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Selwyn Vickers, MD, FACS (Host): Dr. Wende, thank you for joining me on our episode of the Checkup today. I'd like to get started by introducing you to our audience. Can you tell us a bit about yourself and how'd you find yourself at UAB and what work do you do here?

Adam Wende Ph.D. (Guest): Sounds great. Dr. Vickers, first, thank you for this opportunity. So, I was originally a south side native of Chicago and stopped a few places before I managed to get to Birmingham. I started my career in a small liberal arts college in Galesburg, Illinois, studying plants of all things under the guidance of Mark Brotall. And he put Washington University in St. Louis on my radar, which is where I did my PhD with Dan Kelly. And that really changed my trajectory from plants to heart, which is what got me here in the long run.

Spent a few years out in Salt Lake City, Utah with Dale Abel, where I took my interest in studying heart metabolism and really combined it with diabetes. And in trying to decide what I wanted to do with my independent career, I was like, well, how might diabetes affect heart disease? And it led me to this area called epigenetics.

And what I study in that area is how nutrients signal to gene expression. But how I ended up at UAB had to do with going to the right meeting at the right time. So, this glucose signaling leads to a post-translational modification of proteins called O-GlcNAcnatulation and there's only a few laboratories in the world that study it, the majority of them right here at UAB.

So, Dr. John Chatham recruited me here in 2013 and have not looked back. It has just been such a great transition, seen me from first faculty position to tenure last October. So, UAB has just been really great in building my career. And I also just want to shout out to you for doing that. And you got here at about the year after I did Bettman scholarship. And of course, the reason why we're here today, the CHAMPS award. The community, the Center of Healthy African-American Men Through Partnership. And if it wasn't for you, I would not have done this project. So thank you for that.

Host: Well Adam, that's a great story. And we're really excited that you are here and that your career really has blossomed as a part of our faculty. It's also great to hear that journey from how you started at small college, really went to your PhD from a great school in the Midwest at Wash U and then further advanced yourself career before coming to a place that attracted you because of the science and that, that's outstanding. I also appreciate the fact that you had an interest in this space because I don't know that individuals directly think about gene expression in relationship to racial disparities, that's not where you commonly find a really wet lab researcher thinking that they could have an impact in that space. So, I really appreciate the concept and the hypothesis that you were willing to sort of stretch yourself to think about, about in context of African American men and their chronic diseases.

So today, one of the things we want to talk about is this article that you were the senior publisher on or the senior author, if you would, in the American Journal of Physiology, called Racial and Social Disparity Associates With Difference in Cardiac DNA Methylation Among Men With End Stage Heart Failure. That's a mouthful but maybe you can help our audience understand how your thought process led to the studies. And what in part did you learn as you began to ferret out your data? It's obviously had a great sort of showing with over a hundred thousand impressions and editorials written about it.

So, it's really captured a lot of people's attention, but give us a little background. You mentioned CHAMPS already. We had a pilot program and you were part of that, but beyond even the door of opening the resources forward, what were the thoughts that led you to believe that this might be a significant finding?

Dr. Wende: Very great question. I started as a molecular biologist. And really my interests were just, how do genes change heart function? And what we were looking at in general, mostly rodent models was this area called epigenetics, which is really just changes on the DNA that lead to long lasting changes in gene expression and function.

And we started with the question of why do diabetic hearts respond differently to non-diabetic hearts. And the thing that was very fortunate to us is when we teamed up with the cardiovascular surgeons here at UAB, I only thought to ask for 12 hearts, six diabetics, six non-diabetic. And that's all I asked for, but when we got the results back, it grouped into three groups.

One group that was diabetic, one group that was non-diabetic and one group that was mixed. And then when we went back to the clinicians, turned out that those three were African-Americans. So, we knew right off the bat that there was something about these epigenetic marks, specifically DNA methylation, which you mentioned in the title that was changing in response to the self-reported race.

And that's when your CHAMPS pilot award came out. And then we took a much more calculated analysis to get to these other samples where we expanded it to 16 and 16 and really found that this truly is a signal that can potentially define why these patients do differently by how it changes their gene expression.

Host: Adam, what do we know about African-Americans particularly African-American men do in the context of heart failure, which is really a worldwide problem and one of the leading causes of death?

Adam Wende Ph.D. (Guest): And that is, in all honesty, that's something that I wasn't acutely aware of prior to getting into this research, but because of this push have really focused in and changed a large portion of my research group toward that direction. And what we know is they fare worse than everybody else. We know from a 2017 circulation statement from the American Heart Association that our own UAB George Howard was part of, that they do far worse than any other group in our culture. And we're not exactly sure why. There's a lot of ideas out there. And I think, at least I hope, that this measure of DNA methylation may give us a clue on how to quantify that.

Host: Yeah, that's huge. And I think we've sort of nibbled around the problem for a long time looking at hypertension, stress on the heart, diet, overall medical management, but have not looked at how this has impacted the actual ongoing genetic expression leading to protein and function in the heart. So, I think that's tremendously powerful. We've said some words that are important, but I think we need to make sure we clarify for our audience. So, we talked about DNA, we've talked about epigenetics and we talked about methylation and some level of expression. Can you share in simple, more layman terms, what are the connectivity of those words and, and how do they interrelate?

Dr. Wende: No, this is what I like studying the most about this. So the concept of epigenetics is twofold. One is it explains some inherited memories from your parents and even your grandparents. So, stresses that happened to them could influence what happens to you, but it can also change in every day to day environments. So, it changes in response to the pollution level of the air you're breathing, the diet, your stress level and all these other social determinants that we now know are so critical to disease. So, epigenetics is basically the way your cell captures and imprints all those different things that you experienced onto how your body can then respond. So, I think it's just a really powerful tool to get to all those other variables you just mentioned, that each one probably contributes a little bit. DNA methylation or epigenetics in general, I think captures it all.

Host: Gotcha. So, in general, our environments, wherever we live, the factors relate to who we are as an individual. Those factors, that stress and help form who we are actually have some impact on our DNA and they use a marker, if you would, on the DNA that can affect what genes are expressed, turned on or turned off.

Dr. Wende: Exactly.

Host: Now it's impressive because people hear from us with many diseases that we know that there is a genetic cause or gene going bad, but they're confused sometimes that it's not inherited. Right. And it is a gene that's gone awry, but it's gone awry through some other, as a osmatic gene, through some other mechanism that's affected it versus saying you inherited a bad gene. Am I correct?

Dr. Wende: So definitely. And I think that's what makes these chronic diseases so much more difficult, like obesity, like heart disease, like diabetes, versus some of the cancers where you can track it down, you can sequence an individual and find that one gene. This, you could have identical genes, but the marks on them may be different. So, the ability your body to turn them on and off varies. And one thing that where people often get hung up and if I was talking to a geneticist specifically, some of these marks are inherited, which is also kind of interesting when we get to some of these racial disparities in healthcare.

But they can also change just in the process of us having this conversation as well. And that's what makes them very exciting to study.

Host: Adam, so let's just recount, what did you find and what did you actually, what were the results of your paper?

Dr. Wende: Right. So our primary result was to identify how these changes in DNA methylation that we identified were changing gene expression. And what surprised me most was the number that was different. So we found literally hundreds, if not thousands of genes that were differentially regulated in these two patient populations. And what was most striking to me is we've known for, well over half a century, that heart failure is associated with these changes in the way the heart uses its fuels.

And that was still present in both patient populations. But in those that self-reported, as African-American, we found additional stronger signals for things like inflammation and things related to stress signaling, including pathways involved in adipogenesis and fat handling, which was very different between the two groups and much more robust in the African-Americans.

So it basically suggests to us that you have to know that the environmental stressors that an individual went through to know what treatment to give them, because if they just come in with heart failure, it's not one pill that cures all.

Host: So, it's sort of an insight into what might be the future of precision medicine in this population. So, that leads us into a little bit about your sense of the implications as it relates to both the disparities and then in the bigger picture, as it relates to potential therapeutic intervention.

Dr. Wende: And this point is probably what I struggled with the longest in trying to decide how to package this story and get it published because the biology for me is the easy part. We can identify new molecular targets and potentially develop new drugs. What has been the most striking feedback from this and the various other avenues and editorials that I've heard, are the implications that other people have told me that they take from this because of the potential for the inherited aspects of this, because of the potential for the regional environmental impacts and the fact that we may be able to see how the racism that we face in this country impacts individuals biologically.

Host: Yeah, it is a intricately woven sort of story about our history and culture and how it's often framed, not only sort of a lack of opportunities, but also many ways framed a worse outcome in disease, both by treatment and by stress factors that relate to this. I think that's important. Help me understand what are some of the most unique sort of set of feedback and statements that you're hearing and what are some of the editorials saying about the paper?

Dr. Wende: So, for me, it's been the feedback of getting the discussion started. The big limitation is we don't know what the underlying signature is. One of the primary limitations of the study was these were studies done in heart tissue collected during surgery. So, all the patients had heart failure. What we don't know yet, are what are the underlying marks. But the feedback and where people have really pushed me to look is can we use these marks to assess what different limitations that certain individuals have may imprint on them. And how importantly, can we possibly reverse those?

Host: In the context of reversing DNA methylation, what are our tools? I know they're still a bit crude. Are there any tools to even consider in that space?

Dr. Wende: So there are some dietary interventions and then a lot of the lifestyle stuff that all of our doctors tell us that we need to do anyway. Exercise is an efficient modifier of these. Diet definitely is. Finding ways to get your stress under control. The drug area is a little less robust when it comes to DNA methylation. There are other epigenetic marks that we didn't look at in this paper that I'm sure are also involved and I'm sure those have had a lot better success rate.

Host: What do you see as next steps, Adam?

Dr. Wende: So the other glaring limitation that was in this study besides not having healthy hearts to compare to, where there were no women in this study. So, we would really like to, and we have the samples ready. It's a matter of hunting down that elusive funding to get the study up and running. But we would really like to see, because we do know these same disparities do exist in African-American women.

It's not as robust, but it is present there as well. So we'd really like to see how universal this mechanism is as well as looking at different heart failure context. So I mentioned this paper just was focused initially on diabetes. Non-diabetes we do know there are other underlying what we call etiologies of heart failure.

And we'd previously published, looking at specifically ischemic heart failure. And we're now looking to see if these racial differences also impact our understanding of how those treatment regimens would go as well.

Host: Outstanding. Well, I think that hopefully this opens the door, Adam for other basic scientists to understand that they can have an impact in any number of diseases where disparities exist, that we don't have good explanations for. Whether it be heart failure, whether it be memory disorder, whether it be cancers, where we know that there are significant disparities and outcomes that can't readily be explained by access and standard treatment. Which really does speak to the concern about, are there fundamental changes occurring in their DNA, affecting the expression of certain proteins or the lack of expression of these proteins that often can affect our ability to either fight through or not even get disease alone.

So I'm terribly excited. As you know, we talked about this paper when it was put forward and believe it's really seminal in really applying your phenomenal basic science skills that are routinely done in the space molecular biology, but not frequently applied to the clinical pathways and the clinical outcomes for our patients and citizens.

Adam, I really do want to thank you for being here. I think the topic is great. I'm hopeful that you will, in fact, in some ways come back after you've expanded the paper and you've been able to move this science forward in dealing with both racial disparities and outcome differences that we've seen in our citizens in this country. Thank you very much.

Dr. Wende: Thank you so much. I would like to add one additional learning point that I got from this experience. And if you're listening to this and have been intimidated of getting into this space, it's not, it is scary to get into, and I speak of that of as a white male studying health disparities. It intimidated me at first, but probably the biggest lesson I've taken from this experience is that we can't solve the problems until we talk about them.

Host: Well, I think the, sort of the history of Birmingham and particularly its legacy with Martin Luther King's letter from a Birmingham jail, it's with good people of all colors speaking up and not staying silent because they don't think they can have an impact. They can. And you certainly have. Thank you again.