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Sandeep Sahay, MD - phaware® interview #133

Mar 2, 2018

Sandeep Sahay is an Assistant Professor and pulmonary hypertension specialist from Houston Methodist Hospital. Dr. Sahay is a CHEST Foundation PAH clinical research grant recipient and he has been highly active in creating patient education materials for PAH and CTEPH patients and medical professionals. In this episode, Dr. Sahay discusses clinical trials and why they are important.

Hello, I'm Sandeep Sahay and I'm a Pulmonary Hypertension Specialist at the Houston Methodist Hospital. I work at one of the Pulmonary Hypertension Comprehensive Care Centers at Houston Methodist. Basically, we treat patients with all types of pulmonary hypertension.

Today, I would like to talk to you about clinical trials and why they're important.

If you look at the history of pulmonary hypertension, if you go back to early 90s, late 80s era, we really didn't have any medication for treatment of pulmonary hypertension. The only option for these patients used to be getting them transplanted, and at that time in the early 90s, transplant also was a pretty naïve thing.

So in the last two to three decades, we have definitely evolved, we now know so much about pulmonary hypertension, we have got so many more medications, but it's still not much. I mean if you compare it with any other commonly seen disease, we say that the PH is still rare, yes it is still rare, but I feel it's still under recognized because in the community, half the time patients present with these vague shortness of breath symptoms, community physicians, they start with obviously common things are common, so the evaluation starts with the common things and then some people are able to get to the right place and right physicians, and some are not. So, early recognition and all that is really important.

Coming to the clinical research, on why that plays a big role, is that if you compare in the last two, three decades that from one or no medications we have currently 14 FDA approved medications in the United States. Now, what these medications have done, they have definitely improved the survival in a disease, which is still considered to have a median survival of 2.5 to 3 years, but now we have seen patients living over 10 years, 15 years, some of them are even 20 years.

So there is definitely improved survival with the medications. So that's where the importance of clinical research comes, because we are noticing that we have definitely improved survival, number one, with these new medications. Number two, we have noticed that their quality of life is also improved. 

So it's not only about living longer, but it's about having a better quality of life also. That's what we want for our patients. We want for these young people who are struggling with their disease which, by nature, is progressive and it is going to progress, so with these medications we are able to give them hope. And if you look at all these medications, they are basically a result of clinical research.

We first identify different pathways with which we can attack this disease and then with those pathways we are now helping these patients basically. And now, if you look at the newer research in last two, three years, currently we have mainly three different pathway medications with which to treat these patients. But now we are looking for more pathways, maybe we can try something else because still there is room to improve. I mean, we can definitely look for some other pathways. Many clinicians, researchers across the country or world, they are looking for different alternative pathways, more medications, so that we can treat these patients.

We have a bunch of medications for diseases like COPD, asthma, pneumonia, we have infectious diseases, we have thousands of different antibiotics. If a patient doesn't tolerate one medication, you switch him to another antibiotic. You always have an alternative. But that's not the case with PH medications. If your patients do not tolerate one medication, you have to really think hard to find a good alternative agent for your patient, because you just have those 12, 13 medications to play around with, so sometimes that becomes challenging. So that's one other area that you want newer medications. You want clinicians, researchers, industry interest in developing new medications or new pathways.

My particular research, if you look at this CHEST Foundation grant which I got, is basically to identify a role of estrogen as a culprit pathway in development of portopulmonary hypertension. So the whole concept came from what we have noticed in the last roughly 10 years, there is a lot of basic translational and clinical research which has been done to find out if there is some abnormality in estrogen pathway which leads to development of pulmonary hypertension.

Just to simplify things, we say that pulmonary hypertension is more common in women. If that has something to do with their higher estrogen level, we don't know as yet. But that's where the whole idea started. Then one of the very nicely done research studies by Dr. Eric Austin at Vanderbilt which showed that they basically had patients with familial pulmonary arterial hypertension and those familial patients, some were mutation carriers, BMPR2 mutation, and some basically who had disease. So what they compared in that, those who developed disease, they actually had a higher level of urine metabolite of estrogen, which is 16-hydroxyestrone, which is actually considered a mitogenic, it leads to mitogenic changes or angioproliferative. What that means is it leads to blood vessel proliferation, which makes pulmonary arteries thicken and stiff. The higher level of this estrogen metabolite was seen in these patients who developed pulmonary hypertension with this BMPR2 homozygous mutation. So that's where things came to light, that maybe estrogen plays some role.

So what we are trying to do, we are trying to enroll and I just enrolled my first patient. What I'm doing is, I'm basically enrolling patients with portopulmonary hypertension, then I'm checking their estrogen level, and then I am checking their urine estrogen metabolite level. And I'm comparing this with those patients who do have liver cirrhosis but they do not have portopulmonary hypertension. So just cirrhosis verus cirrhosis patients with pulmonary hypertension. So we will see what it shows, if their estrogen or urine metabolite is higher or not. And if it is, then probably we are in the right direction looking for it.

We actually did one more study, and this is not published but it's accepted for presentation as a scientific abstract for this year's American Thoracic Society meeting in coming May. What we did, we used the same thought process that for some reason estrogen levels and metabolism is more in patients who develop pulmonary hypertension in the setting of liver cirrhosis, basically in portopulmonary hypertensive patients.

So what we did, we looked back at all of our portopulmonary hypertensive patients who had liver transplanted at our center. So I took out their liver samples, stained it for aromatase, did a immunofluorescent staining of that. Then I took another control group which was basically just patients with liver cirrhosis and no aromatase stain on that, and basically we tried to compare. We actually found that there is increased aromatase staining in both the groups. It was not discriminatory that aromatase was higher in patients with PAH versus just plain, simple cirrhosis. But it was definitely over-expressed in both groups. We could not discriminate between the two. The conclusions from this study is definitely aromatase is over-expressed in liver, but it was not different in the two groups, probably highlighting that either it's not playing the role with the induction in the liver or it may be happening somewhere else.

Since this study was not able to give us this answer whether the liver is the source of increased aromatase expression, what we did, we had few patients who had died over the year, unfortunately, because of whatever reason, with portopulmonary hypertension. We took their autopsy slides from their lungs and we did their pulmonary arterial endothelial cell for aromatase enzyme. And actually, interestingly, it was positive. So, it kind of gave us a clue that probably this over-expression of aromatase is not happening in liver. It's probably happening in the lung, maybe endothelial cells.

So now what we are trying to do is to take these endothelial cells and there is a special technique like you do when you are doing a right heart cath. You get their catheter tape and then you harvest the PA endothelial cells. And then you basically stain those cells for aromatase. Then we will see. We don't know as yet, but hopefully we'll have an answer. That's what I would think that why it is important to do good, active research in pulmonary arterial hypertension.

My name is Sandeep Sahay and I am aware that I am rare.