Improving Cardiac Health Through Immune System Precision with Edward Thorp, PhD

[00:00:00] Erin Spain, MS: This is Breakthroughs, a podcast from Northwestern University Feinberg School of Medicine. I'm Erin Spain, host of the show. Each year, more than 800,000 Americans suffer a heart attack, and many of those who survive are left with irreversible scarring, and the slow progression towards heart failure. Today's guest, Edward Thorp. Exploring how immune cells influence the heart's ability to heal after such injuries. Uncovering fundamental molecular mechanisms by which the immune system regulates wound repair, inflammation resolution, and tissue regeneration. He is the Frederick Robert Zeit Professor of Pathology here at Northwestern, and I am happy to have him on the show to talk about his research that is helping to pave the way for the next generation of cardiovascular therapies.Welcome. 

[00:01:01] Dr. Edward Thorp: Hi, Erin. Thank you so much for inviting me. I'm very happy to be here. 

[00:01:04] Erin Spain, MS: So let's start off by telling me about the focus of your lab and how you began studying immune cells and inflammation in the context of heart disease. 

[00:01:14] Dr. Edward Thorp: Yeah, happy to Erin. Thanks for the question. My fundamental basic training is in microbiology and immunology, actually right here in Chicago. My lab study is really the fundamental biology of immune cells and their role in inflammation and tissue injury. Now, typically when people hear about immunity, they first think about, you know, immunity against infection, bugs, viruses, and COVID. But it's really important to know that. your immune system performs other key functions besides combating infection. For example, your immune cells or your white blood cells or leukocytes are critical for tissue repair after you scrape your knee and for example, and, and tissue repair declines, unfortunately, as we age, and we can all see this, uh, as we get older. So a major focus of the laboratory is to uncover how immune cells regulate tissue repair and tissue regeneration now. In addition to our basic science research, we also perform, clinically relevant, research. And our clinical, uh, research focus is inflammation during cardiovascular disease and heart failure. So, for example, hundreds of thousands of people each year suffer heart attacks or myocardial infarctions, and after mi. Or a heart attack your immune cells or leukocytes are critical for clearing out the injury and orchestrating a scarring response. The trick is that, uh, your leukocytes don't do a very good job, and this is because, uh, your immune system has evolved mostly to protect us during our childbearing years. So we're living much longer now, and so our leukocytes are being exposed to new types of disease, including heart failure. And so this is actually a big opportunity to translate our fundamental science, uh, into therapy. And so we're fortunate to do research here at Feinberg School of Medicine, where we work very closely with physicians and physician scientists to investigate and translate and implement therapies for disease. 

[00:03:08] Erin Spain, MS: Heart failure with preserved ejection fraction or HFpEF. This is a condition that accounts for more than half of heart failure in the US. Can you tell me about this condition? What makes it so challenging to treat and how have you, paired with other investigators at the medical school , to look into this? 

[00:03:26] Dr. Edward Thorp: Yeah, good question. And, as you mentioned, um, Heart failure with preserved ejection fraction or HFpEF, is really the most prevalent type of heart failure. In fact, sometimes it's called, huff puff because, uh, it. Causes a shortness of breath and, and exercise intolerance. And, so look, I'm not a physician and HFpEF is a technical term, but what it really does mean for the lay audience is that the heart is fine in its pumping capacity, but it can't fill. Properly. And so the results, uh, means that you have reduced blood supply to the rest of your body and some of the conditions that are associated with that. 

So, despite the prevalence and the importance of this syndrome there really are very limited, uh, treatment options. And so research into this area is very ----important. 

[00:04:10] Erin Spain, MS: Yes, because as you said earlier, this really is a disease of aging and people are living longer now, and this is something that a lot of people at Northwestern and beyond are focused on. 

[00:04:21] Dr. Edward Thorp: HFpEF is definitely a disease of aging, as you mentioned, and aging is an important, uh, risk factor for its pathogenesis. Other risk factors include obesity, metabolic syndrome and hypertension. And so there is a large need in order to understand and treat this very heterogeneous syndrome.And so, kind of delving a little bit deeper into the focus of our research and how that interfaces with this syndrome. We've known for years that HFpEF is associated with  a generalized inflammatory syndrome, inflammatory activation in the body. What we didn't know. Uh, however precisely is the contribution and source of this inflammation during disease. And so this was a question of Dr. Mallory Philip in the laboratory when she was a graduate student. And this was also a collaboration with Dr. Sanjeev Shah here at Northwestern, who's an international expert in heart failure and heart failure with preserved ejection fraction. Mallory also worked closely with another physician scientist, uh, Dr. Matt Feinstein, who's also an expert in cardiovascular inflammation. 

[00:05:24] Erin Spain, MS: so in this new study published in Circulation, your team looked at how fatty acid metabolism and immune cells can drive blood stem cell activation and heart failure , or HFpEF. Tell me about this study and the results. What did you find? 

[00:05:40] Dr. Edward Thorp: Absolutely. So, Mallory really was the key driver of this study. And what she discovered was that patients with HFpEF had a very unique immune signature, uh, in their blood. Uh, specifically, uh, patients had an elevated immune stem cell or progenitor cell signature. And what this means is that patients actually had. A very early stage activation of their immune compartment. Now, property of immune stem cells is that they can generate many more progeny immune cells. And so in this context it's really important to point out that immune activation to a certain extent is good and protective. But if you have too much inflammation, for example, activation of these stem cells, this can actually do harm. So, for example, too many leukocytes that infiltrate the heart can lead to, unnecessary scarring response, which can impair the ability of the heart to relax. I will add, you know, a little bit of basic science, uh, test a little bit of the underlying molecular mechanism Mallory discovered in getting to your point about the fatty acids. So in addition to discovering this fundamental insight and into increased stem cells during this condition, she also studied how the stem cells were being activated. And it's really important to point out that these fundamental questions are really important in revealing new molecular therapeutic targets. So a risk factor for Hef. Path is obesity or high body mass index, as well as disturbed metabolism and aging, as we mentioned earlier on. And typically we think about metabolism as contributing to energy demands, right? However, metabolites can also regulate immune cells function that is separate from just energy is really kind of a cutting edge area of research that we don't know too much about now. And so what Mallory discovered in this context with that increased fat and lipids, uh, in these patients we're capable of reprogramming the genetic architecture or the gene expression, in these immune cells to activate stem cell growth factors. so to test the therapeutic principle of her findings, she employed an experimental model I. Of this disease to block the fat uptake specifically in the immune cells. And really impressively, she was able to improve cardiac function by this immune targeting approach. Now this is promising, uh, because it's much easier intractable to target your immune cells in the blood rather than invasively target the heart. 

[00:07:58] Erin Spain, MS: So what's next with this project? You've published these results in animal models. Where, what, where do we go next? 

[00:08:04] Dr. Edward Thorp: Yeah, absolutely., That's, you know, the million dollar question. And I think to translate these findings we would really like to leverage some of the expertise that's here at Feinberg and also in Evanston and the really talented bioengineers who are able to engineer platforms and molecular targeting to really try to, uh, block this, uh, immuno metabolic pathway that's wreaking so much havoc on immune cells and, and the heart. And so we've been fortunate to initiate collaborations with a Dr. Uh, Lisa Ti and Dr. Pang Zang Pang being at Feinberg and Lisa up in Evanston. And so I really. I think this is the next phase of the translational work. But I also, you know, really also wanna stress as a, as a basic scientist that we also are informed for clinical approaches through the basic science. And so really, uh, another parallel main focus of the laboratory is this, again, intersection again, a metabolism and immune function. And I won't get into the weeds of the metabolic pathways, but we've also been fortunate to collaborate with investigators here at Northwestern, including, uh, Nadel and Sam Weinberg for this. And so really a lot that we don't know about how metabolism and metabolites regulate immune cells and their function that's independent of their energy functions. And this is particularly important in cardiovascular disease where these diseases are often accompanied by a number of metabolic syndromes. 

[00:09:24] Erin Spain, MS: So this paper is part of an American Heart Association initiative investigating the role of inflammation in patients with HFpEF. Tell me about this broader project. You were one of three centers working on this $15 million project. 

[00:09:37] Dr. Edward Thorp: So, it's really been one of my, uh, greater privileges to establish a really close and strong, professional relationship with Dr. Matt Feinstein here at Northwestern. He's a cardiologist, in the Department of Epidemiology and he's really reached across the aisle, so to speak, from the clinical domain to the basic research, which is where I live. And through these interactions bridging clinical research and insight with basic Biology, we've really been able to not only come to this discovery, which was published in circulation, but also work closely to secure funds and support from the American Heart Association, with a number of other investigators in this strategically focused research network. and through Matt's collaboration and leadership it's really fueled the next set of questions that can take our fundamental findings into the, to the next level of translation. 

[00:10:26] Erin Spain, MS: In the meantime though, there is a message from this study about diet. We all know that a diet is key to preventing chronic diseases, but what was specifically found in this study is that maybe we could all take away how we look and how to improve our diets to prevent diseases like hype. 

[00:10:42] Dr. Edward Thorp:  The particular types of lipid species that were implicated in this uh, stem cell activation signature that, Dr. Philip discovered were of the saturated fatty acid type. And so, you know, there have been a number of studies you've probably heard about on the radio driving into work which advocate for, you know, certain types of Mediterranean diets or other diets that are high in polyunsaturated or fish oils. And so this is the opposite type of lipid species and a saturated fatty acid, which is often associated with obesity. The trick is that. The patients with HFpEF have unique, metabolic signatures, and again, the disease is so heterogeneous, it's hard to pinpoint one particular type of lipid species at this moment to maybe suggest, you know, a, a diet rich in this or that type of lipid. But, we are getting closer to more of a holistic understanding of this. And I, I think future studies will not only. Again, study the immune system, but also the different types of diets that are interfacing with the immune activation signature for these practical, daily interventions that we can take when we choose the item on our menu. 

[00:11:46] Erin Spain, MS:  So we're gonna shift gears a little bit to talk about another exciting study your team published this year. And that was in the journal immunity that looked at why newborns immune systems can regenerate heart tissue while adults cannot tell me about this study. 

[00:11:59] Dr. Edward Thorp: A kind of cool thing about the laboratory is because I would say our, our primary focus is on the immune system and inflammation and how it interfaces with cardiovascular syndromes is that we can take our basic studies on immunity and particular immune cells and apply this to many different types of cardiovascular diseases in addition to HFpEF, which I just mentioned. And so this means that we just follow the immune cells into different types of syndromes, including myocardial infarction, associated heart failure, and also even solid organ allograft, heart transplant rejection in this particular case. An answer to your question really, the Holy Grail, uh, for heart disease is cardiac regeneration. There was a study, many moons ago from, another group in Texas that identified. When, uh, newborns have a high capacity for cardiac regeneration and sometimes even kids who are, uh, being treated for congenital syndromes in the heart even after surgery, they have a lesser incidence of cardiac fibrosis. Kids are just better at healing. And you and I all know this, that, you know, when we were young, if we had some type of injury, we bounce right back. And unfortunately as we get older, that's less the case. But going into the kind of deeper kind of molecular aspects of this study, we again. Investigated how metabolism interfaces with the immune cells, and how immune cells and their metabolism of a particular lipid species called arachidonic acid, was able to be mobilized to promote cardiac regeneration. And so what was interesting is that a particular immune cell called a macrophage. Macrophage is from the Greek word meaning. large eater. So macrophage, big eater phage, uh, these macrophages when they respond to injury in the heart. In experimental models, in youth in early days after you're born, they secrete factors derive from these arachidonic acid lipids that communicate with neonatal cardiomyocytes and promotes cardiomyocyte proliferation. What's important is that all of these pathways are turned off in adulthood. And so, even at first approximation, these studies may seem very fundamental because, you know, there aren't that many kids that we know of that have this type of injury. Although this could be relevant to many congenital disorders. This is important because it basically tells us what we need to do to reverse the condition in aging by potentially restoring what we see in youth. And, just kinda a last point, we've been really fortunate to Lurie Children's Hospital, also on this study, and a talented physician scientist, Pediatric Critical Care Doctor by the name of Amanda Becker. And this paper also is important for me to mention, was led by another really brilliant scientist by the name of, Dr. Connor Lance. 

[00:14:35] Erin Spain, MS: Tell me about all of these different partnerships you have and how working with these physicians and the clinical side has really shaped the trajectory of your lab. 

[00:14:46] Dr. Edward Thorp: A lot of, it's very practical here at Feinberg. You can walk across the street and you can be in the cancer center. You can be in the cell biology center. You can be be over at the Bloom Cardiology Institute. And so this proximity has really enabled more interactions that are real and that can lead to real collaborations. And because again, we studied the immune system, the immune system goes throughout your body and it affects every type of disease. There's hardly a condition that I can think of in which inflammation driven by immune cells is not. A part of pathophysiology. And so, what's also interesting is that some of our molecular mechanisms that we investigate uniquely affect the disease outcomes that when we just simply study them in different types of syndrome. So for example. One immuno metabolic mechanism may be protective in cardiac regeneration through immune cells, but it may be maladaptive in the adult. And so this is the beauty of just studying biology. You just follow the science and, uh, even though you start out with a hypothesis, typically, at least in my case, you know. We're proven wrong, but it's because the system is so complex over, you know, hundreds of thousands of years of evolution that it's really true discovery and fun to just see what the natural biology and physiology is teaching us. and in a disease relevance way. We have to have a focus and our focus is really immunology and cell biology. But that naturally plugs into a lot of relevance in many different disease states. 

[00:16:10] Erin Spain, MS: So what can we look forward to from your lab, let's say in the next year, next five years? What do you hope to see happen? 

[00:16:17] Dr. Edward Thorp: So, uh, in addition to continuing the fundamental research, which takes us into many different directions, we're very excited about some of our recent findings. Should be published soon, in which we've discovered immune roles for, uh, immunological tolerance. So, for example, when you have a heart transplant, after your heart fails, sometimes you are a candidate for a heart transplant. Unfortunately, these transplants can be rejected. And so it's very important to educate the immune system, to educate your immune system to recognize these foreign hearts as self so that, they're not attacked upon like, A foreign bug or virus. But. It would be nice and helpful to learn the fundamental mechanisms of how to educate the immune system, to tolerate the immune system, and to accept these foreign allografts. And if we can do that, promote immunological tolerance at a fundamental level, I think that there's gonna be a lot of potential to prolong allografts, cardiac and other organs as well. 

[00:17:16] Erin Spain, MS: Well, that's very exciting. As you said, a completely different field of medicine, but again, all within that wheelhouse of immunology and the immune system. So thank you for sharing those exciting updates. One more question before we wrap up today, you mentioned, you've received significant funding from the NIH over the years and, other, federally funded resources. So how is the current funding climate affecting your lab's work? Is it affecting your work or future projects? 

[00:17:43] Dr. Edward Thorp: Yeah, I, I won't sugarcoat it. It's, uh, it's been a, it's been a significant challenge and this is where we are very thankful to what Northwestern University in Feinberg is doing right now to support the mission. I. Of,, our laboratory and many other of my colleagues here at Feinberg and up in Evanston. I've been very grateful to receive continuous funding from the National Institutes of Health over the years, and specifically the N-H-L-B-I or National Heart, lung and Blood Institute. and I'm hoping and optimistic that we'll continue I do wanna advocate if possible, for the, the basic scientists out there that, a lot of our clinical and molecular targets that you know, we're working on really start from fundamental questions and basic biology and, and sometimes that don't immediately have clinical kind of mindset to, to begin with. And so, we're optimistic for the future and doing our best. We're also stratified with our funding support through other institutes, including, as you mentioned, the American Heart Association for which we're thankful for, and also the Department of Pathology, and also of course, Feinberg. And so we're just gonna continue to do our best. That's all we can do. I'm really thankful to my laboratory for, in this unprecedented climate, to continue to keep focused and 'cause that's all you can do. 

[00:18:54] Erin Spain, MS: Thank you again, Dr. Edward Thorp. It was a pleasure to have you on the show to hear more about your research and all of the exciting things ahead. 

[00:19:01] Dr. Edward Thorp: Thank you, Erin. 

[00:19:05] Erin Spain, MS: You can listen to shows from the Northwestern Medicine Podcast Network to hear more about the latest developments in medical research, health care, and medical education. Leaders from across specialties speak to topics ranging from basic science to global health to simulation education. Learn more at Feinberg. northwestern. edu slash podcasts. 

Physicians who listen to this podcast may claim continuing medical education credit after listening to an episode of this program.

Target Audience

Academic/Research, Multiple specialties

Learning Objectives

At the conclusion of this activity, participants will be able to:

1. Identify the research interests and initiatives of Feinberg faculty.
2. Discuss new updates in clinical and translational research.

Accreditation Statement

The Northwestern University Feinberg School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Credit Designation Statement

The Northwestern University Feinberg School of Medicine designates this Enduring Material for a maximum of 0.25 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

American Board of Surgery Continuous Certification Program

Successful completion of this CME activity enables the learner to earn credit toward the CME requirement(s) of the American Board of Surgery’s Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit.

Disclosure Statement

Edward Thorp, PhD, has nothing to disclose. Course director, Robert Rosa, MD, has nothing to disclose. Planning committee member, Erin Spain, has nothing to disclose. FSM’s CME Leadership, Review Committee, and Staff have no relevant financial relationships with ineligible companies to disclose.

All the relevant financial relationships for these individuals have been mitigated.