Director of Hematologic Research at the Vanderbilt University Medical Center, Dr. Michael Savona, talks about 9/11 first responders’ cell mutation helping diagnose cardiovascular disease.
Interview conducted by Ivanhoe Broadcast News in 2023.
How did all of the air pollution, particulate matter, and smoke cause cardiac issues in firefighters?
SAVONA: So what’s interesting is that we do think there’s a certain amount of air pollution can increase your risk of cancer. But the dust from 9/11 was particularly nasty. The dust from 9/11 included a lot of known carcinogens that were formed or that were exposed to the atmosphere when the buildings incinerated. So some of the molecules in the plastics were in the building materials basically became aerosolized. And what we studied was first years ago my colleagues study the risk of cancer in these patients. And of course, the cancer risk was higher among people exposed to 9/11 dust. These first responders and firefighters. But what we really want to look at was, does their risk of clonal hematopoiesis increase. Well, what’s clonal hematopoiesis? Well, clonal hematopoiesis are gene mutations that occur as you age. And these mutations are naturally occurring just because of math. If your cells divide enough sooner or later, they’re going to be an error that doesn’t get fixed. And if that error doesn’t get fixed, and it happens to be in a part of the genome that gives an advantage to cells over normal cells then what you get is a rapidly dividing cell which is more likely to acquire more and more mutations, which is really the basis of cancer. What was discovered several years ago, which is an interesting corollary to this, is not only does this gene mutation puts you at risk for developing cancer, but it also puts you at risk for developing a variety of other health conditions. All because it creates a more inflammatory environment. We know how atherosclerosis occurs. When people have risk factors like hypertension, diabetes, they’re smoker, they have high lipids. What happens is that inside the blood vessels, macrophages are a type of monocyte, eats fat and they become foamy macrophages and they invaginate into the wall of the blood vessel. And just like cells go in-between, almost like layers of tissue paper. And when there’s a change in blood pressure, the wall of the blood vessel can open up and that’s what clot rupture is. That’s what a heart attack is. Well, these clones that are developed when we age, if they are present on more and more of the cells in your blood system, they can create this inflammatory environment that can lead to one hand a blood cancer but on the other hand, a variety of different vascular diseases. And what we found with the first responders was that their risk of clonal hematopoiesis or these gene mutations was much higher than firefighters who didn’t go to 9/11. So we were able to look at firefighters who were far enough away from New York. People specifically in the National Era who had come to Vanderbilt at some point in their health care journey. And we found that the rates of these mutations at every age level were much higher for those exposed to the dust. It’s hard to find a control group for people exposed to 9/11 particulate matter because there were firefighters from around the country that went there, but our firefighters did not. And it’s not just being exposed to fire as it’s being exposed to that particular dust. And that clonal hematopoiesis, that gene mutation puts you at risk for developing cancer again, or heart disease, which was the surprise, but it’s the thing that’s been gaining a lot of steam and attention now medical research.
Cancer would be expected, but cardiac issues is a different matter, can you explain that?
SAVONA: So in the study of atherosclerosis through the years, researchers have learned that the reason that high lipids or blood pressure or diabetes are risk factors for cardiovascular disease because they cause a lot of inflammation at the level of the blood vessel wall. We call it endothelial dysfunction. And endothelial dysfunction is when you have lots of inflammatory signals being fired and interactions when the blood cells in the blood vessel wall. The mutations that occur in blood cells make the blood cells angrier. And what’s fascinating is we’re finding that different mutations that occur with aging in these blood cells cause the cells to be more aggressive and more inflamed in different ways. And sometimes it affects monocytes and the monocytes, instead of just patrolling through the blood system as an immune fighting cell, they become activated and start eating fat and invaginate into the walls of the blood vessels. That’s the basis of atherosclerosis. Sometimes mutation cause neutrophils which roll through the blood and do immune surveillance and tried to fight infection. But that rolling is impeded by special hooks that grow from the neutrophils called integrins that are upregulated when people have these mutations. There’s lots of reasons these mutations cause changes in the blood cells to make them angrier, to make them have a more inflammatory phenotype.
How do you treat these elements and how old are the workers, now, on average?
SAVONA: So I’m going to talk about how we treat CHIP. And I’m going to talk about what’s being done with 9/11 consortium as a secondary part. So we don’t really have great ideas on how to treat, let me back that up. We have a lot of ideas on how to treat CHIP. CHIP is here. We have a lot of ideas on how to treat these gene mutations that occur with aging. But it’s tricky because most patients who get these mutations never get disease. And you have to give a treatment that’s very safe to patients who aren’t going to get disease otherwise you’re causing more trouble with the treatment than good. So we’re working hard to find ways to understand which of these patients who get these gene mutations with aging actually are at risk for progressing to a more aggressive situation, are more likely to get cancer or vascular disease. If we can understand that, then we can target those patients specifically. And we can target them sometimes with things that are already approved on the market, like anti-cholesterol medicine or inhibitors of certain mutations that are available in cancer care. Is that helpful? The second thing I’ll tell you is about, you asked about the worker, you asked about the 9/11 consortium. So in our collaboration with the survivors are 9/11, the fire department, New York, the medical team there, and Albert Einstein School of Medicine, we’re working to try to understand what risk those exposed first responders were put at by inhaling the dust. And we’ve learned they have increased risks of cancer. We learned they have increased risk of these age-associated gene mutations that put you at risk for cancer or vascular disease. But we haven’t really figured out exactly how best to treat them because we haven’t understood yet which of those patients who are at risk for developing a secondary problem. It’s not an easy problem to solve but because this is such an important patient population to take care of, there’s a lot of focus going into them right now. I guess that’s all I can say about that.
What did the event teach you, as a physician, on how people get sick?
SAVONA: So there are a lot of intrinsic and extrinsic forces that impact how these gene changes lead to disease. For example, some people are born with mutations in their DNA that every cell in their body has. They’re at a risk like Down syndrome. Down syndrome is trisomy 21. So I had three copies of that 21st chromosome. That puts people at risk for all disease. Once the same way we’re learning that certain inherited diseases puts you at particular risk if you were to get these age associated gene mutations that occur only in blood cells. That’s intrinsic. There are cell extrinsic influences as well, such as environmental exposures. Now, we knew that radiation is a risk for developing these gene associated changes. And now we’ve learned as we suspected, that the dust from the 9/11 catastrophe actually has a lot of terrible hazardous chemicals in it and those put people at risk for not only developing cancer, but developing age associated mutations that puts you at risk for vascular disease.
So, going into your patient, Roger Grad, how did the research directly impact him?
SAVONA: Well, Roger is an interesting character. Now, let me back that up actually. Roger is a fantastic individual, has a lot of energy. And when he first saw me, he didn’t even know why he was there. He felt very well. He was quite open about discussing his workout regimen, which for a man of his age was pretty incredible, 90 minutes of vigorous exercise a day. His cardiac screening was normal 10 years before. So he really didn’t think he was at vascular risk. However, he did have high lipids, he did have some blood pressure issues, and he came in with some small changes in his blood that seemed a little suspicious. So, I looked at some genetic screening and found mutations in his blood cells. And 30% of his blood cells had one mutation and 30% of his cells had another mutation. Both of which we know increase your risk for vascular disease. So as part of our program, which we call CHIVE or clonal hematopoiesis and inflammation of the vasculature, we enrolled him and had him screened by the cardiologist as well. We look for markers in the blood or at risk of- puts you at risk for developing heart disease and we did some baseline screening. Make a long story short, as I suspected, those risk factors actually put Roger at high risk for disease. He was at such high risk for disease that he needed to have a bypass to repair his coronary arteries and now he’s back at his vigorous exercise regimen now not at risk of having an emergent myocardial infarction. There was a runner years ago, Jim Fixx, who you may remember that lost a lot of weight and was a professor of a vigorous aerobic exercise routine and died while running. And what was thought later as Jim Fixx had developed a lot of atherosclerotic disease, which he didn’t reverse with all his training and weight loss. And he put a lot of stress on his heart, which led to a blood clot and a heart attack, a myocardial infarction. Well, even though Roger is an active exerciser, he had these risk factors and now he has these gene mutations that accelerate his risk for developing changes in his blood vessels. So it was important to make sure we looked to see how much at risk his heart was. So I’m glad we picked it up.
Can you talk about Roger’s 100% blockage in one artery?
SAVONA: So, what’s really amazing about Roger and shows the power of these mutations that occur in blood cells, is that he had a normal heart screen 10 years ago. So when I told him you should see the cardiologist, he says, “I don’t know if I really need to see the cardiologist because I feel fine, I’m exercising, I look younger than my age, I’m doing well.” Well, with these mutations combined with his high lipids and his blood pressure, I thought he was at risk and in fact, he had blockages in three major vessels which required a bypass. And having a bypass probably saved his life and help them avoid having a heart attack during one of his workout routines.
Does research like this indirectly help other people like Roger’s case?
SAVONA: Well, that’s what I get really excited about. Everything I do is in human beings and human cells and in models to help translate quickly to the patient care. We have a model in the laboratory providing the best therapy to the appropriate patients as quickly as possible. If what we’re doing is not translating, I’m not interested. So this is very exciting because we make observations that we know can help people. We meet a person who checks the boxes and we get that person in to see the proper consultant and make a big impact. That’s what we all want to do in medicine.
Is there anything that you would like to add?
SAVONA: So it might help because we’re actively enrolling in this thing and it’s pretty cool. So throughout the world there are several large biorepositories where there’s blood samples collected from patients and researchers can go back and say, what’s the epidemiology of this mutation in the blood or that? And we get a good sense of how common these things are. But what’s really difficult is to study prospectively. What happens if you have this mutation? What’s the expected time between getting that mutation and getting that disease? And then if you understand that, how do you treat those patients so they never get the disease. Well, we’re studying this- sorry, well, we’re studying this formally in a program that we call CHIVE, clonal hematopoiesis and inflammation in the vasculature. It’s an acronym that basically means we’re going to track patients who have these clonal hematopoiesis, these gene mutations that occur in your blood cells with age and then see what happens over time in their blood. We might be able to help with patients that enroll in the study. Ideally we can, but more importantly in the future, we will certainly be able to direct our therapy so that we can locate, identify patients who have these mutations early and then treat them with medicines that keep them from ever progressing and developing the disease.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
If you would like more information, please contact:
Craig Boerner
Sign up for a free weekly e-mail on Medical Breakthroughs called First to Know by clicking here
