The Role of Iron in Cardiovascular Disease with Hossein Ardehali, MD, PhD 

Erin Spain, MS [00:00:10] This is Breakthroughs. A podcast from Northwestern University, Feinberg School of Medicine. I'm Erin Spain, host of the show. Cardiovascular disease is the number one cause of death worldwide. And finding new treatments is critical. Today's guest, Dr. Hossein Ardehali, is focused on the role of metabolic processes and cardiovascular disease. His discoveries can also be applied to other chronic conditions associated with aging. Dr. Ardehali is a Northwestern Medicine cardiologist and also director of Feinberg's Medical Scientist Training program. He joins me today to discuss his research and his passion for educating the next generation of physician scientists. Welcome.  

Hossein Ardehali, MD, PhD [00:00:55] Thank you. It's great to be here.  

Erin Spain, MS [00:00:57] Give me a very broad picture right now of cardiovascular health in America and around the world and why you're choosing to focus in on mitochondria and looking for new treatments that target iron.  

Hossein Ardehali, MD, PhD [00:01:11] When I was a medical student, I remember we talked about cardiovascular disease being the number one cause of death in this country. And when we were talking about the world, infectious diseases were the number one cause of death in the whole world. That has changed now. Cardiovascular disease is the number one cause of death in the whole world. And that shows you how critical it is to come up with new treatments. Specifically, I think preventive cardiology is a really important area of research and treatment strategies for cardiovascular disease. So my research is focusing on the number one cause of death in the world and think there is a lot of room for new therapies and new treatments. Now, how did I get into the field of iron? You know, iron is a very essential molecule. When I give my scientific talks, I start by talking about how the earth was formed and how the first organisms were created in this world. And they were using iron as a major source of their electron donation and acceptance, which is needed for energy production because oxygen wasn't around. So this is an element that organisms have been dealing with for 4 billion years. We have really sophisticated our systems in the use of iron. But think about the iron is that too little of it is bad for us. As you know, patients who have low iron, they don't feel well. But if there is too much iron around, that can also cause significant damage to the cells. Why does too much iron cause significant damage to the cells? It's because of its properties, its chemical properties. It can cause oxidative stress on the cells and the oxidative stress. You know, I'm sure everybody knows about oxidative stress. You go to these health stores and they're antioxidants that are very expensive, by the way, but they are sold as this way of treating patients with different chronic diseases and for preventive measures. Those are the treatments to reduce oxidative stress and iron is a source of oxidative stress. And the goal is to reduce iron in some chronic diseases that may have beneficial effects by reducing the oxidative stress that this molecule can cause.  

Erin Spain, MS [00:03:13] Tell me about what happens in the body as people get older and they're dealing with iron and some of the repercussions when it comes to cardiovascular disease.  

Hossein Ardehali, MD, PhD [00:03:23] As you know, as we age, our body also changes and there are several processes that occur within our body that can have significant health consequences. One example of that is atherosclerosis. And the atherosclerosis is basically these plaques that are build up in our vessels and that can lead to vascular disease. And the disease everybody is aware of is atherosclerotic cardiovascular disease, which is the cause of myocardial infarction in patients. So if you have an atherosclerotic plaque, that plaque is very susceptible to oxidative damage. And our goal is to reduce oxidative stress in the body. That's why people tell you that, you know, antioxidants are good for you in young people and especially in older people. So the goal here is to reduce oxidative stress and iron by itself can be a source of reactive oxygen species and oxidative stress. The other thing that people have notice is that many neurological diseases such as as we age and several chronic diseases that are associated with aging and neurological diseases are also associated with iron accumulation in our brain. So Parkinson's disease, Alzheimer's disease and a number of other neurological diseases that are associated with aging, they have been shown that there is iron accumulation in the brain. Now, whether or not this is a cause or a consequence of aging, we don't know. But we know that iron accumulation can lead to oxidative stress and can damage the neurons within our brains. So it makes sense that this accumulation can cause damage to the neurons and may be the cause of these diseases.  

Erin Spain, MS [00:05:01] You recently just published a paper that does look at that overlap between the brain and the heart. Tell me about the recent discovery you had published in Elife.  

Hossein Ardehali, MD, PhD [00:05:10] My lab was very interested in studying how iron accumulates in our body as we age. As I mentioned, there have been some studies that have shown iron accumulation in the brain of patients with Alzheimer's disease, with Parkinson's disease and other neurological diseases. But what we decided to do was to get mice at different ages, you know, young age and old age. Now, as you know, it's very expensive and time consuming to get mice and keep them for a long time as they age. But we were fortunate that we collaborated with an investigator at the University of Michigan who had these mice, and they sent us tissue from these mice, and we decided to look at three major organs that are either of major iron consumers or sites of iron in storage. One of them is the liver. Liver is the site of iron in storage. And that's why deliveries actually looks red and that's because of the iron that it stores in the liver. Another one is skeletal muscle. And skeletal muscle is, of course, the site of iron usage in our body. And then the brain, something that we were very interested in to see if there is iron accumulation in the brain. And we measured iron levels in these different tissues, both in the cytoplasm, which is basically a major part of this cell and also in the mitochondria, in the liver, in skeletal muscle and in the brain, in mice and our young and also in mice as they get older. And to our surprise, we saw that cytosolic iron increases both in the liver and in the skeletal muscle, but in the brain it's both the cytosolic and mitochondrial iron. Now, why is it important? Well, the reason it is important is that the mitochondria are the major sites of production of oxidative stress. So if you accumulate iron in the mitochondria, that can lead to more oxidative stress in the brain and that can cause damage and death of neurons in the brain. That can eventually lead to some of these neurological diseases that are associated with iron accumulation.  

Erin Spain, MS [00:07:05] A long time goal for your team is to try to create drugs that help strip excess iron from the body targeting this mitochondria iron and the heart. Tell me about where you are on that frontier.  

Hossein Ardehali, MD, PhD [00:07:17] The good thing about this field is that over many years of research in the past, people have identified these chemicals that can bind to iron and can make iron inactive. And those chemicals are called iron chelators. So they basically kill iron, and that means that they make your iron inactive. So those iron chelators have been available and they are actually some of them are FDA approved for some diseases that are associated with iron overload. And there are patients, you know, like sickle cell disease or thalassemia. And these patients have iron overload and they can get these iron chelators orders to reduce their iron. So those chemicals have already been approved. But the problem is that these chemicals sometimes they don't reduce mitochondrial iron. So they are not always effective in reducing where iron can cause oxidative damage. There have been a lot of research to try to identify iron chelators that can target mitochondrial iron. We have used some of them in our clinical practice, but one thing I want to mention is that there is a research project that we have initiating in collaboration with investigators at UCLA. And our goal is to see whether or not a reduction in iron levels by using iron in chelators n patients who have coronary artery disease, it would reduce the size of the plaque of coronary plaques, of plaques, or basically these atherosclerotic lesions or atherosclerotic processes in our vessels that can lead to myocardial infarction. So we want to see if treating with iron chelaton can reduce the size of these plaques. So what we are doing, we are using iron chelators in these patients and we do an imaging modality called CT angiogram. And CT angiogram is basically a CAT scan that looks at the coronary vessels and it identifies or it measures the size of plaques or coronary atherosclerotic plaques in patients. So we look at them at the beginning of this study and 12 months or a year after they have taken this iron chelators. We are going to hopefully start this study soon. But that's the kind of study or that's the kind of approach we have. You know, we are doing a lot of studies in mice and in tissue culture, but we are hoping that our studies in, you know, in the preclinical phase will guide us to translate those into clinical practice and treating patients with various chronic diseases. So this kind of treatment I just mentioned is not just limited to coronary disease. We are hoping that if you see positive results, we will extend it to other chronic diseases, including, you know, neurological diseases that we I just mentioned and maybe other chronic diseases like cancer.  

Erin Spain, MS [00:09:50] You are a physician scientist, the past president of the American Society for Clinical Investigation. You're the director of the MSTP Program here at Feinberg. Tell me what it's like to be a physician scientist at Northwestern. You were just mentioning. You know, you're working in the lab with tissues from animals. You're also working in clinical trials. Just explain what that's like and then what's happening right now at Northwestern to really bring more physician scientists into the field.  

Hossein Ardehali, MD, PhD [00:10:17] This whole thing started when I was a very young, you know, college student that I got exposed to research and that changed my life. You know, I never thought I would be a physician scientist. And that's why I think it is really critical that everyone who is at a young age and also those who are doing research to give this opportunity to young people to get exposed to science that can really change people's lives. As a result of that, I decided to do an M.D., Ph.D. program at Vanderbilt, and during my residency fellowship, I continued to do research. And then when I came here, I was very fortunate that I was in a wonderful environment at Northwestern that supports the career of physician scientists. And I also want to mention that this institution has become more and more supportive of physician scientists our Dean, Dr. Eric Nielsen. He's is a physician scientist himself, my chairman, Dr. Doug Vaughn, the institute director here, Dr. Sue Quaggin, Dr. Beth McNally here. Al George. You know, I can go on and on. There are so many good physician scientists who are, you know, leaders in their field, and they are really good role models for all young people who want to be physician scientists. And our program is becoming more and more appealing to candidates around the country. And we think that it's one of the top programs in the country right now. And the students we recruit are wonderful students. And they come here, they spend eight years, sometimes eight, seven, nine years. They get two doctorate degrees, M.D., Ph.D. and then they go on and do their residency and fellowship and make us proud. And that's our goal. And because of the growth we have had in the M.D., Ph.D. program and the support the institution has provided, this place has grown tremendously in terms of the number of physician scientists we have had. I think being a physician scientist gives you a different perspective about science and medicine, and it prepares you to have a different approach to science. And I'm really proud of what our students do. I'm very proud of what this institution has done to generate or produce physician scientists who are at the forefront of the research.  

Erin Spain, MS [00:12:21] I mentioned you're the past president of the American Society for Clinical Investigation. Tell me about your work and leading that honor society for Physician Scientists. And what are some of the key issues that you worked on and that you hope to see move forward?  

Hossein Ardehali, MD, PhD [00:12:37] Our goal is to find ways to improve our training of young physician scientists and also to lobby for more funding for the career of physician scientists. Over the past year, as you know, we had a lot of challenges because of COVID, and we tried to move many of our initiatives to an online form. And we have started a different lecture series and also different awards to support young physician scientists. And a lot of effort has been put into providing career guidance for young physician scientists. How to make it. The number of physician scientists in the country is going down and we need to really find a way to improve that. So the NIH is aware of that. They are trying to support more physician scientists and institutions like Northwestern are also aware of that. That's why there is a lot of effort into trying to improve that process and support young investigators.  

Erin Spain, MS [00:13:28] Maybe there's some young people listening to this podcast and they want to know more about the MSTP program, or is being a physician scientist the right career path for them? What advice would you give. 

Hossein Ardehali, MD, PhD [00:13:39] Them if you are considering being a physician scientist I really encourage you to continue that path. It's a wonderful path. It's a great life and it's a rewarding life because you end up treating patients, which is extremely rewarding, coming up with hopefully new therapies and conducting research and making a change in the lives of younger people, the next generation. And that's basically what I am doing and I'm really excited and I really feel fortunate to have this opportunity in my life. And I also want to mention that we are very fortunate to be in this country. I travel all over the world and I know that they are training we have for physician scientists is unique in this country. The NIH or the National Institutes of Health pours a lot of money into research and also to support this program of being a physician and a scientist. Again, we are very fortunate to have that luxury in this country.  

Erin Spain, MS [00:14:32] You've spoken about the importance of physician scientists getting involved in public policy and political science. Why do you think this is important?  

Hossein Ardehali, MD, PhD [00:14:40] Well, physicians and scientists are definitely underrepresented in politics. If you look at the Congress or the Senate, there are very few physicians and there are very few scientists who are in both of those chambers. There are a lot of factors that go into the science policies in this countries or clinical policies. And as you know, health care is a major issue in this country. So we need to have more and more physicians and scientists at the level of policymaking to improve health care in this country. And I tell all of our young people that, you know, if you guys decide to go into politics, I'm 100% supportive of that because we need more of us, physicians, scientists in politics to be able to educate our politicians of where the future should go.   

Erin Spain, MS [00:15:27] Thank you so much for joining me today, telling us about your research. And we will be directing people to how to find out more information about the MSTP program at Feinberg.   

Hossein Ardehali, MD, PhD [00:15:36] Thank you. Thanks for having me.  

Erin Spain, MS [00:15:48] Thanks for listening and be sure to subscribe to this show on Apple Podcasts or wherever you listen to podcasts and rate and reviews. Also for medical professionals, this episode of Breakthroughs is available for CME Credit. Go to our website, Feinberg.Northwestern.edu and search CME.