Part 1: An interview with Professor Mark Ledwidge, Co-founder and Director of the Heartbeat Trust, H&L Pharma and Solvitron Therapeutics

Elaine Quinn

One in five people will develop heart failure in their lifetime. With such a high prevalence, the importance of early diagnosis and a better understanding of the underlying causes of heart failure are key to determining the most effective treatments for this potentially serious condition. There has been growing interest among researchers in exploring how Whole Genome Sequencing or the reading of our entire DNA code can better inform the way we approach prevention, diagnosis, and treatment of the different subtypes of heart failure so that we can look at improving our management of individuals at risk of developing the condition in a more precise way. One of the people, spearheading this research is Professor Mark Ledwidge, Co-founder and Director of the Heartbeat Trust, H&L pharma and solvitron Therapeutics. Mark, you’re very welcome to this episode of In Sequence.

Mark Ledwidge

Thank you very much, Elaine.

Elaine Quinn

Now, before we get talking about your research, maybe you can give us a little bit of background first. I know you graduated as a pharmacist and completed your PhD in pharmaceutics at Trinity College Dublin in Ireland. What was it that led you to have such an interest in heart failure research, specifically?

Mark Ledwidge

I didn’t like being a bench scientist so, as soon as I finished my PhD in Trinity, I did everything I possibly could to stay away from the lab and I got a job working in a drug development company or a medicine development company based in France. And I was leading some of their Irish research around heart failure, so I developed an interest in heart failure. And at the time we started doing some studies with Professor Ken McDonald who is a cardiologist based in St Vincent’s hospital and Ken had just come back from Minnesota in the US, and he was setting up his research program in heart failure in Dublin and we were providing some support. And I got to know Ken, and then, when I left my job Ken convinced me to come and work with him for a year to help him to build his program and Ken and I had a shared interest in multi-disciplinary research for heart failure and I promised I would do it with him for a year and you know, more than 20 years later, I’m still doing it.

Elaine Quinn

That’s wonderful – We all know that heart failure presents a significant health challenge in society today. We all know people who are taking medication for something that’s heart-related whether it be for high blood pressure or high cholesterol or who have other known risk factors maybe like diabetes where they require monitoring for other related heart issues. Can you talk a little bit about what heart failure is and perhaps more importantly, where the gaps are in our knowledge around heart failure?

Mark Ledwidge

You know, knowing what the heart muscle is and what it does when it’s healthy, the term heart failure is probably a little bit unfortunate because it sounds very, very definitive. It sounds like the heart has stopped, that it’s no longer working and that’s not the case. In heart failure really what we mean is that the heart is not producing enough blood to meet the needs of the body. And that can be a very gradual process that can happen over many, many years. And what we understand about heart failure is that whereas a normal, healthy heart is providing each of the body’s cells with oxygen and nutrients, in heart failure, because the heart is not producing enough blood to meet the body’s needs, these cells that are a little bit starved perhaps of oxygen or a little bit starved of nutrients. And so, when the heart is not working as well as it should, and that is heart failure, it affects lots of different parts of the body and it causes lots of different symptoms.  And I think it’s probably worth remembering that long before a person with heart failure gets to the point that they have symptoms there’s a process of damage that doesn’t produce symptoms that’s ongoing. And that’s really the focus of our care programme and our research into prevention.

And the typical symptoms that people will feel over time are symptoms like fatigue or shortness of breath. Some people find that they they’re coughing a lot even though they don’t have an infection. They might find that it’s very difficult when they’re lying flat to catch their breath at night, they might have difficulty sleeping properly and their sleep might be disturbed and they might have fluid retention and maybe some swelling for example, in the ankles and those are the kind of symptoms that would suggest that maybe along with some heart damage, a person has now graduated to symptomatic heart failure.

There are two major types of heart failure, one where the pump function is not working so well, the other where the heart is not filling in between pumps properly and if it doesn’t fill properly, it doesn’t matter how well the pump function is working it’s not going to produce enough blood to meet the body’s needs. And our major gap is we have fantastic therapies to improve people’s symptoms, improve their well-being, their quality of life, and the length of their life if people have a problem with the pump function. And we have virtually no therapies that can do all of those wonderful things when people have heart failure, with a filling problem and that’s sometimes-called heart failure with preserved pump function or preserved ejection fraction.

And it’s also it’s also really important to remember that right now heart failure with preserved pump function or preserved ejection fraction is the major form of heart failure. So, 6 in 10 people in the community with heart failure have preserved ejection fraction and we just don’t have good therapies for them. And what we end up doing is managing symptoms and managing risk factors, but we can’t really say we’ve got a definitive therapy that’s going to help them live longer, as well as feel better and that’s really the Holy Grail right now and because this form of heart failure is associated with older people it’s becoming more common. Because, as we get very successful in other areas of medicine and health care and the way we live, people are living longer. And therefore, they’re more likely to develop this form of heart failure. And the last thing I think that’s important to mention is that this form of heart failure is also much more common in women than men. And that might be related to the fact that women live longer than men in general in most parts of the world. It might also be related to the fact that women are less inclined to think about heart problems because men tend to get heart problems at a younger age and at a given age men tend to have more heart problems, but heart failure is a very important issue for women, especially as they get older.

Elaine Quinn

Right, so if you’re trying to identify these people at an earlier stage where maybe the symptoms aren’t apparent yet, then you’re looking at the risk factors that increase the chances of a person going on to develop the more serious or more symptomatic phase of the condition. There have been numerous awareness campaigns focused on what these risk factors are, whether it be smoking, reduced exercise, increased weight, poor diet, diabetes. But what about the less common risk factors. How are you identifying these people before they move into the more advanced stages of heart disease?

Mark Ledwidge

Okay, well, first of all, the best way for us to pick out people who are likely to have that early-stage heart failure and it’s probably worth mentioning that, according to the American Heart Association, there are four stages of heart failure. So, stage A is when somebody has risk factors. So that might be that they’re overweight or that they have high blood pressure or diabetes, but they’ve no heart damage – their heart is working fine, and they have no symptoms. Stage B is where there is a little bit of heart damage. We can usually only see that when we use a heart scan, for example, an ultrasound scan but there’s no symptoms, because the heart damage is at a very, very early stage. And before the person starts to develop symptoms, which is stage C, the heart is trying to adjust. It’s trying to accommodate this lack of efficiency let’s call it, and it does that by maybe enlarging so it gets a little bit bigger to try and produce more blood. The muscle mass gets a little bit bigger, so the muscle is trying to perhaps pump more, for example. And then, sometimes the heart will pump faster so in a given minute it’s still trying to compensate for its poor performance by managing to move a little bit quicker, move a little bit faster. And in that phase, there are a number of signals that we can detect in the blood of somebody who has no symptoms but has risk factors to decide whether they should go for a heart scan. And what we do is we try and pick people out using our program and our screening and blood tests and research and heart scans to identify these people at a much earlier stage, so that we can put in place a management program to prevent the heart failure.

Elaine Quinn:

And how aware are the general public of this more difficult to detect and treat form of heart failure, this preserved pump function heart failure where the pump is still working fine but the heart chambers aren’t filling adequately to ensure there is enough blood being circulated with each pump.

Mark Ledwidge:

I would say that the awareness of that in the general public is still not there and some research shows that when women present to their doctors with heart failure, they’re usually at a more advanced stage in the illness than men, and maybe that’s an awareness issue. You know, maybe they’re not consciously looking for problems with their heart in the same way as men are. I think amongst doctors, primary care physicians, cardiologists, there’s a lot of awareness about this, and in fact it’s a major frustration that we still don’t have good therapies, to offer our patients. And I think, also the major frustration that we’ve tried a lot of different approaches in terms of medicines to improve the outcome of people with preserved pump function heart failure and it hasn’t worked. So, we really need to try different strategies and I suppose, for many reasons, that’s why people are now interested in the work that Ken McDonald and myself started 20 years ago, which is really about prevention of heart failure. Because the most obvious thing to do, if you can’t cure something is to prevent it and in many ways the healthcare system is much more adapted to curing illness or trying to cure illness. We put a lot of our resources into the hospital system which right around the world tends to be reactive and primary care is more about prevention and we probably need to resource it more and, interestingly, I think that the public and patients are very interested in prevention and I think that this is something, and this is a system of care of that can really work.

Elaine Quinn

So then 20 years ago you and cardiologist Ken McDonald set up the Heartbeat Trust. Was the motivation behind that then to shift the focus from a more reactive model of addressing heart failure to one that is more preventative?

Mark Ledwidge:

So yeah, this was really one of the cues for us to set up the Heartbeat Trust. We founded the charity in 2003 to support the St. Vincent’s Screening to Prevent Heart Failure program and that’s the STOPHF program. And what we did was we decided to link in with about 150 primary care physicians in about 40 practices on the east coast of Ireland and we asked them to send into us patients that had high BNP levels but were otherwise well. BNP is a protective hormone that’s produced by the heart when it’s under stress or strain. Now it’s a good guy so it’s actually protective to the heart, but the levels are up and it’s a signal that the heart is under some duress and trying to repair itself and trying to protect itself and that level, we can detect in a simple blood test in a GP clinic or in a hospital. And if the level is elevated, we will often then immediately refer the person for a scan and we can see if the damage is there, what type of damage it is and then what the treatment approach can be to best prevent the development of let’s call it stage C heart failure.

So, if you had risk factors for heart failure like diabetes, obesity, people who’ve had a previous heart problem, like a heart attack or they’ve had some bowel problems and you had a high BNP on this blood test that could be carried out in the general practitioner’s clinic, we wanted them to proactively send them in – long before they had any symptoms and long before there was any concern. And we did some heart imaging on everybody and we identified about one in four of the people that were sent into us that had a problem. And that were already at this stage B heart failure. And for those people we were able to really intensify the risk factor management, we were able to make the people aware that they were having this brewing problem with their heart that they maybe weren’t conscious of. We were able to encourage them to stop smoking, to maybe reduce their alcohol intake, to improve their diet, to exercise more because exercise is a really, really important way of protecting and preserving the heart’s function. And we were also then able to collaborate care between the hospital clinic and the general practitioner, so this wasn’t a cardiology clinic doing everything it was real shared care between the primary care physician, the pharmacist in the community, the patient and the cardiology clinic.

And what we showed at the end of five years of follow-up was that we could prevent heart failure to the extent of about 40% in the people that were randomly allocated to this, in many ways, quite simple approach to care, but at the time, very unusual approach to care. And also, what we found was that, when we looked at the data, we reduced the incidence of lots of other cardiovascular problems because with the treatments that we were providing to reduce risk factors, and the good advice that we were giving people to you know exercise more, cut down on smoking, and reduce their alcohol intake that was having a beneficial effect on lots of different parts of their body, not just their heart. So overall, it was a fantastic program. We did a cost effectiveness analysis in 2015 – showed that it is a very, very good use of healthcare resources – it’s highly cost effective. And then, a number of different countries, including in the UK it received an award – the Royal college of general practitioners gave it an award in 2015. In 2017 the American Heart Association adopted it into its guidelines and also the Canadian guidelines in heart failure adopted this program and it’s also now the standard of care in our practice. And more and more it’s becoming the standard of care around Ireland, again linking in with primary care physicians around the country. So, it’s a good news story. In many ways, it’s a very simple concept, but on the back of it we’ve been able to come up with some other ideas.

Elaine Quinn:

I mean what an impactful program to have developed and starting from, as you said, such a simple concept and for it then to have expanded beyond Ireland and be adopted into other guidelines internationally is such a huge credit to you and Ken McDonald. And it just shows the value of the program that you both initiated. And being able to combine your expertise in research and pharmaceutics and Ken’s expertise as a clinical cardiologist means that these findings can then be translated into the clinical setting. So, you’ve since expanded on this programme – what have you been up to more recently?

What we realised maybe back in 2013, 2014 is that relying on a simple blood test to screen people is definitely interesting and good but it’s not perfect. And in fact, what we noticed was that about one in five people who went on to develop heart failure actually came to us at the outset with what you might call a relatively low BNP, so we weren’t picking up everybody. And we decided that one of the best ways of maybe trying to improve that risk prediction would be to look at the person’s genetic profile. And so we re-consented as many patients as were willing from the original program into a genetic study, where we were going to follow them up for again a long period of time, and right now that follow up period extends to about eight years, and we were going to Whole Genome Sequence them and use that Whole Genome Sequence to risk profile them further and to see how could we use the genetic information that a person’s body will provide to tell us something about their future risk of events and to see, therefore, can we improve the risk profiling. That led us to form a partnership, not just with the clinical staff and the research staff but also now computer scientists and data managers and bioinformaticians and the wonderful team in Genuity Science, because they bring a whole level of expertise and analytics and managing large volumes of data, because that’s what we’re generating for each patient we generate billions of data points. And managing that information and extracting from it, usable actionable clinical data is a huge challenge and it’s beyond my ken and it’s beyond the ken of cardiologists and pharmacists generally. But these researchers in Genuity Science have been able to add so much value to our program and one of the things that we’ve found we haven’t published this yet, but one of the things that we’ve found is that amongst our patients with high BNP – if we look at their genetic risk profile for cardiovascular disease and there are increasingly validated genes that we can look at, sometimes thousands of genes, to get a view of somebody’s total genetic risk for cardiovascular disease. And if we put that on top of BNP, we can separate out people with a 2 in 10 versus a 4 in 10 risk of heart failure and other complications over a period of five years. And that’s really important because, when we look at these people in the clinic, we can’t see differences. You know the obvious things like their age or their gender or the profile of illness that they have or their risk factors. We can’t really see that much of a difference. We can’t even see that much difference in terms of their BNP level but their genes are telling us that some of these people are at a much higher risk and for those people, then we can again begin to try and reduce their risk factors more, encourage them a little bit more to do the good things, and make adjustments if they need to in their lifestyle and perhaps exercise more, sometimes rest more, maybe lose a little bit of weight – that can often help.

And I think it’s also important for me to remind people about the importance of lots of disciplines so, even though the STOP HF program was the brainchild of Ken McDonald and myself, the fundamental ethos of the unit and the heartbeat trust on the Stop HF program is multi-disciplinary care. Bringing the pharmacist, the GP but also, I should mention the nurses, psychologists, the dietitians, the cardiac physiologists – all of these people contribute in their own way, and you can’t deconstruct it and say any one part is not important. We think it’s all more than the sum of its parts, but each of the parts are really critical.

Elaine Quinn

And so, looking at it from a pharmaceutics perspective then, would you say that pharmaceutical companies are recognising the value of genomic research, so Whole Genome Sequencing combined with clinical information from people with heart failure and how this information or looking at a person’s entire DNA code can better inform the development of more targeted treatments for heart disease?

Mark Ledwidge

That’s a great question and there’s a lot in it. There are two really important aspects, I think. So, the first is that from about 2015, we have some really good evidence that when a medicine development program has supporting evidence from genetic analysis, it’s twice as likely to succeed. And that means that what we’re doing is we’re using a genetic profile to identify the winners, we can identify the really important pathways that we want to try and modify. And we’re identifying medicines that are much more likely to succeed at that final hurdle. And that final hurdle is the really expensive one and it’s the one where actually right now 6 in 10 medicines this year will fail at that hurdle around efficacy. So, having genetic evidence to support that program improves the odds of success by a factor of two, which is fantastic. What we also know is that having evidence of very high impact gene variants can increase the probability of success by a factor of up to five. What that tells us is that the more impactful the gene association, the more useful it is to help guide medicine development.

And then the second aspect of that is that the more impactful gene variants or changes in our genes tend to be pretty unusual, they tend to be pretty low frequency or even rare. And unfortunately, the affordable ways that we have of looking at a person’s genome tend not to pick up these low frequency or rare variants well. They tend to tell us, to a certain degree, what we already know and, for example in 2020 the largest ever genotyping study or genetic study in heart failure to look at variants that might be associated with heart failure and its different subtypes, including the preserve pump function type of heart failure – It didn’t really tell us anything new, and that was a big disappointment to some of us. But on the other hand, if you take the whole genome approach where you’re looking at absolutely everything, it creates its own challenges around the data management, the data storage, the data interrogation, however, you have everything in there. And if you have large enough populations with the whole genome, you can identify low frequency, high impact variants and those are the ones that are most likely to tell us, we believe, the direction of travel for the next medicines in heart failure, particularly with heart failure and preserved pump function. So, because of the results in Hermes showing pretty much no new biology, I think pharmaceutical companies are really interested in the research we’re now doing. It’s much more ambitious. It’s much more difficult to do but ultimately, we think it’s going to produce more results. And I think pharmaceutical companies are, in my experience, very, very interested in this. I think, in a way, not having a genomic strategy for your heart failure development program to me seems unwise at this stage, and I think most pharma companies would recognize that.

Elaine Quinn

And there are the cost savings that you mentioned, of course, when you’re talking about the fact that drugs often fail at the very last phase of the drug trial. And so, if looking at the genome can increase the chance of success, then it makes sense for pharma companies to be looking at Whole Genome Sequencing as part of the drug development process.

Mark Ledwidge

Absolutely, and so far with Genuity, we have created what is probably the largest ever whole Genome Sequencing study in heart failure to date. We have whole genome sequenced more than 6000 patients to date. And already we’re identifying new variants and as we predict, we’re identifying very low frequency, but really high impact variants. So, these are again exciting variants that will hopefully guide new research, but it also shows that there is a lot of value in the work that we’re doing, and it is worth the investment. And you mentioned about the cost of developing drugs – I mean everybody knows that it costs somewhere between a billion and 2.3 billion to bring a drug to market and it normally takes in excess of 10 years and if that cost can be halved, if it can be reduced by a factor of five by having the support of evidence of high impact variants, then I think that’s great news for the development of medicines it’s great news for pharma but ultimately it’s good news for societies, because ultimately we pay for the cost of the drug development as part of the cost of having a pharmaceutical industry to produce the medicines that allow us to live longer, so I think there’s a real medium and long term benefit for society, as well as for pharmaceutical companies.

Elaine Quinn

And then on the flip side then, there are the physicians who are making their assessments of people with potential heart conditions. How do you think research like this, that’s incorporating Whole Genome Sequencing, is going to change the way cardiologists are managing or treating people who come into them with potential heart failure?

Mark Ledwidge

Yeah, so first of all, as I mentioned, I think we can use genetic profiling to risk stratify patients and figure out who are the people that we need to see more frequently in the clinic, who are the people that we need to be a little bit more ‘aggressive’ is a term that we might use – aggressive in trying to manage things like blood pressure or cholesterol or blood sugars. People that we really want to encourage strongly to take lifestyle adoption. Genetic risk profiling, I have absolutely no doubt will add on to the profiling that we do in the clinic based on physical examination and also based on blood biomarkers, for example in our program like natriuretic peptide or BNP. Secondly, as I mentioned, I think we’re going to use this type of genetic analysis to identify brand new areas that we can research, and right now in heart failure we need as much of that as we can get because we’ve had so many consecutive failures in this really now prevalent form of heart failure with preserved pump function. I think the third thing is that we can use these gene variants to help give us confidence about pursuing repurposing research and what repurposing research really means is taking medicines that we already have, perhaps for another indication or a related indication and investing time and energy into trying them in a new setting, in a new illness, a new type of patient. And that research is also expensive, and that research is very complicated, but, for example in 2015 we were interested in this idea of boosting BNP for a certain type of person with pre-heart failure. This stage B heart failure. The costs in setting up a sort of a moderate size research program to look at this over a period of two years were really quite considerable and as a team of researchers, the only way that we could justify that risk and that cost to ourselves, but also to the people that we were meeting in the clinic and that we wanted to maybe participate in the research, was by having a good sound rationale for why it might work, convincing ourselves and the participants in the research that it was a safe thing to try, but also we had some evidence from the gene profile that boosting BNP would actually be beneficial. So, there’s a certain variant that people carry – about 15% of the Irish population it seems will carry where, from birth, their natriuretic peptide levels being produced by the heart predominantly are about 40% higher than normal. So, they’re born producing lots of this hormone. Now that might seem like a weird thing or maybe even a bad thing, but it’s actually a good thing if we remember that BNP Is a protective hormone. And so, by the time they come to us in the clinic, they already have a much better heart profile than people without this gene variant – this BNP boosting gene variant. And when we follow them up for five years, it looks like they do better than people without this BNP boosting gene variant so that gave us the sort of confidence to say, well, if we can use a medicine to boost BNP, it will probably work. And we still don’t know if it’s going to work because we have just completed this particular study, but it was five years of our time, our energy, our patients’ time and energy but we’re very optimistic that it will show some good results. And that’s going to be grounded in the knowledge that genetically if you’ve got high BNP levels from birth it’s a good protective thing for your heart.

Elaine Quinn

That’s really interesting and I think as well in talking about what you’re learning about people through analysis of their DNA, it’s also true that some people have genetic variants that might mean they are resistant to certain medications being effective for them. And that’s just another example of why having these genetic profiles can really tell us an awful lot about how an individual might respond to a particular treatment and why this approach to precision medicine, is so important for complex conditions like heart failure.

Mark Ledwidge

Yeah, that’s a really good point and one of the thoughts I have on that at the moment is that, unfortunately, most medical research is concentrated in hospitals. And that’s because the resources and the expertise is often concentrated in hospitals. And in many ways, that’s not surprising because we spend 80% of our healthcare resources in hospitals. But actually, we’ll often find that the protective variants are more likely not to be found in hospitals if you think about it. And so, one of the things that I love about our STOPHF research program and one of the things that I think is important for the next maybe five or 10 years for researchers all around the world is to try and build up that expertise in the community. So, for example, many, many heart failure patients don’t see a cardiologist in hospital regularly. Some don’t see cardiologists at all. On the other hand, if you have a protective variant for your heart, you’re not likely to ever need to see a cardiologist. So, we’re going to need to find you a different way, so I think for lots of really good reasons, particularly for looking for the really important objective of looking for those serendipitous protective variants, I think we need to build up the research infrastructure in the community and that involves creating capacity in primary care amongst our general practitioners and amongst our pharmacists, but also in other healthcare settings where people are interested in accessing healthcare and then interested in contributing to the research. Not everybody is but, but many people and, as you can imagine all the people that we work with in the STOPHF Program you know, give selflessly of their time to be part of the project. It definitely helps them, but they also know that most of the benefit of the research that they partake in is probably going to help the next generation and they’re motivated by that.

Elaine Quinn

Absolutely, and in talking about those very people who are participating and contributing to research, it really wouldn’t be possible without them and they are so key to all of this discovery and what we’re learning about how we can improve our management of heart failure. And I guess many people are motivated to take part in heart disease research because either they have a heart condition themselves or perhaps have a family member with heart disease. Can you talk a little bit about where the family history element comes into all of this?

Mark Ledwidge

Yeah, that’s a really good point. I mean one thing that I should mention is that it’s really obvious in some ways that genetics should play a really important part in risk profiling patients as in the STOPHF program or trying to identify new variants that might help give clues about new medicines because we’ve always set a huge store in cardiology by a family history. It’s one of the first things that you know, a cardiologist or general practitioner will ask about every patient, you know what is the first-degree relative family history of cardiovascular disease, of diabetes? And that tells us that the genetic profile that we carry through our lives is important and, in my case, on my 42nd birthday, I was at a match with my dad, and he remarked that he was 42 when he was first diagnosed with a blockage in one of his coronary arteries. And I remember thinking to myself – well, I should make a mental note at the end of this game to go and talk to my GP. He was talking to me about how his father had gone in for a routine operation and had suffered a heart attack during the operation and died and when I talked to my GP, my GP said oh, you know well Mark, you’re fit as a fiddle, you’re working in healthcare, you look after yourself, you’ll be fine. But it turned out that I had a little blockage in one of my coronary arteries as well – quite mild, no symptoms but it was very powerful, and it really showed to me that I needed to be really careful about my own health. That I really needed to manage my own risk factors, and it really underlined for me that I was carrying genetic risk that came from my father and his grandfather, and probably many Ledwidges before them. But I guess, it becomes more important now that we’re living longer, so the consequences of this genetic risk is much more impactful and these illnesses tend to emerge. So, my dad has lived a very healthy life, but he’s also had quite a number of cardiovascular events in the last 40 years because he’s now in his 82nd year. He is doing, really, really well and, in many ways, he has defied the genetic risk that he carried into this world. He has beaten his own bad genetic risk for heart failure and cardiovascular disease and that’s fantastic and it’s a testament to the care that he was provided, but it also tells us a story about how important it is to focus more on the genetic profile and what we can learn from it and how we can develop new ways of treating people and new treatments for those people with genomics.

Elaine Quinn

And why do you think your dad has done so well. Did he have to make many changes to his lifestyle?

Mark Ledwidge

Oh yeah, it had a huge impact on his lifestyle, and I remember, particularly in his late 40s him changing job because he really needed to have a very different way of living and his previous job just you know it just didn’t allow him to have enough time off, enough leisure time. He started working for himself which maybe sounds stressful, but he loved it and still loves it, at 82. But I think, in many ways, Tom has also benefited from being part of almost all of my research projects because he’s really enthusiastic and so he’s part of the Genuity Science genomics research project that we’re working on together, and he loves being part of it because, well, first of all, he loves the extra care that he gets and the extra attention that he gets and the extra scans that he gets. He thinks it’s really useful. He’s built up a great relationship with the research team. But I think underneath it all he knows that, as well as getting good care himself, he’s giving back to the next generation. And he’s looking at me and he’s looking at my son who’s now 16 and thinking well you know wouldn’t it be fantastic if some of the research that he’s involved in produces therapies that help maybe our generation. So, and I think that that’s really likely to happen. And I think the other thing to remember, people are sometimes afraid about research into genetic risks because we think – oh it’s very pre-determined. The picture is much more complex than that, and when I say that Tom has truly modified his genetic risk, I say that deliberately because there’s really fantastic emerging research that shows that your lifestyle and the way you treat your risk factors can have a much, much bigger impact on your healthcare outcomes than your genetic risk. And we’re also learning about, biologically, how that can happen because, in many ways the expression of proteins in the body that come from genes is also regulated in ways that are modifiable and that’s a whole field called epigenetics. And again, that’s something that we can look at in the whole genome in a way, that we can’t really easily look when we’re doing the kind of snapshot of a genotype and we might be only looking at one 10 thousandth of the information that the body’s genome can provide. So, again that’s another argument for whole genome sequencing which at the moment is really expensive, but you know, in five- or ten-years’ time, I feel it’s going to be part of routine care. And I think that the work that we’re doing together with people like Tom and people I can like Ken McDonald and all of the team in the Heartbeat Trust and the STOPHF team and the team in Genuity – it’s going to prepare us for making the most out of that technology when it becomes affordable.

Elaine Quinn

And that’s a great ambition to be working towards and it’s fantastic to hear about people like your dad who recognize the value of clinical and genomic research and are happy to contribute to these advances themselves by taking part and as you said they’re helping to improve future health for the rest of us. Well Mark, thank you so much for joining me today. I really appreciate you sharing with us, the great work that you’re doing at the Heartbeat Trust, as well as how genomic research is advancing the way we approach the different types of heart failure. And what that might mean in terms of us being better able to tackle heart disease in a more targeted way in hopefully the near future. Thank you so much for your time.

Mark Ledwidge

Thanks a lot, Elaine.

Part 2: Personal Story

So many of us have been impacted by illness – we wanted to take some time at the end of each episode to share a personal story that helps exemplify the need for precision health. The personal story we share with you today comes from Professor Mark Ledwidge’s father, Tom Ledwidge who, at 81, has defied his genetic profile by leading a lifestyle that maintains a healthy heart.

Tom Ledwidge

Well, what can I say about myself? My name is John Thomas Ledwidge, but I’m known as Tom because my father was Tom and it was a question of little Tom and big Tom and Tom stuck with my name. If my name appeared on my passport, which is John Thomas, people were saying but hold on a second, you’re not Tom you’re John and it was very funny at times and people would look at you and some people looked up my passport a couple of times.

I’m a banker all my life and I’m working what since I was nineteen and I’ve changed jobs four times. And in 1993, I decided to go out on my own because the way banking was going in 1990, there was a recession. But I had enough experience in banking that I decided to form a company of my own and I formed a company called National Corporate Finance. But I don’t do it full time at the moment. I’m semi-retired and I’d say by the end of COVID I’ll probably retire completely because in that business it was all communication with people, traveling to people, meeting them in their own home, talking about what Finance they wanted and what loans they wanted.

When I went out on my own, I retired on a Friday evening, and we had a good night out including my daughter and family were with me and friends and we retired and on Monday morning, I was operating on my own.

So, like I had an active life, very active. Prior to that now, I started smoking, I think the at age of 20 and I started drinking at the age of 20, but that was because my boss, said to me when I was transferred down to Cork, he said now you want to take a drink now and socialize with customers and that’s when I took the drink but giving up the drink for lent was a regular thing – smoking and drinking and I succeeded in doing it six weeks, every year, but this particular time, when I told my secretary I said, by the way, keep Tuesday free we’re going out – yourself, myself and Mary, my wife and we’re going to eat drink as much as we can, because of lent and it was only when I was going out the door, she said, by the way, Tom, Lent is not til next week, it’s not this week. Well as far as now I’m concerned, lent starts now.

So, it was it was great we did a pub crawl around Tullamore, and of course we were chatting with a lot of people and they had a great laugh over the fact that I was starting my lent a week earlier. It was it was hilarious now – the craic was mighty, and the slagging was fantastic. and that was it and I never went back smoking again. But when I gave up the smoking, then I realized that that was it, you know I’ll feel better and I did feel better and I stopped playing rugby when I was 33 – prematurely, but I decided to give up while I was ahead, and I was lucky to play for a couple of counties in the rugby you know. So, I had a very successful life.

When I was aged forty-two. I remember my father had angina and at 42, I was having a little bit of trouble with my heart, you know, I’d get pains, very slight pains and I went to the doctor and he asked me questions, like what I worked at and everything else like that, but I was on The Fast Track all the time. I would travel through lunch time to meet a client and then have a 10-minute break and have my lunch, you know that type of thing. He advised me to get out of the business I was in. This is when I was forty-two and I said you must be joking. He says no, because at the pace you’re going like, you know, your you’ll just cause damage to your heart. But I got tablets and I eventually went to a surgeon in Dublin who he recommended. And there was a little blip, a tiny blip in one of the veins and he said it wasn’t big enough to have an operation on it or do anything with it at the time and that was as I said when I was forty-two forty-three. And it was in 1966, I got stents. And that was the first time I had to get stents into my veins. I got three stents. So, I remember waking up after the operation and the doctor’s assistant saying to me, he says now he says that’s another twenty years on your life.  And here I am 81 going on 82. So, health-wise. I was an avid rugby player and athletics – I used to run and played rugby and I was always out on the scene and then when the rugby stopped, I took up golf and I think play golf to this day and I wasn’t too bad at the game anyway, you know, I made a good handicap and everything.

My father now unfortunately was different. In my own family, in the Ledwidges, most of the Ledwidges lived over their eighties and I’m hoping to reach as high as I can and be active as often as I can. My father was unlucky – he had angina and he went in for an operation, but the heart failed during the operation and he died at 67 and he would have been the youngest member in the Ledwidge family that would have died early, you know, and it was just unfortunate.

In the recent past I did take part in clinical research studies because I was conscious of looking after myself and taking part in this research, to me, it was very helpful, and it was great to know that if there was anything amiss that I was going to be taken care of and this type of research would certainly help loads of people. I mean, it’s something I would recommend to anybody because the staff that you’re meeting are professional doctors and nurses and they’re so kind and helpful. They make you feel at ease, you know, there’s no there’s no mystery about what they’re doing and they’re very helpful and I would recommend it to anybody.

The situation at the moment, as you know, it’s COVID and that has the restricted me both with my work and my activity and I’m looking forward to the day when COVID is over, it’s something that a lot of people are going to be disappointed when they get out there because they may not be able to do what they were used to doing you know. Me, I keep myself fit by exercising in the house here and I do the shopping every week for myself and my wife and no problems absolutely no problems. But over the years, I’ve always minded myself since I got that warning. I always maintained my sporting activities and kept myself fairly fit and watched my diet but did enjoy life.

I’ve got the vaccine – I got the first jab last week, last Saturday and I’m waiting for the phone call for the next jab we can’t wait for the weather, to get better, so we can go walking at least you know yeah. I can’t complain at all about my life and I’m looking forward – and my wife is going on 76 and I’m looking forward when COVID’s over that she and I will resume what we did every year was go on two holidays a year, we go to the canaries for a week and then we’ll go to Thailand where my daughter lives and she’s married over there and has two lovely grandchildren and we go over to see them.

I have a full life and still have you know and had COVID not happened, I’d still be as active as I was when I was forty-two years of age because I love my work. I love meeting people and helping people out and I always did. I’m looking forward to a long life.