Diagnosis

Pulmonary Arterial Hypertension: Critical Observations in Pulmonary Medicine, Ep. 3

​​​​​​This podcast series aims to highlight clinical advancements in pulmonology, sleep medicine, and critical care medicine. Moderator, Albert Rizzo, MD, interviews prominent health professionals to help our community gain insight on leadership lessons learned. 


 

In this episode, Dr Rizzo interviews Paul M. Hassoun, MD, Johns Hopkins School of Medicine (Baltimore MD), about his research on Pulmonary Arterial Hypertension (PAH), including its pathogenesis, the evaluation required to establish the diagnosis, available therapies, and what is in store for the future direction in treating patients with the PAH. 

Additional Resource:

  • Hassoun PM. Pulmonary arterial hypertension. N Engl J Med. 2021;385(25):2361-2376. doi:10.1056/NEJMra2000348

Paul M Hassoun

Paul M. Hassoun, MD, is the director of the pulmonary hypertension program and a professor of Medicine at Johns Hopkins School of Medicine in Baltimore, MD.

Albert Rizzo, MD

Albert A. Rizzo, MD, is the chief medical officer of the American Lung Association and a member of ChristianaCare Pulmonary Associates in Newark, Delaware.


 

TRANSCRIPTION: 

Moderator:

Hello, and welcome to Critical Observations in Pulmonary Medicine, led by Chief Medical Officer of the American Lung Association, Dr. Albert Rizzo. The views of the speakers are their own and do not reflect the views of their respective institutions.

Dr Albert Rizzo:

Today, we have the opportunity to speak to Dr Paul Hassoun, professor of medicine at the Johns Hopkins University school of medicine, and the director of the Pulmonary Hypertension Program at Johns Hopkins Hospital. He received his medical degree from the University of Paris in France, and completed an internship in residency at Brigham and Women's Hospital, and a fellowship, in pulmonary and critical care medicine at Massachusetts General Hospital, both at Harvard Medical School.

Dr Paul Hassoun:

Thank you very much for inviting me, Dr. Rizzo.

Dr Albert Rizzo:

I was intrigued and pleased to see your New England Journal of Medicine article in the December 2021 issues, that talked about a review of pulmonary hypertension, and certainly, in the field of pulmonary medicine, this is a topic that keeps coming up, but probably isn't as addressed as often as it should be. So, before we get into the specifics of that article, just tell me a little bit about your background and how you became interested in pulmonary hypertension?

Dr Paul Hassoun:

I had a great time writing this paper because it's a passion of many years. So, I got interested in pulmonary hypertension when I was a pulmonary fellow at Mass General Hospital in Boston. At the time I had just finished my clinical training as a clinical fellow, and I was asked to pick a topic and actually my first direction was control of ventilation. So, something that has to do more with the brain and the neurotransmitters, et cetera. And then I attended a talk given by a person who would become one of my mentors, Dr Taylor Thompson, who still at MGH, he's a big name in critical care. And he was working with Charlie Hills, my official mentor. And he gave a talk, really 1 month before I had to choose my research. And he gave a talk on pulmonary hypertension, and it really struck me, the pathology is what really caught my attention.

Dr Paul Hassoun:

So, I went to the head of the division and I told him, "I'm interested in neurotransmitters, but I'm much more interested in the pulmonary circulation." And this is what decided me to join Dr Charlie Hills and Dr Taylor Thompson. And as it happened, my first week in the lab was during Hurricane Gloria in Boston. I don't know if you remember that. So, I got stuck in the basement of a historical building called the Bulfinch Building at MGH for a few days with several Guinea pigs. And I started doing cardiac catheterization on these 300 to 400-gram creatures. So, you can imagine how difficult it is to go through in humans, but Guinea pigs are using magnifier lenses, et cetera. It was quite challenging, but it was very exciting to put the Silastic catheter at the time into a Guinea pig and measure hemodynamics. So that was my first introduction to pulmonary hypertension.

Dr Albert Rizzo:

Very interesting background there to get to where you are.

Dr Paul Hassoun:

All right. Yes. And so after a year, I think I must have catheterized about 300 Guinea pigs. I was very much interested in hemodynamics. I had reviewed the work of Cournand and Dickinson Richards, and Forssmann who had introduced cardiac catheterization of the right ventricle at the time. And this really excited me, but at the same time, there was Lynn Reed who was a pathologist at the children's hospital in Boston, along with Martin Rabinovich, who had worked on animal models of pulmonary hypertension, and also looked at the pulmonary circulation. But what got my attention is that at the time in the late '80s, everything seemed to point out to the endothelial cell as the main dysfunctional selling pulmonary hypertension.

And I said to myself, hemodynamics are interesting, but let me get to the core of things. And I decided to leave MGH and go to Tufts University to work with Barry Fanburg at the time who was an endothelial cell biologist. And so, the idea was that if you have a dysfunctional endothelial cells, then you have uncontrolled growth of cells that are under the intima, so smooth muscle cells, fibroblasts, et cetera. And for many years I got fascinated by endothelial cell biology and how a dysfunctional endothelial cells could lead to uncontrolled growth of cells that then would cause major remodeling of the pulmonary vasculature.

It sounds like a very good way to get to where you are now and explains a lot about, well, the interest in the different pathophysiology that we're going to talk about as we go through this. One statistic that jumped out at me in your article before we talked about the classifications of pulmonary hypertension, was you said that 1% of the world, and up to 10% of people over the age of 65 have pulmonary hypertension. And unfortunately, I think it was 80% of those live in parts of the country where they really have limited access, whether it's cost, access to care and things of that nature. So, it just points out that many people are not really being treated for what is much more common disease. I think many people thought. So having said that, I know there's different types of pulmonary hypertension and classifications. Can you just briefly tell us what those are and then we'll break down more information about it?

Yeah. No, thank you. This is a really interesting point. And I think this classification of pulmonary hypertension done by the world symposium on the PH, WSPH has evolved over several years since the first meeting, which was in 1975 or '76. And right now... So, the classification has been refined over 6 world congresses. But the classification includes 5 different groups. And that relates to your question about how many people in the world are affected by this. And I think for anybody who is interested or remotely interested in pulmonary hypertension, knowing and understanding the classification is really the first step. And we'll go briefly through it. We have 5 groups. Group one is pulmonary arterial hypertension. I have to say that this classification is based on clinical methodological and treatment responses of the various groups.

I would also like to say that we have treatment mainly for group one at this point, just a recent treatment for group 3 and then some treatment for group 4. And I'll get back to each one. So, group 1 is pulmonary arterial hypertension. So, it's what we call precapillary pulmonary hypertension where, by definition, the mean PA pressure is greater than 20 millimeters of mercury before the sixth WSPH conference, the threshold was set at 25 or greater. And this was changed based on a meta-analysis of several thousand healthy individuals showing that the mean PA pressure of 20 or less is normal, and only... You have pressures greater than 20 is 2 standard deviations above this number. So, this is why during the sixth WSPH conference, the threshold for a defining pulmonary hypertension was changed to above 20.

Now for PAH, you also need to have a wedge pressure less or equal to 15 millimeters of mercury. And even this number is a bit high when you consider that the normal wedge pressure is about 8 to 10. And finally, you need a pulmonary vascular resistance greater or equal to three wood units. So in group one, you have idiopathic PAH, which was called before primary pulmonary hypertension or PPH. And the denomination was changed to idiopathic. You have heritable PAH. So these are patients who have a history of pulmonary hypertension or genetic mutations, or somatic mutations. One of the most common mutation here is the mutation affecting the BMPR2 or bone marrow for genetic protein receptor 2. And then we have in 1.3... So group 1.3 drug and toxin induced PAH. Now I would like to remind the audience that the First World Symposium, which was under the auspices of the WHO was held in Evian in France.

And this was following an epidemic of pulmonary hypertension caused by an appetite suppressant called Aminorex. There were later other epidemics of pulmonary hypertension related to appetite suppressants like Phenformin and redox, which also prompted more meetings on pulmonary hypertension. So, to go on drug and toxin induced PAH is a cause. Now some of the tyrosine kinases are included in this group that can be used in the treatment of cancers. Then a subgroup, I'm mainly interested in is PAH associated with connective tissue disease or HIV, portal hypertension, congenital heart disease cystinosis. These are important. And you mentioned that many patients around the world are afflicted with pulmonary hypertension.

Well, one of the most common cause of pulmonary hypertension worldwide is caused by parasitic disease cystinosis. So, just to give you a few numbers, there are about 250 million people affected with cystinosis. If you think that 10% of these patients will develop PAH, we have 25 million individuals around the world with pulmonary hypertension related to cystinosis. And then you have a group called group 1.5 also under PAH. These are patients who are very lucky because they respond to calcium channel blockers. So instead of giving them very expensive PAH-specific treatments, you can give them vasodilators like calcium channel blockers, nifedipine, diltiazem.

And the way to identify these patients is during Cardiac catheterization, to use inhaled nitric oxides, or adenosine to have to see whether their pulmonary vasculature will respond to it. And these patients then can be, if they respond with certain criteria can be started on calcium channel blocker therapy. So moving on to group two, group two is due to left heart disease. Not congenital heart disease, because this is in group one, but group two left heart disease. So anything postcapillary, any blockage postcapillary. So mitral stenosis, aortic stenosis, diastolic dysfunction, systolic dysfunction, and group two is also extremely common throughout the world. Cardiac disease is quite prevalent in the world, and we have really no adequate treatment for this aside from the treatment of the underlying disease. So if you have diastolic dysfunction, you can do several things, weight loss, control of systemic hypertension, et cetera, but we don't have any treatment targeted to pulmonary hypertension that complicates left heart disease.

And you have to understand that every time you have pulmonary hypertension complicating a disease, the prognosis is much worse compared to the disease without pulmonary hypertension. Group three pulmonary hypertension is characterized by chronic hypoxia. So you can think about any cause of chronic hypoxia, like COPD or restrictive lung disease, sleep apnea, living at a high altitude. So there are millions of individuals living in the Andes or other high-altitude mountains. The people who were born there are naturally selected to survive in such a hypnotic environment, but people moving to these areas may eventually develop their attention. Group four is a separate group. And mainly because there is a treatment to group four, this is related to obstruction of the pulmonary artery. The most common is chronic thromboembolic pulmonary hypertension. And often you don't... These patients don't have an initial event that's diagnosed with PE, but maybe 50% of these patients have a known past history of thromboembolic disease.

But basically, the pulmonary vasculature became filled with fibrotic material, which was at some point thromboembolic and becomes fibrotic. And these patients benefit from pulmonary endarterectomy. So you for the surgeon, this is in an open pulmonary artery surgery, open chest. They find a plane between the intima and the media and go and dissect as far as they can go throughout the pulmonary vasculature on both sides. And, this can be a complete treatment. Some patients are left with residual disease, and we have other options like medical options. Some of the PH targeted treatments can be used here or balloon angioplasty, where an intervention radiologist would go into the pulmonary artery and open up a balloon in a different section that may need different sessions. So successive sessions of balloon angioplasty.

And then the fifth group is a mixed bag group because either we don't understand the mechanisms or they're multifactorial. So an example is a hematological disorder, sickle cell disease, and thalassemia can be complicated by pulmonary hypertension. These hematological disorders were in group one several years ago before I think the fifth WSPH conference, they were moved to group five because we really don't understand it's multifactorial. So it's not just pulmonary hypertension and remodeling of the pulmonary vascular, but they can have high cardiac output failure from severe anemia. So sheer stress on the endothelium and the different charities.

And then you have in that group, 5 of mixed-bag diseases, you have systemic and metabolic disorders, surcharge disorders, and other complex congenital heart diseases. So that's the classification. And I think it's important to know that because when we have fellows coming to the PH clinic and we have a new patient referred for pulmonary hypertension, the first challenge really is to decide where to place the patient, find an underlying disease, if there is any, and then target that underlying disease. And if we exclude all the causes of pulmonary hypertension, then you're left with idiopathic.

Dr Albert Rizzo:

Now you make a good point. And part of what I was going to ask next is certainly group two and group three, the chronic heart disease, chronic lung disease represent a lot of individuals that come into primary care offices every day. And, maybe you can talk a little bit about, and you mentioned the fact that pulmonary hypertension if it coexists with these other diseases really worsens the prognosis. So can you talk a little bit when somebody comes in with the exertional dyspnoea, which is often some of the symptoms, what should be going through the mind of a physician and what would be some of the diagnostic algorithms that you could suggest to help sort this out?

Dr Paul Hassoun:

Yes. So this is important because the symptoms, these patients come in with symptoms that are really nonspecific, exertional chest pain, some fatigue, sometimes fluid retention. They don't understand why. What is really disturbing for a clinician is when they see a young woman. And I say women because this disease affects women much more than men. Their ratio is almost three to one, in group one at least. And so when you see a young woman with the picture of health coming to your clinic, complaining of shortness of breath, or having had the syncope running after a bus, for instance, it's not, you don't think about pulmonary hypertension at the first diagnosis. It's amazing how many patients are referred to us with the diagnosis of asthma for a couple of years. And they're misdiagnosed.

The clinician has missed sometimes the tricuspid regurg murmur or [inaudible 00:19:36]. So the diagnosis can be very subtle. And of course, all patients who come to our clinic don't have IPAH, these are very rare patients. So our goal is really to rule out the underlying diseases. And there are diseases that can produce you to this. So connective tissue disease is a particularly interesting, patients with HIV, you have to think about other causes of aside from infection. They can have disease of the pulmonary vasculature, severe pulmonary arterial hypertension, patients with liver disease, cirrhosis, or portal hypertension are at risk of portal pulmonary hypertension.

So it's really fun. As a PH expert, you have to be a good general practitioner because you need to be comfortable with all these diseases. Sleep apnea is also quite common among the male population, but also among women. Not very common, but can be complicated by pulmonary hypertension. You mentioned group 2, which is extremely common. And I actually enjoy very much seeing patients with diastolic dysfunction, which is so common when you have uncontrolled systemic hypertension when you have uncontrolled obesity that can predispose you to diastolic dysfunction and pulmonary hypertension. And the treatment here is really exercise, weight loss, and control of systemic hypertension. So it's really internal medicine here. You need to be a very good internist to try to find out what's the underlying problem and focus on what can be addressed.

Dr Albert Rizzo:

Yeah. As in so many things in medicine, the very good history and physical really can narrow things down a bit. Once you get past that, and you're talking about testing, is the echocardiogram fairly early, as far as one of the tests that help you determine...

Dr Paul Hassoun:

Sure, the echocardiogram is actually our best screening test. It is cheap. It can be done in any center, and it will give you a flow of information about what you're looking for. So patients, people, or clinicians often focused on the right ventricular systolic pressure, which is estimated based on the tricuspid regurg velocity. This is not what I focus on, but of course, if it's greater than 30 or 40, you get concerned, but you can first look at the left heart. You can exclude secondary causes of pulmonary hypertension. You can find mitral stenosis, you can find aortic stenosis, diastolic dysfunction, left ventricular hypertrophy.

So it's an extremely useful test to exclude things that are not PAH. And then when you focus on PAH, I look at more than the RVSP, I look at the size of the right atrium and the right ventricle. And it's unlikely to find a patient with severe PAH who does not have severe or moderately dilated right atrium and right ventricle. And sometimes you can have some, of course, you can find the natural myxoma on the left. So group two disease. So it is in a very important screening test for patients who come in with and explain this of course.

Dr Albert Rizzo:

And I guess in clinical practice, my practice, at least we use the echocardiogram to help decide about sending people off to get the more invasive cardiac catheterization. If there's some suggestion of pulmonary hypertension that can't be explained, is that a reasonable next step in those individuals?

Dr Paul Hassoun:

Yeah, so unfortunately several years ago, we used to see patients who were treated by their general internists based on the echocardiogram. And this is really nothing to do. What you have to do is you have to confirm the diagnosis of pulmonary hypertension for many reasons, doing a right heart catheterization allows you to exclude the half path or diseases of the left heart, but it also gives you information on the actually mean pressure. And we've done studies in the past, comparing the echo findings with cardiac catheterization, hemodynamic findings done within a few hours of each other. And we find that the estimated RVSP, right ventricular systolic pressure can be 20 to 40 millimeters of mercury, either up or down by echo compared to the gold standard, which is obtained by right heart catheterization. So, yes, before you do anything, and of course, before you give any treatment, you have to perform a right heart catheterization.

Dr Albert Rizzo:

I know maybe touched on this a little bit, many people, especially those who have the group two, group three, it's a matter of treating their underlying disease, managing fluid, giving them supplemental oxygen. And then there are some individuals where there has been a role for anticoagulation. And then there's also the targeted pathways that you mentioned. Can you talk a little bit about the specific therapies there?

Dr Paul Hassoun:

Sure. So you want me to talk about the conventional treat treatment before...

Dr Albert Rizzo:

Sure. That would be fine.

Dr Paul Hassoun:

Yes. Okay. And, I'm glad you asked this question because, for me, it is the first and very important step in the treatment of patients with pulmonary hypertension. So often these patients, I'm talking about group one, PAH, they may come to you with already some RV dysfunction. And so the first sign is fluid overload. And before you send them for a right heart catheterization, it's really important to optimize their volume status. And so we treat and I take my time, I might take two or three weeks before getting a cardiac catheterization. We diures them, that will make them feel better just losing the fluids. And I think the role of diuretics is and recognized... There have never been studies comparing diuretics with placebo for the treatment of PH, because it's such an obvious, important part of the treatment.

So yes, you have to diures these patients. You have to place them on oxygen. If they are hypoxic in particular with exertion, one of the first tests we do in clinic, the first visit is a 6- minute walk test, which can give us an idea of their functional status. It also has some prognostic value in terms of survival, even at baseline. We give them a specific diet. That's important for any patient with cardiovascular disease to avoid salt and limit their fluid intake. Often these patients say "my internist told me I need to be well hydrated," but when they come in with evidence of congestive heart failure, they need to avoid salt and excessive fluid, in terms of general supportive measures. And I would get to a more specific treatment. As I mentioned, most of these patients are women and some are very young.

And so they may be of childbearing age and fortunately, pregnancy can worsen pulmonary hypertension. And our recommendation is to use contraceptives for these women of childbearing age. I have to say that some patients don't listen to us and become pregnant. And we get into very complicated pregnancies where pulmonary hypertension might get worse, and the fate of the mother and fetus are at risk. So we suggest using contraceptives, referring to counseling and genetic testing are important for group one disease, IPAH. Because we find about 6% of our patients may have genetic mutations and that has implications for their families, their offspring. And so they need genetic counseling and the family members may need to be tested at the same time. We also insist on vaccinations. These patients with cardiopulmonary diseases are at the risk of getting worse with infections. So influenza vaccination, et cetera, COVID now. COVID vaccination is important. So this is for general supportive measures.

One group I need to talk about is the vasodilator-responsive patients. We get really excited when we have these patients. They are rare, less than 10%, but they have an amazing response to inhaled nitric oxide during right heart catheterization. And that's exciting for many reasons, their survival is going to be much better than the typical IPAH patient. And they do very well with high-dose calcium channel blockers. And as long as they respond to vasodilators, so every year or every other year, we need to retest these patients with inhaled nitric oxide or adenosine, depending on your practice to make sure that still respond to vasodilators. And if they don't, then you need to add PH-specific therapy.

Dr Albert Rizzo:

And before you talk about the different pathways, does anticoagulation still play a role...

Dr Paul Hassoun:

Oh, yes. I'm sorry. You asked me...

Dr Albert Rizzo:

That's right.

Dr Paul Hassoun:

So anticoagulation was recommended based on mainly retrospective studies. I think one was by Valentin Fuster showing that patients with coumadin had better survival. The other study was on patients responding to vasodilator therapy, the study by Stuart Rich, which found that patients who were on coumadin had better survival, whether they were responders or non-responders to calcium channel blockers. So coumadin seemed to give you a survival advantage. So the latest recommendations that patients to IPAH should be considered to be on anticoagulation with coumadin for instance. I have to say that my young patients who are active, who don't have necessarily severely dilated right ventricle, may decide not to start on anticoagulation in particular, if there are some risks. We also know now essentially based on large registries, to compare a registry where patients with connective tissue disease actually have no advantage and may have harm done by being on anticoagulation.

I can tell you that our scleroderma patients, we never start on anticoagulation. And the reason is very simple. They end up after few months having severe anemia and the workup for anemia becomes extremely difficult. They often have AVM, small AVM, along the intestine, sometimes not accessible to colonoscopy or upper endoscopy. So they have AVMs in their small intestine, and they are a source of bleed, very slow bleed. And they end up with very severe anemia and iron deficiency. So we never treat patients, aside from group 1 IPAH, we don't use anticoagulation.

Dr Albert Rizzo:

And I guess the other group is the targeted therapy, the 3 pathways. If you could explain that, especially with your background of being so interested in the endothelial cell. I think that...

Dr Paul Hassoun:

So I have a figure in my review where, this is what I call the 3 classic pathways. So, as I mentioned at the beginning of our discussion, endothelial cell dysfunction seems to be at the origin, or this is what, that's my feeling at the origin of the whole remodeling of the vessels. Now, other people think of outside in meaning fibroblast may invade the pulmonary vasculature and create the remodeling. But I like the idea of endothelial dysfunction. So when you have endothelial dysfunction, you have excess release of endothelin, decrease release of prostacyclin, and decrease release of nitric oxide. So these are either vasoconstrictors, endothelin, or vasodilators, prostacyclin, and nitric oxide. Now you should also remember that any of these molecules with a vasodilator has an anti-proliferative effect and molecules that are vasoconstrictors like endothelin have a vasoconstrictive effect and pro-proliferative effect.

So it makes sense then that if you have excess endothelin to inhibit the endothelin pathway, and I'll get back to this. With prostacyclin, when you have a loss of prostacyclin, you can add prostacyclin and for nitric oxide, I'll get back to the pathway. But to get back to the first pathway with endothelin, the treatments we have are medications that inhibit the endothelin receptor A or the receptor B. So either dual receptor antibodies, antagonist, or you inhibit endothelin receptor A. The endothelium receptor A is the bad receptor, in the sense that it is responsible for vasoconstriction and proliferation. Endothelin receptor B, you want to leave uninhibited because it can help with vasodilation and it decreases proliferation. So the 3 drugs we have currently are ambrisentan, which is a receptor A selective inhibitor and bosentan or macitentan which are dual receptor antagonists.

So the problem with ambrisentan, not a problem, but you should be aware of the immediate side effect of ambrisentan because it inhibits the vasoconstrictor receptor and leaves the vasodilator responsible receptor uninhibited. You can have vasodilation and fluid accumulation, in which case you need to optimize your diuretics. So these 3 drugs, I mentioned ambrisentan, bosentan, macitentan, or endothelin receptor antagonists are commonly used in the US, at least.

In terms of, let me focus on nitric oxide. You can give nitric oxide by inhalation, but it's not practical. It's expensive. So if you look down the signaling pathway, the second messenger for nitric oxide, the target for nitric oxide is soluble guanylyl cyclase, which makes cyclic GMP. So this is the second messenger, which causes dilation on the smooth muscle cells. And so to increase the levels of soluble guanylyl cyclase, you inhibit Phosphodiesterase-5, which it causes the breakdown of cyclic GMP into GMP. So this is what we do. We use sildenafil, or tadalafil and Phosphodiesterase inhibitors. You can also use riociguat, which is a direct cyclase stimulator, will work independently of a functional nitric oxide pathway. So it does not need nitric oxide to produce cyclic GMP. So that's how it causes vasodilation. And then for prostacyclin, we have a number of drugs, you can give prostacyclin agonists by inhalation, by in intravenous infusion, subcutaneous infusion, and now orally as well.

Dr Albert Rizzo:

And correct me if I'm wrong. But I think if it's available, are most of these patients who require these types of drugs best handled at pulmonary hypertension centers, places that specialize in dealing with these patients?

Dr Paul Hassoun:

Yeah. I should have said that from the beginning. In one of the figures, in like a review, I mentioned that if you suspect group 1 disease, or if you have patients with group 2 or group 3 disease, but with severe pulmonary hypertension by echo, the best is to refer these patients to a pulmonary hypertension center, because you need the multidisciplinary practice to deal with these patients. And of course, these drugs are expensive. They need to be approved by the patient's insurance. And you need to know how to handle these drugs because they have side effects. I also forgot to mention... I did mention that some of the prostacyclin are given intravenously or subcutaneously, and so they're not as practical as drugs given orally.

Dr Albert Rizzo:

So based on your obvious experience and interest, where do you think the field is going? I think you touched a little bit on it at the end of your review article, where do you think there are going to be some potential breakthroughs or additional therapeutics in this area?

Dr Paul Hassoun:

Okay, so this is what I find most exciting for the next few years or decades. So for the past, I would say to 25 years, we've been focusing on these 3 signaling pathways. And we have actually, I think most experts in the field will tell you that we have improved survival in these patients. We've gone from the first report, by the NIH of a 2.8 median survival in these patients, 2.8 years median survival to now close to eight years or 10 years for IPAH. It's good, but it's still not very good. I tell my patients, I don't have a cure for you, but I can try to make you survive until we have a cure for this disease. So what I find exciting are drugs that are coming up in the pipeline that are separate from these 3 signaling pathways.

There is a paper that was published I believe in September 2021. It's using sotatercept. It's the STELLAR trial. So sotatercept is a trap for active in. So I mentioned that BMPR2 signaling is disturbed in these patients. And I would have to say that it is altered not only in patients who have mutations for BMPR2, but in most causes of pulmonary hypertension, you have a decreased expression of BMPR2 and decreased signaling through BMPR2. So there is a yin and yang between BMPR2 and the TGF signaling pathway. So this drug sotatercept is a bind active in basically, it's a trap to a ligand that stimulates the TGF pathway. So the TGF pathway is bad in the sense that it promotes cell growth. And so we contribute to the remodeling. BMPR2 on the other hand is... Endothelial cell function will keep the vessels in a state of acquiescence.

So you want to inhibit TGF and promote BMPR to signaling. And sotatercept binding active end will inhibit TGF and will stimulate actually BMPR2. So, this is one thing. I'm fascinated by strategies to increase BMPR2 signaling. A Stanford investigator, Spiekerkoetter, a few years ago screened about 3000 known drugs to find what drug could increase BMPR2 expression. And out of all these drugs, she found that tacrolimus that we use as an immunosuppression drug for patients who received a lung transplant, for instance, can activate BMPR2 and increase its expression. So there are clinical trials related to this particular drug.

I have not talked about inflammation, which is a subject that is very close to my heart. In particular, when it comes to connective tissue disease, inflammation around the vessels seems to be quite prominent. And A French group has described almost neogenesis formation of lymph nodes around the remodeled vessels. And these lymphocytes are made of B and T lymphocytes. We don't know what they do there, but they probably have some role. We know that steroid does not do anything to pulmonary arterial hypertension, cyclophosphamide has been tried in scleroderma doesn't work. It works in some mixed connective tissue diseases. You can have a tremendous reversal of PAH with immunosuppression in nonscleroderma patients with CTD, connective tissue disease. So I think information is the area that we have not targeted at all. We know that cytokines like IL-1, IL-6, and other poor inflammatory cytokines are increased in this disease. And they correlate with survival. Their levels correlate with survival.

There have been trials of for instance, a drug like Tocilizumab, which is an IL-6 receptor antagonist. This was a very small trial from the UK, which was negative, but I think this needs to be further explored in other trials. So drugs that increase BMPR2 expression, drugs that can trap Ligands to the TGF signaling pathway, and inflammation that we have not targeted yet are drugs of the future. I think, oh, I forgot to mention also drugs like tyrosine kinase inhibitors. There was a large trial called IMPRESS, looking at imatinib by tyrosine kinase inhibitor used in blood cancer. That seemed to be quite effective in pulmonary hypertension and had a significant decrease in pulmonary vascular resistance. Fortunately, the drug was never approved by the FDA because of side effects, but 8% of patients said subdural hemorrhages.

I think we did not use the proper dose. We rushed into the trial. We did many patients abandon the drug because of side effects: nausea, vomiting, et cetera. So I don't think the trial was, there was enough thinking before this trial was conducted, but right now there are ongoing trials of inhaled tyrosine kinase inhibitors that are maybe promising. We don't have results yet, but that is following. So what really will cure this disease is if we can kill the cells within the vascular lumen, that cause all the obstruction. That this is really the secret, and this is the holy grail.

Dr Albert Rizzo:

So it sounds like there's a lot of work to be done, but some promising therapies on the horizon for this population, this has been enlightening for me, and I'm going to again refer to your December 16th, 2021 New England Journal review article. There's just a wealth of information there. We only touched the surface these last 35 or 40 minutes. So I want to thank you again for your time and hopefully more to come in this field.

Dr Paul Hassoun:

Thank you very much, Dr Rizzo. It was a pleasure to talk to you.

Moderator:

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