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Eric Austin, MD, MSCI - phaware® interview 514

I'm Aware That I'm Rare: the phaware® podcast

Release Date: 04/01/2025

Eric Austin, MD, MSCI discusses early detection among people who are at risk of pulmonary arterial hypertension (PAH), particularly those who would have genetic susceptibility, or who may have congenital heart disease, or who may have connective tissue disease or other features that would make them more at risk of developing pulmonary arterial hypertension than the rest of the population.

My name is Dr. Eric Austin. I'm a physician and physician scientist at Vanderbilt University Medical Center. I direct the Pediatric Pulmonary Hypertension Program at Vanderbilt and have done so since 2012. I have studied children and adults with pulmonary hypertension, in particular pulmonary arterial hypertension, but other forms as well, for nearly the last 20 years, with a particular interest in people who are at risk of pulmonary arterial hypertension for various reasons or are resilient to its development for reasons. 

I have great interest in the topic at hand today – early disease detection among people who are at risk of pulmonary arterial hypertension, particularly thinking about people who would have genetic susceptibility, or people who may have congenital heart disease, or people who may have connective tissue disease or other features that would make them more at risk of developing pulmonary arterial hypertension than the rest of the population.

When you think about people who are at risk of developing pulmonary arterial hypertension, the most commonly thought about group in the current era are individuals who actually have familial disease; that is to say they have pulmonary arterial hypertension, or PAH, that occurs in families. This would be two or more family members with truly documented pulmonary arterial hypertension. We and others here at Vanderbilt and others around the world have been interested in studying families who are impacted by pulmonary arterial hypertension as a way to investigate the factors that lead to disease expression or presentation of PAH among people who are at risk.

Years ago, in 2000, the initial genetic discovery was the association of bone morphogenetic protein receptor type II, or BMPR2 gene, with PAH. This association was discovered by several groups working in concert and several groups working independently, who discovered that single-gene mutations or rare variations in the BMPR2 gene can associate with pulmonary arterial hypertension. I intentionally said associate, because while I think they cause PAH, we don't actually definitively know that those mutations, ”cause pulmonary arterial hypertension.” We just know that beyond a shadow of a doubt, families with BMPR2 mutations are much more likely to have people with PH in them than the general population. 

Other genes have emerged over the past 20 years associated with pulmonary arterial hypertension, including mutations in the gene TBX4, mutations in ALK1 and endoglin, which actually also associate with hereditary hemorrhagic telangiectasia, SOX17, and several other genes. There's a smattering of genes that are now known to put a person at risk of developing pulmonary arterial hypertension. You may ask, "Well, what's the risk?" Well, that's the hard part. If you look at families who have individuals who have mutations but are healthy, it does appear that not everyone with a mutation in the genes that we think essentially “cause” pulmonary arterial hypertension will ever develop pulmonary arterial hypertension in their lifetime. Stated another way: a person with a mutation in one of the ‘PAH genes’ will not necessarily develop PAH.

Most of this data actually is from BMPR2 mutation-carrying families, because mutations in this gene are by far the most common--about 75% of families that have PAH due to BMPR2 gene mutations. So most of our data emerges from those people. We know that on average, about 20% of all people who carry one of those mutations will develop PAH in their lifetime. But that's not a yearly risk; that's in their lifetime. We also know that mutation-associated PH can develop not only at any point in the life; but, it's actually different from men and women. People of female sex are much more likely to develop PH than those in male sex who have BMPR2 mutation. In fact, it's about a 42% lifetime risk for a female to develop PH if they have a BMPR2 mutation and about a 14-16% lifetime risk for men.

For reasons we don't totally understand yet, although a lot of work has gone into this, as you can imagine, BMPR2 mutations don't equally cause PH between biologic females and males. That's a point of interest that makes you think, "Well, are the people of male sex resilient in developing PH, or are the females more susceptible, or somewhere in between?" It's probably somewhere in between, but we don't know for sure.

You may then ask, "Well, what is the risk of a person to develop it in a given year if they have a mutation?" I told you there's a lifetime risk of about 42% for females and about 16% for males, but what is the yearly risk? Some of that work has now emerged from groups in Paris and in the Netherlands who have been studying individuals who have pulmonary arterial hypertension in families. Recent data from the French registry of these individuals suggests that about 2 to 3% of people per year in their cohort convert and develop PAH every year. If you take a group of people and they say to you, "Well, what's my likelihood of developing PH in the next year," it's probably about 2% to 3%. We don't know specifically yet. That's the best indicator we have. 

Here at Vanderbilt, we follow about 250 families who have pulmonary arterial hypertension in their family, and many of those have a BMPR2 mutation, and that's probably about the data that we have as well, though we have not published that. We also are now excited to be studying individuals who have BMPR2 or other mutation-associated PAH and then their family members who have those mutations but are healthy. We call that the RARE study, R-A-R-E. It's funded by the National Institutes of Health. I'm pleased to work on this with my collaborators and friends, Drs. Anna Hemnes and Evan Brittain, where we're studying people who have PH in the family, looking at healthy and unaffected as well as PH-affected people. We're interested not just in what makes the person who has the disease develop the disease, we're interested in what helps the person who is healthy stay healthy. By studying genomic and transcriptomic information, which tells us about their DNA and RNA, and then protein-based factors in their blood that may ultimately associate with whether they develop the disease or whether they stay healthy, we hope to learn more about ‘resilience’ to and ‘susceptibility’ to PAH.

We hope that one day if we can figure out what factors are more present in the healthy people who should be sick and are less present in the diseased people who should not be sick, we can harness that to both prevent disease, but also maybe someday develop treatments built around that. You can imagine if there's something that... We find a protein that really helps someone stay resilient to or prevents them from developing PH even though they ought to have it, what if we could harness that as a therapy in the people who already have the disease? We're really interested in this notion, both here at Vanderbilt and around the world, of using people who have genetic susceptibility to understand the disease better and to understand how to prevent it and how to treat it better. 

You see a great example of this in the recent approval of sotatercept in the EU and in North America by the FDA. The drug sotatercept really emerged because of the genetic discoveries around BMPR2 and the associated pathways that go with it. We think that there's a lot more opportunity to learn a lot more from our genetically susceptible and genetically resilient people. 

There are also other forms of disease that associate with PAH. We know that individuals who have an illness known as HHT, or hereditary hemorrhagic telangiectasia, we know those people also are at higher risk of developing PAH in their lifetime. It's still quite rare for those people. It's not a common presenting symptom, but all of our PH clinics have multiple people with PAH and HHT, so it's common enough that we see at a fair amount. There are actually two different genes that most strongly associate with HHT, and that's endoglin and ALK1, or ACVRL1, and a few others. You probably don't care the names about them per se, but just to know that there are families of individuals who have HHT that courses through the family, and those people are also at risk of PAH.

For people who have genetic susceptibility, whether it's HHT families or families with BMPR2 or other gene mutations, there's a little bit of controversy onto how often to screen the healthy people for pulmonary arterial hypertension. You may ask me, "Well, what do you do?" Most people would recommend that first-degree relatives, that is a mom, a dad, or a son or daughter, or a sibling, of a PAH patient due to a mutation like BMPR2 or HHT PH be screened every one to three years with a clinical evaluation and an echocardiogram for pulmonary arterial hypertension. I told you earlier, I direct the Pediatric PAH Program here at Vanderbilt, and here at Vanderbilt we actually tend to see the children who are at risk about every year with a clinical exam and an echocardiogram. I also like to get spirometry with DLCO to look at their diffusion capacity. If they seem at all impaired, we'll do a full six-minute walk test and lung volumes as well.

But what we're doing is we're trying to screen them and perhaps detect PH earlier. If their echocardiogram is abnormal, you can imagine we would activate a full PH workup, including ultimately cardiac catheterization, because we think that earlier therapy will probably lead to better outcomes. We don't actually have that definitively proven, though, in clinical studies. But we also know that every year we have people who have syncopal events or pass-out events or other dangerous events that occur with their pulmonary arterial hypertension. I would be devastated to know that someone was at risk and we never looked for PH and then they died or had a bad event in the community because they passed out. So we screen our people who are children every year. In the adult world, you may see it more commonly every one to three years of screening those at risk.

Another form of at-risk population would be the individuals who have connective tissue disease. The most common connective tissue disease that we know associates with pulmonary arterial hypertension is scleroderma or systemic sclerosis. But you can actually see PH in other forms, including lupus, mixed connective tissue disease and the like. So individuals, and they're usually but not always adults, who have connective tissue disease but are not known to have PH should be screened for pulmonary arterial hypertension every one to three years as well with a clinical evaluation and echocardiogram.

Now, the reality is if you have connective tissue disease and you're well-connected, you're probably seeing your provider every three to six months, and part of the evaluation at every visit is considering progression of disease; is it possible the person has a new diagnosis of PAH? It's not extremely common in those groups to develop PH, but it certainly can happen. They can also develop pulmonary hypertension due to what we call Group III PH, which would be more lung-disease-driven, perhaps due to interstitial fibrotic changes in their lungs that can cause low oxygen tension and can cause PH, as well. So it's not always a pure pulmonary arterial hypertension Group I phenomenon.

That's a quick once-over of the main types. The other things you see in children but not as much in adults, although you certainly can, is congenital-heart-disease-associated pulmonary arterial hypertension. So people who maybe had profound severe congenital heart disease that was operated on when they were young, such as a tetralogy of Fallot, or people who have less severe congenital heart disease, such as an atrial septal defect or a ventricular septal defect that's being monitored or was repaired, can all develop PAH at any point in their lifetime, as well. There's not strict guidelines for pulmonary arterial hypertension or pulmonary hypertension screening for repaired individuals who have had congenital heart disease in the past, but certainly if you were a provider and you saw a person with a history of congenital heart disease repaired that presents with unexplained shortness of breath or difficulty in breathing or other features that could be suggestive of pulmonary hypertension, then you would certainly want to activate some sort of more aggressive screening evaluation for pulmonary arterial hypertension for those people.

Lastly, this is a group that may be less likely to seek care until they're very sick, or they may be depending on the scenario, would be people who are using recreational or other forms of drug use, such as amphetamines or cocaine. Those people are at higher risk of developing pulmonary arterial hypertension. So too are people who use the dietary drug fenfluramine, which has largely gone away in the United States and in Europe, but is known to associate with pulmonary arterial hypertension. This is not the diet drug that you're seeing now that's so popular across the world right now. Ozempic would be a common name for semaglutide and related GLP agonists. Those drugs do not, to our knowledge, associate with pulmonary arterial hypertension. But a traditional weight loss drug called fen-phen, or fenfluramine, did associate with pulmonary arterial hypertension. We still see it's used sometime among people with seizure disorders, by the way. I recently had a patient with this exposure, and we decided to stop that for safety reasons for that person.

If you think about people who are at risk of developing pulmonary arterial hypertension, as I mentioned before it's pretty rare. Thankfully there's a lot more common diseases out there than pulmonary arterial hypertension. But it's really challenging to develop that disease because pulmonary arterial hypertension can significantly impact someone's quality of life and their survival over time, and so we like to be vigilant about it.

If you ask the question, "How would one use the information we know about people at risk in a day-to-day basis," what I would say is that certainly for those individuals who are in a family known to have people with PAH in the family, two or more people in particular, of pulmonary arterial hypertension, it would be great for the family to be aware of it as a group and understand that, “Hey, cousin Jimmy died of pulmonary arterial hypertension and his son or his daughter also has it. I should think that if I ever feel short of breath, or if my daughter ever feels short of breath or has difficulty with walking or not really the same cardiovascular fitness that one would anticipate, that person should go be screened and seen by a medical professional.”

One great way is to be aware of it on your own. It can be hard for families, because sometimes some of the people who are impacted in the family may be multiple branches of the pedigree or multiple branches of the tree away from the person who's actually at risk; that can happen. For individuals who have other risk profiles, like if they have connective tissue disease, if they have congenital heart disease, it's that partnership with your provider or your physician or your nurse practitioner or your PA or whoever you're working with for your care, and both of you together being aware that not only are you being cared for your current problems, but being vigilant for the associated conditions that can occur in the setting of your current diagnosis. 

If you have connective tissue disease, having a good discussion with your provider about, "Hey, Dr. so-and-so, thank you so much for your care of my rheumatoid arthritis, but what other things should I be thinking about as we move along through life? Do I need screening for pulmonary hypertension? Do I need screening for such and such?" Having that dialogue with your provider can be really helpful. Obviously, we're hopeful that would never actually come about and you would not be impacted by PH, but we would want to be on top of it in the event that you did have that happen.

A thing that we're finally becoming a little more aware of in the PH community is the incorporation of people of all backgrounds, shapes, and sizes. For whatever reason, for many years, a lot of the individuals who we were studying at least, and even the people in our clinic, skewed toward a Caucasian population. But we've recognized in the last 10 years in particular that that needs to be rethought and more sensitively thought about. There are people in disadvantaged groups, individuals who are native people of the region, individuals who have African ancestry, individuals from LGBTQ+, who may not be seeking care or receiving care with the frequency with which other populations are. 

Many of us have worked with many groups to improve our distribution of information about pulmonary hypertension across all providers and into populations of individuals, as well, because that is a really important thing. I know Dr. Vinicio de Jesus Perez at Stanford has worked very closely with disadvantaged people across the world, which is another issue that's important. The PVRI (Pulmonary Vascular Research Institute) has been working on this ,as well, spreading the information about screening and about notification of PH and awareness both within North America, but also around the world in places that may be less able to access care or less able to access screening.

Right here at home, I think we've done a much better job in the last 10 to 15 years of being aware of this and made sure that we are getting into all communities. Just like any other medical condition, if you don't have access to the care or you're not receiving care that's aware of the problem, you can miss it. I think through the years we've been not as aware of that as a group as we can be, and we've seen a real improvement of that over the last 10 years or so. I absolutely know that I have learned a lot about that, and so that's a really important point and it’s something that we, as providers, need to be thoughtful about.

My name is Dr. Eric Austin, and I'm aware that my patients are rare.

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