 50 families actually responded and used those intervention opportunities. So we really have to find ways to better reach the families as well.

So to offer is one thing, but to optimize actually getting the children who benefit the most is also difficult. OK, the last question is, again, on lifestyle intervention that reduce BMI and blood pressure. But we have seen that the effect is small.

Our colleague asked, what else should we try to have a better, I mean, a bigger effectiveness in terms of clinical outcomes? I think, I mean, you have already replied somehow during your talk and then, but probably this can be the really the take home message to conclude this amazing session. Hanner, do you want to, Hanner, Peter? Well, I think, yeah, thank you. The reason why it hasn’t been shown so effective perhaps also means that the interventions have, A, looked at the wrong outcomes, perhaps not only focus on BMI, but also improve the interventions and have a continental offices or actually programs, offer more programs and better programs that not only focus on weight reduction, they may have better outcome, I think.

So there’s a way to go. And then, of course, we’re opening the, but we can’t do that at the end of the session. Of course, the GLP-1 analog for children over the age of 12 are being discussed, I guess, in combination with lifestyle, at least for those who have extreme obesity.

That is something that is gaining. We have more data on that. And I think in five, 10 years time, this will be, this may be a combination lifestyle and pharmaceutical treatment, but only in those children who have a severe obesity.

Peter? Peter, your second message? Yeah, just wait. Tools that can tell us much earlier when a child is moving from health to risk and interventions that can push them back. And among those, I think we need to look broad.

Everything that we’ve said to the individual, but not in the least addressing societal aspects. Also, that is also addressing the stigma. So we need to do it, well, you know, easy for people to make healthy choices.

Thank you both. Thank you for your excellent talk. Thank you to all our attendees who, I mean, stayed with us, even though we run six minutes out of time.

Thank you to IASO for organizing this webinar. And I mean, we will stay in touch for the next webinar. Thank you again.

Thanks, everyone. Bye. Bye.