Richard Jacobs: Hello, this is Richard Jacobs with the Finding Genius podcast. I have Adam Lewandowski. He is a University research lecturer and British Heart Foundation research fellow. He is in the Oxford Cardiovascular Clinical Research Facility, the CRF in the Division of Cardiovascular Medicine. He is from the US, he sounds like it at least or Canada but he is over in England. So, Adam, thanks for coming. 

Adam Lewandowski: Hi, thank you. so, yeah, I’m Canadian but I moved to the University of Oxford in 2009 to start my Ph.D. studies. So, I have been here for almost 11 years now.   

Richard Jacobs: Wow. So, what’s the focus of your work? 

Adam Lewandowski: The main area of my work is looking at the effect of pregnancy complications. So, specifically related to things like preterm birth and how that affects heart development and interaction with other systems or organs. So, things like the brain and liver and blood vessel and how those things are changed within people born pre-term. 

Richard Jacobs: So, pre-term birth, is it divided into like, very early preterm, late pre=term, or is it just one monolithic thing?  

Adam Lewandowski: No, exactly. So there are different categories largely based on gestational age.

So, normal gestation would be between, we say 40 weeks if you are full term but the full term definition actually ranges from 37 to 42 weeks gestation. Anything less than 37 weeks gestation is considered pre-term. You are absolutely right, there are different categories. So, if you are 32 to 36 weeks plus 6 days, you are considered moderate to late preterm. If you are 28 to 31 plus 6 days weeks gestation then you are considered very pre-term and if you are then less than 28 weeks gestation, you are considered extremely preterm.  

Richard Jacobs: Are babies able to survive if they are born super early? What’s the earliest that you’ve seen is possible for a baby to survive?   

Adam Lewandowski: So, the earliest that I’ve seen within a hospital setting has been 22 weeks and that’s becoming more and more common actually. So, I know, in some centers actually, in the US there was a study published out of Iowa that actually showed that even 22 to 23 weekers, I believe the figures were about 60% to 70% survival now within that cohort of individuals which is pretty impressive actually because we wouldn’t have seen that say, 10 years ago. But I would say that the survival rates, in general of pre-terms, are now up in the 90% across all the gestations. 

Richard Jacobs: So, when does the baby’s heart develop throughout the gestation and when do the features of the heart develop?

Adam Lewandowski: So, I think intuitively you may think that it may not have a big effect because if you actually, if you go back to physiology, when we learn about the development of organs, actually the heart is fairly early on. So, within the first weeks and within the first couple of months, by week 7 or 8, you already have that functioning chambers and heartbeat of the heart. Now the reason why whereas with the brain, the developmental period is actually very late in gestation and that formation of the different components of the brain but the reason why this is important and why prematurity affects the way the heart is developing is because in the later period of gestation is actually a big period or an important period for growth for the heart. So, what we have early on is called Hyperplasia and that’s when the cells are rapidly dividing in order to expand the myocardium which is the heart muscle wall.

Then as you move to later parts of gestation, you will see the heart actually start to increase several-fold larger over those last weeks of gestation. But once you switch towards the outside environment, you have changes in; you have a big shift in the pressure and the flow around the time of birth and then you have those pressure and flow changes outside of the room as well because you are now faced with a situation where you have a functioning pulmonary system and you also have a high resistance systemic system whereas inside the womb you had that low resistance placenta. You’ve also got these shifts in oxygen tension and everything too and what you see basically is that the cells change from that hyperplastic growth to hypertrophic growth. So the individual cell size is actually increasing. 

Richard Jacobs: Also, could a baby end up with a heart that is too large, too early for their size if they are born prematurely?  

Adam Lewandowski:  Because you are actually affecting; we don’t tend to see that as much because what you are actually affecting is if you disrupt the amount of cell division but you are actually increasing the individual cell sizes, it may not be that the overall heart size increases. We actually see the opposite, we actually see that we have smaller internal cavity diameters, smaller actual functional diameters not just gestationally but then that you actually get thickening of the wall. 

Richard Jacobs: I’ve heard, I believe when someone has a heart attack or heart problems later on in life, that’s exactly what happens is you get; part of the heart dies off and the remaining cells in an attempt to cover everything become hypertrophic. So, I wonder, babies that are born prematurely, later in life, they have less cardiac reserve if they have heart problems because they have maybe fewer cells overall and are hypertrophic already. 

Adam Lewandowski: So, we call this the reduction in a cardiac endowment that they had. The studies that I have been doing have sort of expanded from or are going to cross all the way from looking at the kind of early fetal development of the heart largely in humans but in collaboration with other groups that do work in animal models but also looking at what happens in those first weeks to months in the post-natal period. So once they are neonate infants and a lot of my Ph.D. work were focused on the adult period and looking at what those long-term effects were looking at things just in terms of morphological changes. So, changes in structure and function volumes type thing, and what we’ve seen is that they do have these distinct changes between the groups which may adversely affect them in the longer term. 

The work since I’ve been doing in my post-doc which was started in 2013 and now transitioned into my role as a PI now, running my own research team has been to try to link up what’s actually happening at a tissue level, what’s actually happening to the heart when it’s faced with physiological stress demands, so things like exercise stress but also what’s happening at a cellular level as well and understanding how that heart development changes through that life course. So, we’ve actually followed some of the same individuals that have been seen early in life. So, during fetal and neonatal and infancy, and are actually tracking them into childhood now. Some of the findings that we have been seeing primarily in our young adult studies are that when they are faced with that kind of stress response, so when they are put into moderate to high-intensity exercise levels, you are exactly right as you brought it up before that they have this highly reduced functional reserve, so we call it a myocardial functional reserve and they are less able to elevate the amount of contractility of the heart and amount of blood volume needed to meet the demands of the body. 

Richard Jacobs: So, when a baby is born prematurely in the incubator system, what does this tell you about how to set the pressures and maybe the percentage of oxygen? Is there anything that you can do to try to encourage the heart to continue more normal development instead of just going hypertrophic?     

Adam Lewandowski: Yeah and I think that’s still a remaining question actually as to what’s the best environment and one of the challenges that we have is that in a very positive way, clinical medicine is advancing quite quickly and the absolute main thing to remember is what needs to be done in immediate clinical care to keep the babies alive is the most important thing as well. So, understanding what’s actually going to be able to achieve that immediate benefit but also promote potentially long-term benefit or reduce long-term harm has been a challenge that we can only right now look at in terms of correlative manner. There are some studies now, investigating specifically the effects of different amounts of oxygen exposure, different ventilation parameters, and things as well. But the challenge with those and what I am hoping for the future is that a lot of follow-ups that are being done is very short-term. 

What we are actually seeing is that we need to follow up into longer-term and I don’t mean until elderly, I mean like, at least until childhood, because coming back to that kind of risk to pre-term born individuals, we are seeing now from big epidemiological studies now that actually is these cardiac changes may mean making them vulnerable already in not just long-term but it may have immediate risk because we are actually seeing that they have an increased risk of heart failure early in life. So, childhood, adolescence, and into young adulthood and even by young adult life have increased risk of hypertension including a higher number of hypertensive medications, even in their 20s and they also have the risk of ischemic heart disease. 

Richard Jacobs: What causes babies to be born prematurely? What are the main drivers of it?  

Adam Lewandowski: so, there’s a number of different causes. So, there are things that can be familial. So, you can have a genetic predisposition that may make you deliver pre-term. One of the biggest antecedents to prematurity is Preeclampsia which is a more severe form of a hypertensive pregnancy, so that can count for up to about 20% of pre-term births. Things like infection can also lead to pre-term birth and then you have other risk factors including things like obesity and smoking as well. 

Richard Jacobs: In general terms what have you observed that’s done, even without specifics but generally what do you see that’s done for the premature babies?  

Adam Lewandowski: So, the main thing is obviously maintaining the appropriate; so in terms of monitoring and maintaining their lung function. So, it’s things like providing Surfactant but also providing oxygen to make sure that their brain and bodies’ needs are being met.

The other aspect of that of course is one of the struggles early with pre-term units is the fact that feeding is often quite challenging. They are often very small, so providing parental nutrition and providing appropriate feeding is an important component of that and of course, because of the immature physiological system, they are also more prone to infections as well, so kind of taking a prophylactic approach to that is also an appropriate component. 

Richard Jacobs: So, when a baby is premature, what happens to the heart, let’s say in the first; what do you call the gap in between the time the baby is born until it would normally be born, let’s say, in the 40-week mark? Does that gap have a name and if so, what happens to the heart in that time? Is that different from what happens to the heart after that? Say, the baby is born at 30 weeks and you said, let’s say the full term, in some instances, I’d say 40, I know it’s that range but, so is that 10-week gap called anything? If so, whether it has a name or not, what happens to the baby’s heart between week 30 and week 40, and what happens at 40 and beyond? Is it different or does the same thing happen in the heart whether the baby is born at 30 weeks or 40 weeks? 

Adam Lewandowski: Yeah, so, this is a good question. I mean, in general, it’s called kind of pre-term post-natal period and once they have reached term gestation, so say, you were born at 40 weeks, you would then say, the term equivalent age of the pre-term born individual, once they reach say 42 weeks, which is 12 weeks post-natal would be what their term equivalent age would be. What happens during that period, we can use some of the investigations that others and our own groups have looked at in terms of looking at using say, MRI and Echocardiography which have shown that the heart in that period undergoes very similar changes to what you would normally expect to happen later and that includes that you switch from a right heart dominant to a left heart dominant system and again, that’s to maintain the required demands for the lung system which is much lower resistance than say, the systemic system which is why the left ventricle remodels to be able to take over that flow through that system. 

But again, going back to the cellular shifts is we see that big shift in hyperplasia to hypertrophy. So, the way the cell is dividing to being more hypertrophic. The other aspect of that is that from, a lot of this has been; our understanding of how the heart remodels is how to rely on investigations on animal models. So, studies in rats sheep, and pigs have kind of been the main ways of actually interrogating this and the big thing that has been found from that is that although there are these cellular growth shift patterns but there have also been changes at the DNA level, in terms of nucleation as well, which is shown to have abnormal maturity within the individual monocytes but it’s also shown that outside of the individual monocytes, you also have differences in the structural components of the heart. So, the collagen content within the interstitial spaces which may be driven by pressure overload. 

Now one of the things that have been discussed as well is that a lot of these models can’t mimic the full-pre-term birth conditions which often involves things like inflammation especially if you had underlying placental abnormalities which is common in things like Preeclampsia as I mentioned, is a major contributor to preterm birth. So, if you have those changes as well, it’s expected that you are going to have more of this collagen deposition vibronic formation as well which may make the heart less compliant and less able to meet the demands of the body as well. 

Richard Jacobs: Does the heart have a different shape? Is it preferentially thicker in one of the ventricles, for instance, does it look pretty close to what a normal heart looks like? 

Adam Lewandowski: So, our group has been largely using MRI and we also use computational modeling so we work closely with biomedical engineers in order to actually interrogate the 3D structure of the heart. By young adulthood, what we’ve seen is that the ventricles are actually smaller internal cavity, a similar external cavity which is suggestive of an inward thickening of the muscle wall and shorter ventricular length as well and this seems to be consistent with both ventricles though we’ve seen greater changes in both the remodeling as well as the number of systemic functions that are pumping function of the heart in the right side. One of the things that we believe it could be related to the part of the link between the pulmonary circulation. 

We have published on this as well but this effect with the pulmonary circulation seems to be more driven in those that are earlier gestations. In terms of looking across all of the different developmental stages, we just actually, on the 7th of July, I made an analysis in pediatrics that we published from our team that we’ve actually interrogated what is actually happening across all of the key developmental stages, including neonates, infants, children, adolescents, and young adults and breaking them down to understand what is the actual difference in cardiac parameters between pre-term and term-born individuals. Now, what we’ve found from this actually is that many of the changes that are seen in young adulthood actually start to emerge in neo-nates. So, things like these smaller right ventricular and left ventricular volumes but also, things like the reduction in right heart pump functions, systolic function as well as the ability of the left heart not to relax and fill with blood so that systolic function which actually worsens with age as well. But we also showed that even from childhood into young adulthood, we have this accelerated rate of hypertrophy of the heart.  

Richard Jacobs: is there any protocol that kids can do to strengthen their hearts? What if they are put on like a light exercise program, ongoing, early, for a long time? Is there anything that can still be done? Perhaps they have quite a bit of stem cells running around and maybe the heart can remodel if there is intervention early enough. 

Adam Lewandowski: yeah, it’s a good point. So, I think, as you mentioned a little bit earlier about what some of the interventions are that normally happen in clinical practice early in life. So, that kind of, first months but of course, as you said, the heart is continuously developing throughout life as well. So, although there may be really that negative period, early on, negative in the sense that abnormal development early on with these individuals. There must be a way that we can at least improve cardiovascular function throughout development as well and I think your mention there of things like exercise has been a primary focus for us actually. So, looking into lifestyle interventions like nutrition and diet and exercise to kind of promote a heart-healthy lifestyle and reduce that risk is still under investigation. 

So, we are actually running a; we just finished our last visit and performed the data log for our randomized control trial in young adults of pre-term and term-born individuals that went through a 16-week exercise intervention. So, these were people that were either born pre-term or term, had elevated blood pressure or stage one hypertension, and were relatively sedentary in the beginning and the intervention actually involved 3 exercise sessions per week with a personal trainer for that 16-week period and with intensities of about 60% to 80% of maximum for the aerobic training for both for roughly 45 minutes per session. So, relatively intense but very aerobically stable exercise intervention. 

Richard Jacobs: Yeah, that’s great. Perhaps other things like low impact things like meditation may work, I don’t know. I guess there’s a lot of things that could be tried. 

Adam Lewandowski: Yeah, so one of the good things with this field is that and to mention going back to the meta-analysis is there, we’ve actually identified since 2013 which was our first big paper came out in circulation describing the left heart and then a few months later published in circulation again describing the right heart changes. Since then, what we’ve found actually is there are 32 unique research studies that have been done and that’s what we’ve described in the meta-analysis. I think the good thing about that is there are more and more people researching this area to be able to understand what’s going on and taking different approaches to understand potential mechanisms as well but what it also means is that there is now wider discussions between different allied health professionals, scientists and also with patients and participants trying to understand what are the best ways of actually intervening as well and what can be done in terms of raising awareness within this phase.  

Richard Jacobs: What are parents told? Are they, is there a conference on what may happen if parents are told that hey, your child will have a harder time with hypertension and may have more heart problems later in life. If there are clinical trials to be done, is it they are difficult to do because there are kids involved, or is it easier to do because the parents will say yes, I want to see if there is anything you can do to help my child? What’s the situation there? 

Adam Lewandowski: So, I think, in general, what we’ve found is that actually a lot of pre-term born people and their parents are very willing to take part in research studies and are very wanting to get more information as well. I think that’s a good thing. I think the other thing to assure people is that just because you were pre-term, you may have some of these cardiac changes. It doesn’t necessarily mean that you are going to immediately have heart failure, heart attack or any of those things as well. It just may increase your risk but those things are still fairly rare in that early life period. So, if we look at heart failure from non-congenital causes, it’s less than 1 in 100,000. So, even if you have, what we’ve seen in pre-terms is a seventeen-fold increased risk which sounds huge, it’s still a fairly rare occurrence within that population. So, providing that realistic information and out of context, I think, is important. 

But I also think that having that engagement early on, as I said is an important component in terms of being able to incorporate those healthy lifestyle components and ways of monitoring. So, if hypertension is developing, for instance, which is one of the most widely reported cardiovascular changes in pre-terms, if that is developing and isn’t being managed with lifestyle interventions, having that monitoring to being then able to intervene from other angles such as pharmacological means is a positive, the fact that you’ve had them in more continuous monitoring and being able to catch those things earlier to prevent long-term more serious cardiovascular events. 

Richard Jacobs: Okay, alright Adam, what’s the best way for people to find out more? If, unfortunately, they see that they have a child that is going to be pre-term, what are some places that they can go to for information? You and beyond you, where can they go? 

Adam Lewandowski: So, I think there are some very good websites or organizations that talk about what happens in terms of the immediate stages of pre-term but also, in terms of long-term, as well research, especially bigger research studies which have provided more concrete evidence. So, things like March of Dimes always has a lot of good information on that space. In the UK there are also several charities that list as the one here but I think those kind of things are going to do the, like to March of Dimes, even the WHO provides credible information as well but I think the big thing and the hope as well, especially talking to a lot of my clinical colleagues is that GPs and other physicians become more and more familiar with this as a potential risk factor and start to be a resource for that information as well. 

Richard Jacobs: Very good, Adam. Thanks for coming on the podcast. I appreciate it and this is an important issue. These poor babies that are born early, at least they are able to survive but it would be nice to have them live as normal lives as possible. So, you are doing a good thing.  

Adam Lewandowski:  Great. Thank you for having me.