POTS Research both Past and Future with Dr. Satish Raj

Episode 100: POTS Research with Dr. Satish Raj [00:00:00] Announcer: Welcome to the Standing Up to POTS podcast, otherwise known as the POTScast. This podcast is dedicated to educating and empowering the community about postural orthostatic tachycardia syndrome, commonly referred to as POTS. This invisible illness impacts millions, and we are committed to explaining the basics, raising awareness, exploring the research, and empowering patients to not only survive but thrive. This is the Standing Up to POTS podcast. [00:00:30] Jill (Host): Hello, fellow POTS patients and marvelous people who care about POTS patients. I'm Jill Brook, your hyperadrenergic host, and today we have a very special episode. We are speaking with the one and only Dr. Satish Raj, whom you probably already know and admire unless you are very new to POTS. But for any newbies out there, Dr. Raj is a POTS physician, researcher, and expert extraordinaire. We have mentioned his research many times on this podcast because there's so much wonderful research. If you have POTS or if you treat POTS, you have probably benefited from his research many times over. He is a cardiologist and cardiac electrophysiologist, a professor of cardiac sciences, and medical director of cardiac arrhythmia service at University of Calgary in Canada. He is also recipient of this past year's Standing Up to POTS Research Grant, and we are so happy to be supporting his research because he has a wonderful track record of doing very high quality research that helps our community in so many ways. Dr. Raj, thank you so much for joining us today. [00:01:41] Dr. Raj (Guest): Thank you for having me and for the very kind words. [00:01:44] Jill (Host): So we wanted to speak with you today about POTS having its 30th birthday since I believe researchers at the Mayo Clinic first published an article describing the syndrome and giving it the name POTS about 30 years ago. And according to your website, I think that was also about the time you were graduating from medical school. Do I have that right? [00:02:08] Dr. Raj (Guest): That is, I did graduate in '93 and, and I will say that at that time I had no idea what POTS was. Maybe part of the broader issue in the medical community in, in terms of how and when we learn about it. It's one of those things that I think people pick up at different phases of their career as they come into patients with POTS or interact with it in some way. [00:02:28] Jill (Host): Is that how you learned about POTS? [00:02:30] Dr. Raj (Guest): I guess my entre to POTS actually was a little later after I'd finished most of my clinical training in Canada. I'd done my internal medicine, cardiology, and my cardiac arrhythmia training. The question was what to do and, and from a research point of view, I needed more skills and so my mentors here actually suggested I go down to work with David Robertson at Vanderbilt, and my goal in going down there actually had nothing to do with POTS. My goal was to try to understand the physiology of fainting and why people have reflex faints and use that as a basis to try to treat that or make that less likely. But when I went down there initially for a visit and then, and certainly afterwards, this was in early, the early 2000s. It was shortly after a couple of seminal papers that they'd had out, uh, in the New England Journal actually on some different, uh, groupings of patients with POTS. And they just had a big NIH grant where multi-project ramp, but David had a project dealing with the pathophysiology of POTS. And one of those projects became my project when I went down there because I needed something to sort of glum on to quickly. And that's actually how it began. So obviously more exposure to POTS, uh, being at Vanderbilt because they had active programs bringing patients in. There was a very specific initial study dealing with blood volume regulation, but one of the things is when you do clinical research is that, you know, you're not studying rats or studying mice, you're studying people. And it was a great opportunity because we had this research unit where patients would come and spend days with us. So, in addition to the time and the studies questions would come up, you'd sort of see people intervally over days and you'd get a sense of both the symptoms that bothered them and, and other issues that they felt were important, that they'd bring up for questions. And that was really probably where a lot of that initial interest began. That first study, as I mentioned, dealt with blood volume regulation, and that's still an interest, but some of the other studies actually came out of those conversations with the patients about other things that were bothering them and thinking about, you know, how to address X or Y or how things are linked. So, it really stemmed from sort of, I guess, being in a place where you have the opportunity to sort of see, not just one or two patients, but a lot of patients and, and not in clinic. I mean, the problem with clinic is it's usually very short time-defined interactions where, you know, you have to be organized and run through checklists because there are things that have to get done. The research unit at Vanderbilt really afforded, I guess, the luxury of, of having a little more time and little longer time windows to interact. Did we make everyone better? Absolutely not, right? Hopefully we made some people somewhat better. But it did give us a chance to better understand some of the issues. [00:05:11] Jill (Host): That's so interesting. So that's what got you into POTS originally, what keeps you there? You know, what makes it interesting to you and why do you choose to specialize in it after all this time? [00:05:22] Dr. Raj (Guest): It's almost a question of career path. I think I live by that old saying that's credit to Yogi Berra, that when you come to a fork in the road, take it. I'd be lying to you if I told you there was sort of a pre-ordained path or method to the madness, right? I think you keep coming up with different questions or different opportunities and, you know, there's just a lot that's unknown and a lot left to answer. And, you know, one opportunity leads to the next and then you can look back and say, "well, I had this all planned and we did this and this and this for this reason." But really everything builds on prior work, prior experiences, things patients say to you, tell you about in clinic, on the research environment, when you have a little more time issues that are important to them, you know, ideally you want your research to try and address issues that are gonna make people better and ideally issues that are important to the patients. [00:06:13] Jill (Host): So you mentioned a moment ago your early research being about blood volume. And I know that in POTS we focus so much on the importance of drinking more water and eating more salt to help manage blood volume in POTS, but I don't think we've ever dwelled on this podcast very much about why it's a problem in the first place in POTS. And I know you were among the very first to publish on the Renin/Aldosterone paradox, and I'm wondering if you could explain what's going on with those hormones in POTS. [00:06:46] Dr. Raj (Guest): Sure. So, let me take a step back and, and say the first challenge in POTS is that it's so heterogeneous. I think that anything that is offered as the answer for POTS is, is problematic because as I often tell patients, POTS isn't a thing, it's actually a cluster of a bunch of things. And so ideally we wanna identify the specific sub bunches, if you will, for more targeted treatment. Having said that, you know, what we found - this is back in the early 2000s - the study I had, actually, was focused on fluid shifting. So that that initial study I mentioned that I was working with David on, actually, the hypothesis was that the blood vessels in POTS patients may be leakier, and so when they stood up, they'd lose more blood from their vasculature, and that was actually what was driving the tachycardia, driving the heart rate increases that patients would experience. And the short version was, uh, not so much , right, that it turns out that it wasn't really that different. There obviously is sort of fluid shifting down and uh, you know, if you use sort of serial hematocrit methods, some blood, some of the liquid part of blood does actually leak outta the vessels with prolonged standing. But that happened actually in the POTS patients and in our healthy control subjects. So, that wasn't sort of the answer. But one of the things that with just measuring hematocrit, so the percentage of red cells sort of over time when you're standing, you can get a percentage change, but we wanted to try and quantify the actual amount of blood that we're talking about. And so, as part of the protocol, we were doing a blood volume measurement. We used a technique with radio labeled albumin, so it's a commercial FDA-approved blood volume system we we're using it on the research lab where we'd inject a tiny bit of tracer, if you will, in a sample of blood, and we can measure the blood volume and if the folks are interested, the, the principle is what's called indicator dye dilution. The underlying principle is if, if you have a bathtub and you dump a cup of red dye in, it'll turn really red. And so if you know how much red dye you put in and you know what the concentration of the red dye is in the bathtub, you can do some sort of junior high math and figure out the volume of blood in the bathtub or the volume of water in the bathtub. If you took that same thing and dumped the same cup in a swimming pool, you know the concentration would be less, and you, again, you could figure out the volume and it's a little more complicated in people, obviously, but that's the underlying principle. So we did that, and what we found was that very reliably, the POTS patients had less blood than expected. And assessing blood volumes a little bit complicated because size matters. So one would expect, don't know if people in your audience are old enough to remember Andre the Giant, the wrestler, and Hector from the Princess Bride, if you will. [00:09:32] Jill (Host): [Laughs] Right. [00:09:32] Dr. Raj (Guest): Um, huge man. You would expect him to have more blood than a petite figure skater, for example, just because there's more of him. And so, the nice thing about the method we used is that there were formulas based on old sort of height and weight charts and differing for males and females of what was an expected blood volume. And so, we used that and what we found is that the people vary, but if you look at the population of the healthy control subjects, the formulas actually averaged out pretty well, right? So some were a little over, some were a little under, but for the most part, if you look at the plasma, the liquid part of blood, it was what the formula said you should. The POTS patients had a deficit of about 12 or 13% on average, so some a bit more, some didn't. Again, the heterogeneity of POTS sort of coming through any population. But there was a clear deficit. So, then we said, okay, well we were also looking at part of our routine assessments at the time in POTS patients. We were looking at some hormones regulating that, including plasma renin activity and aldosterone. So renin activity helps regulate angiotensin and aldosterone. And aldosterone is the main hormone in the body that tells the kidney to hold onto sodium. So, very important in terms of regulating the blood volume cuz the water follows the sodium in the kidney. And so we looked at this and what we found was that the aldosterone level was a bit lower in the POTS patients measured the same way, both lying and standing than, than in the healthy controls. And that didn't seem right. If, for example, I was to put an intravenous catheter in you and suck out a liter or two of blood and make you lower your blood volume, right, acutely, let's say a liter, we don't wanna be too aggressive, and then we sort of watched what happens, the expectation is that your aldosterone level and your probably renin activity would increase as the body tries to compensate for that, as the body tries to get you to hold onto more of the sodium and hold onto more of the fluid. But we found the opposite. We found the levels were low, and so that was what we were saying is the paradox was it should be high and it was low. The renin levels weren't actually lower, but they weren't higher. And the argument is they should have been higher. Everything should have been revved up and it wasn't revved up. And so it suggests that there may be a problem in salt handling. It may be a problem in, at least in some patients, in sort of the renin and angiotensin aldosterone system. And then after that there was some work out of Dallas - Qi Fu and uh, Ben Levine - that found sort of similar low aldosterone levels. And there's some work out of Julian Stewart's lab in New York suggesting sort of some abnormalities in angiotensin, slightly different findings. There's something there, but again, not enough of something, it's not that it was absent, right? It's, it's a bit lower. And if you're looking at these groups, certainly statistically significantly different, but not enough to say that if you just look at this number, it should be higher than this or that, 'cause one of the challenges with hormones like aldosterone that are involved in regulating the amount of sodium you retain is that it's very responsive to the amount of sodium or salt that you take in. And so, it's hard in a clinical lab where people come in the way they are, eating however much salt or so that they're eating, to sort of have an absolute cutoff of this being lower that. In our studies we can bring people in and put them on a set sodium diet, which we were doing at the time, which allowed us to standardize it a little bit for that comparison. Now, for years afterwards, we were doing blood volumes regularly at Vanderbilt, and it would be a lie to say that everyone with POTS had a low blood volume, but, but a majority did. It was probably about 70, 75% had a low blood volume and, and about 25% didn't. So again, should everyone be treated the same way? You know, hard to know. In some places, assessing the blood volume formally is easier than in other places. So right now in Canada, the technique that is FDA approved that we used when I was at Vanderbilt isn't actually approved in Canada. So getting a clinical blood volume assessment's actually quite difficult. And so we've taken the approach of trying to target that blood volume by encouraging patients to: a), get in lots of water, and then also to take in a lot of salt to hold onto some of that water. The truth is most of the water that's taken in is gonna be peed out. The deficits we were talking about, that 12 or 13% I think was about 300 milliliters, right? It's, it's sort of a glorified can of Coke. Um, the problem is it's not, it's so simple to just put the can of Coke in the person, in their bloodstream and say, we're done, right? So we're sort of working the edges of trying to get the kidneys to hold onto a bit more fluid and we want it in the bloodstream. We don't know how to do that. So the salt approach gets the fluid in the body overall and then the body distributes it such that some goes in the bloodstream where we think it'll be useful and some probably goes into the tissues in your finger where it's probably not as useful. But that's the goal. That's why we encourage patients to take a lot of salt. The low blood volume work and POTS, it's certainly got us interested in the regulation of it, but that has been shown before as well. [inaudible] at the Cleveland Clinic years ago, had some techniques where she looked at it and, and others have shown similar things, either focusing on the red cell mass or on the plasma part, the other parts of blood. So, I think it's a finding that's real in POTS, uh, and certainly anecdotally, I, I think a lot of our patients will come back and follow up, sometimes surprised at how effective the salt and water is at improving some of the symptoms. I don't, I don't wanna make it sound like this is a cure all for everything, but in terms of helping that, that's often one of the things that does help if it's done aggressively enough. So more recently, just last year, we published a paper that was done a few years later at Vanderbilt, where we actually brought patients in as well as healthy controls for one week at a time, but twice and one time they were on a very low sodium diet for a week and one time on a very high sodium diet for a week, and then at the end of the week we did our various assessments looking at orthostatic vitals, looking at plasma norepinephrine levels, looking at blood volume, mainly because while the high sodium diets had been recommended for a long time, there was actually no data that it did what we thought it would do. And what this study showed is that it does do what we thought it would do, at least in the short term. So one week of the high sodium diet does increase the plasma volume, the liquid part of blood. At a week, it actually doesn't increase the red cell part of blood, which makes sense, right? I mean, you're actually working on retaining fluid, the sodium retaining fluid. Over time, the effects may be different. The red cell portion is regulated over a longer cycle. There's reasons to think that might be the case, but acutely the the liquid part went up, the norepinephrine levels in the blood on standing went down, and that's a crude marker of sympathetic nervous system activity. So, some of the revved up stuff we think was being caused by the low blood volume, you can actually reverse with the, uh, high salt diet, and the standing heart rates came down. Now, did they come down to normal if we compare it to the healthy controls? No, but it came down significantly. So it's not to say that low blood volume or low inadequate sodium intake is the cause of POTS or is even accounting for all the abnormalities in POTS, but it certainly is contributing and taking high sodium does seem to help that. [00:16:42] Jill (Host): Do we have any ideas what causes that renal aldosterone paradox in the first place? [00:16:49] Dr. Raj (Guest): We don't. The challenge of understanding the why is, is much more complicated. And again, part of the challenge with this is that different people are different. Like in the dietary salt study where we put people on the high sodium and low sodium diets, we didn't actually see the same difference in aldosterone between the POTS and the healthy controls. These were smaller numbers than some of the earlier studies, so that could be part of the explanation. It could be sort of sampling, if you had a heterogeneous group and you're selecting different bits so harder to know. Lots of different theories, right? I mean, people talk about partial autonomic neuropathies, and I think when we talk about the partial neuropathy or neuropathic POTS, we're often thinking legs, but it's also possible the kidneys are affected. The, you know, sympathetic nervous system does help to regulate the renin. These different hormone systems do interact with each other, and so, the synthetic nervous system certainly regulates rein activity and thus angiotensin and they can feed back on each other. That could be part of it. There's a study that was done by a fellow at Vanderbilt several years ago named, uh, Dr. Sam Mustapha, where they looked at infusing angiotensin on the research unit. This wasn't a treatment study, but to look at the what happened in POTS patients and healthy controls. And there wasn't actually a difference in aldosterone release, which is what we thought would happen. But what we did find was that the POTS patients actually increased their blood pressure less so the angiotensin tooth is a vasoconstrictor. It squishes blood vessels. That's well recognized, and it did do that. But that increased in blood pressure, which presumably is a reflection of the squish in the blood vessels the arterial squish, was less in POTS patients. It was blunted. And so we reported it, but we didn't really have a great explanation for why, and perhaps we still don't. But several years later, as there was more interest in auto antibodies to G-Protein coupled receptors um, and we got involved working with David Kim's lab in Oklahoma. And our primary interests initially were on adrenergic receptors, receptors that affect the sympathetic nervous system like alpha one, beta one, beta two receptors. But he also did use sort of similar samples in the POTS patients, and looked at antibodies to the angiotensin-2 receptors and actually found a higher rate of autoantibodies in the POTS patients to that receptor. So again, what that means is not clear, but you could certainly conceive that some of those patients may have had autoantibodies to the receptors such that things weren't as responsive, that would've affected the responsiveness to angiotensin-2 that could then then affect aldosterone or ultimately sodium handling. But has that been shown? No, 'cause those two studies were done probably close to a decade apart. Not quite. And I don't think in the group with the autoantibodies, anyone's ever gone back and tried to infuse angiotensin to see if that would make a difference or not. [00:19:39] Jill (Host): So that would ultimately suggest that there's an autoimmune basis potentially accounting for that? [00:19:45] Dr. Raj (Guest): These are all theories, Jill. I mean, realistically, I think for a long time there's been sort of a suspicion that there's an autoimmune cause in at least some patients. So if we go back to our big POTS survey, when we asked the question, did something happen within three months prior, uh, to the onset of your symptoms that could be a trigger, and three months is picked this as a window of reasonable nearness, the most common answer was no, that the patients weren't aware of anything specifically. But if you looked at the answers that were yes, the most common answer was a viral infection of some sort, that there's a postviral component to it. And exactly how you got from A to B was never clear, but the presumed implication was that this was related to sort of an autoimmunity or off target antibodies that were produced in response to the virus that caused the illness. That was always sort of the thinking, which is why, when David Kim started finding auto antibodies, it did increase interest. I think the broader issue of autoimmunity certainly is, is of great interest now. I mean, if anything long Covid has probably increased the interest in that space. Steve Vernino's group in Dallas is doing a, a randomized study of IVIG in POTS patients, I think with other sort of autoimmune features, but in, in POTS patients to see if that helps. There's certainly a lot of open label series and anecdotal case reports on the use of IVIG, but great data is not there yet. Hopefully it's coming. I mean, hopefully that's, that's a matter of time. But what exactly this all means and how to measure it is, is unclear. So we recently published a paper in circulation with Artur Fedorowski's group in Sweden looking at POTS patients and control subjects both from Calgary and Sweden. We sort of blinded the samples and sent them to Cell Trend, which is a lab in Europe that does commercial ELISA assays that I think a lot of POTS patients are at least aware of, and and some have actually sent their blood to the lab. And basically what we found was that there were different antibody reports. The one that was most prevalent, I guess, was the alpha-1 antibody, and 96% of the POTS patients were positive for it. [00:21:56] Jill (Host): Wow. [00:21:57] Dr. Raj (Guest): About a hundred percent of the control subjects were positive for it . So again, and this is the challenge is, is what are you measuring and how are you measuring and is it the best way to go? I know when we were working with David Kim's group, they were looking at functional auto-antibody assays as opposed to ELISA. So ELISA, it's looking for the presence of a protein sequence from the antibody. So it's sort of saying, this part looks like it's from this antibody, and we're gonna look and see if we see this part. It doesn't necessarily tell you if that part or whatever it's attached to is actually functional and does anything. It could be something that actually works or it could be something that doesn't work. For example, you may have an autoantibody that detects the presence of your car, but it may detect the presence of your car, whether it's able to run or whether the engine is broken down, right? And obviously the running is more likely to be important in terms of getting you around or causing good or bad things to happen. And so functional assays are tougher to do and that's been part of the issue and why some of that's been a bit slower, but functional assays actually have like the full receptors on a cell that has some way of reporting when that receptor's been activated. And so sometimes it involves light, sometimes it involves releasing another chemical that you can then measure or light up to look at activity, and then you put the patient's blood or a portion of the blood in with it and you sort of look at responsiveness. And so those are tougher. Maybe they will prove more enlightening. So, I think it's important that our cell trend paper be interpreted not to say that autoantibodies aren't an issue, but I think the same time I think it's, does call into question using the ELISA type assays for, that they may not be robust in terms of being able to tell you whether that's an issue for you or not. And certainly an issue that's actionable, which is really, I think what people are seeking is, you know, if I have this, what should I do about it? And right now the answer is we don't know, but probably nothing. But there may be better assays and, and I think that's what we still need to look at. And then obviously immunity is, is complicated and some have suggested that it may not be one specific antibody that's the culprit. It may be that when you're finding levels of these different antibodies, you know, a bunch of them, it may be a marker or there may be a regulatory effect that's just pointing out that someone is, you know, more hypersensitive from an immune system point of view. So I think there's a lot more to be learned, I guess, is the short version of what I'd say. I don't know that the answer is known. I think there's a lot of smoke still around the issue of autoimmunity in POTS. For the most part, we haven't found the fire, at least not the big fire. [00:24:36] Jill (Host): So that actually brings up my next question, which is kind of a big question. I'm wondering what you think are the most important POTS findings of the past 30 years, 'cause I think you've mentioned two of them: the low blood volume factor and the presence of some auto antibodies, but are there other studies out there or or other findings where you say, "oh, that one, that one seems extra important, or that one might lead us to where the fire is?" [00:25:08] Dr. Raj (Guest): Yeah, I'm not sure about where the fire is, but I think there, there are several that provide sort of useful insights for, for different reasons. I alluded to the fact that shortly before I went to Vanderbilt, they actually had a couple of very high impact papers published in the New England Journal of Medicine, right? And it's very difficult to get anything published in there and, and there certainly hasn't been a lot of POTS literature published in there. But they reflected two sort of areas where interesting and, and sometimes difficult to perform studies were done. So one was led by uh, Giris Jacob who, uh, was a Fellow at Vanderbilt in the late nineties. He's now the head of a medicine department in uh, Tel Aviv. And he basically did studies with technique called norepinephrine spillover. In fact, he used sort of segmental norepinephrine spillover, which is probably the best test of actual sympathetic, biochemical sympathetic nervous system traffic, right? You can directly measure sympathetic nerve activity in different parts of the nerve, but this is the norephinephrine and the vascular part of the sympathetic nervous system is the neurotransmitter. We can sort of measure levels in the blood, but that's a combination of release and clearance. But this, this technique actually allows you to sort of look at release in response to different stimuli and if you could look at different body parts, if you can sort of look at blood flow in and out. There'll never be a clinical test, and even on the research side is very difficult to do, and so it's not done very often. But what he showed is that there was a subgroup of patients that actually had less norepinephrine spillover in their legs compared to their upper extremity and compared to to other folks. That's where probably the best data for what we refer to as neuropathic - they coined the phrase "neuropathic POTS," I think, and, and used that in the title of the paper. But that's probably the best data 'cause it actually looked at the part affecting the vasculature, right? If you're trying to explain heart rates and blood pressure responses, that's what they were looking at. The truth is we don't actually use that test because it's so difficult to do. And so people will sometimes use surrogates like QSART or QST tests, which are measuring activity in the sympathetic nervous system, but the neurotransmitter is totally different. The types of nerves are different. So it's a little bit of a jump. But from a proof of concept point of view, it was probably very important because that concept is still widely talked about, sometimes mis-talked about, but widely talked about now, certainly over 20 to 25 years later, maybe not quite as long as the 30. The other paper that came out in 2000 was a report on twin sisters who had a mutation in one gene that caused a POTS presentation. And there were some very specific features, and I don't wanna make it sound like New England Journal just said, Hey, mutation, heart rate, great. They fairly extensive physiologic and biochemical studies sort of documenting the what happened, and, but basically it was a loss of function mutation in the gene encoding what's called, uh, the norepinephrine transporter or NET. And this is a clearance transporter in the sympathetic nervous system. So the nerve releases norepinephrine into the synapse and it has to get cleared somehow, and most of it, it turns out, gets cleared by this transporter under normal circumstances. [00:28:18] Jill (Host): So with this gene, you're saying the norepinephrine build up. [00:28:22] Dr. Raj (Guest): Right. It doesn't, I mean it goes away eventually it whafts away into the bloodstream. That's what we measure actually, right? But, but the point is less of it's taken back up so it lingers in the synapse for longer and it can work on the receptors more. So effectively, it causes a hyperadrenergic state. If you want two times the effect for sympathetic activity, you could fire at twice the rate or you could fire at the normal rate and just not clear it. You clear it half as fast, right? And this is the clear it half as fast. So when it gets there, it goes away eventually, but it, but when it fires, you have a longer and stronger effect. And at one point I think that was exciting because there was a sense that the cause for POTS has been found. We just, and for several years, uh, in my time at Vanderbilt, which was shortly after this paper came out, we routinely collected DNA and, and we did look for this mutation in this gene. And outside of the family, we never found, we never found that same mutation again. [00:29:18] Jill (Host): never a single time? [00:29:19] Dr. Raj (Guest): It was a private mutation. Other members of the family had it, but outside of that, that wasn't the case. Since you can say, well, why would I talk about that as something that's actually been important? And I think the answer is the story may not be fully known, right? I think that there are a couple of answers. The first is that there are a lot of drugs that are commonly used that work by blocking the norepinephrine transporter. [00:29:42] Jill (Host): Oh. [00:29:43] Dr. Raj (Guest): And so the simplest way to think about or find them are, you know, we, we've all heard about SSRI drugs, selective serotonin reuptake inhibitors. And more and more we see drugs that are SNRI drugs, serotonin norepinephrine reuptake inhibitors. Well, that norepinephrine reuptake inhibitor is blocking this NET. Blocking that transporter. [00:30:04] Jill (Host): Same thing then. [00:30:05] Dr. Raj (Guest): Yeah. And so there are aren't many drugs, but Atomoxetine, for example, is a drug that's marketed as an ADHD drug that's a non stimulant. That's actually in North America, probably the purest inhibitor of this norepinephrine transporter. And so it's, it's, I mean, it's enough norepinephrine, they left out the serotonin part. But drugs like Effexor, Pristiq, Wellbutrin, to a slightly lesser extent, these are drugs that are marketed as blocking, not just serotonin, but blocking the norepinephrine transporter. Right? So a priority there's, there's sort of reason to believe that these might not be optimal drugs in patients with POTS, right? I would expect them to make the heart rate worse. [00:30:46] Jill (Host): Do they? [00:30:47] Dr. Raj (Guest): When as a Vanderbilt, we brought in inpatients and we did a series of these acute trials, acute drug trials that lasted four hours. So take that for what it's worth, it's obviously we're not giving you long term experience. And so at one point we actually studied Atomoxetine, which was the most potent NET inhibitor on the market in Europe. It's a drug called reboxetine. Similar drugs marketed for slightly different things. You know, those studies were interesting because we would start roughly the same time in the morning and finish in the early afternoon. And what we found is that if, if we gave placebo, the standing heart rates would fall by mid-morning. There's a diurnal variability to the heart rates, and so any drug that wanted to be better had to decrease the heart rates more than just what was happening anyway. [00:31:27] Jill (Host): Okay. [00:31:28] Dr. Raj (Guest): But the Atomoxetine is the only drug we use that as a group increased the heart rates, both supine and standing. It increased the orthostatic tachycardia, it increased the amount that went up on standing and it worsen symptoms. Now, I'd be lying to you if I told you that everyone got worse. Big group, we're getting ratings. I think it was something like two thirds or three quarters got worse and the remainder didn't, right? Either there was no change or even a marginal improvement in their ratings. And this could reflect just if you get 10 people to sort of rate things, they're gonna rate it differently and there's, there's gonna be noise in every sort of study that you do, and that's, it's possible that's the case. Or maybe that one quarter to one third are different. I keep coming back to the fact that POTS can be heterogeneous and so that has a couple of implications and I'll get to sort of scientifically what that means. But from a patient point of view, I think it's worth at least sharing that those drugs can be worse. I often will try, if, if someone is referred with tachycardia, it's, it's pretty common for them to be on Effexor, wellbutrin, or other drugs like this, and I'll often sort of see if their doctors can switch them to, uh, perhaps a straight SSRI or something that doesn't also block the norepinephrine transporter. And the truth is sometimes that can happen and sometimes that can't. I mean, what I tell people about, uh, antidepressants and anti-anxiety agents are that some people respond to everything and some people don't. And so if this is the first drug your doctor used because your doctor has experience with this drug, and it seemed to help with whatever it was being used for, it may be worth seeing if the second and third drug your doctor could use gives you the same good beneficial effect in terms of treating depression, anxiety, whatever you were being put on it for, without the heart rate effects. Like if you can switch and you get that, that's, that's a win-win for everyone. But if you have an issue where this is the ninth drug and the first eight just didn't work and without it, you're in a really bad way from a mental health point of view, this may be something you have to live with. The tachycardia may be the price that has to be paid. And so it's not as simple as everyone switch out. It's, if you can, it's worth at least trying that. And there's some people that'll say, "no, no, I, you know, I went on a drug. I had no, made no difference to me." And that's, that's possible. Like I said, we had a quarter to a third that didn't report any worsening, but the majority did. So if you're looking at sort of groups and trying to hedge your bets, and I've also had patients tell me if they went on Cymbalta and for a while this was being written about as the wonder drug for chronic fatigue issues and some patients with fibromyalgia, you know, things that certainly some of our patients have co-diagnoses with. But I've had other patients tell me even before I talked to them, that I went on it and I just felt horrible. I had to get off within a couple of days and the tachycardia was worse. So it, this has certainly happened before I teach patients about the pharmacology where it's at high risk of happening. It does happen to some folks. So, again, is that advice for everyone? No, but I mean, if you're playing the percentages, it's probably best to try other things first. I mentioned that the genetics of it were such that we didn't find anyone with it, so is it really that relevant? And I think the interest in it was high for a while and then it sort of waned. And then maybe about 10 years ago now, the Australian group at the Baker Institute who've done sort of lots of great work on this, they published a paper that was interesting. So they have done a lot of work looking at vein biopsies. [00:34:52] Jill (Host): Vein biopsies? [00:34:53] Dr. Raj (Guest): Yeah, so they basically decided, probably correctly, that we have more veins than we need. And, and the truth is, if you block off a vein, your body finds a workaround, right? It'll sort of find, uh, little veins will become bigger veins and you'll work around, it a little like if you get construction on a, on a main road, the traffic goes through the communities. And so they basically would find a little vein in the, in the forearm that they decided people didn't need and would do a minor procedure where they just sort of make a small incision ligate either end of the vein so you don't get bleeding, doesn't bleed out, and cut a small bit of vein and take it and then close them up. The Australians are tough people... [00:35:30] Jill (Host): [Laughs] Apparently! [00:35:31] Dr. Raj (Guest): So they claimed they had no trouble recruiting for this. I'm not sure I'd be as successful either when I was at Vanderbilt or here. But what they found is they, when they took the vein and they crushed it up, and they ran a gel and they stained it for the norepinephrine transporter. And the reason the veins particularly good tissue is because there are a lot of sympathetic nerve endings. So that's the type of tissue you'd expect a lot of this neuro epinephrine transporter protein to be on. So, now they weren't looking at the genes, they were looking at the end result, the protein, is there a lot of that protein there, which arguably is more directly relevant because everyone talks about genes, genes, genes, but genes are sort of the instruction guide, if you will. And then you have to get from the instruction guide to the construction, which, you know, you could argue that's where the RNA fits in, is sort of the signal to get that done. But the proteins are actually the business end. Nothing's happening in the body without proteins. If you have the genes and no proteins, good luck, right? [00:36:26] Jill (Host): Right. [00:36:26] Dr. Raj (Guest): Not, not gonna do much. Now, is that perfect? No, because those patients that were in the New England Journal paper, if you look their protein, their NET levels might have been okay, because the problem was there was a mutation in the protein, so it wasn't working. Not that it wasn't there, although maybe less of it was on the cell surface, and we don't know what would've happened. What the Australian group reported when they did this gel is that they, and it was a small study, there are other things in it, but the protein part, this gel thing, I think they had maybe six patients with POTS and then, and I think three controls or four controls or something. All the controls, they had gels that looked similar, right? You had, there were two bands where the NET was, 'cause two different things, but the POTS patients didn't all look the same. So one POTS patient looked like the controls, the gel looked normal. One POTS patient looked like a faded out control. So there was something there, but it wasn't nearly as strong or robust as in the controls, right? So maybe less of it, there is, I think, how you can interpret. And I think the other three or four POTS patients sort of staring at the gel, wondering if there's anything there at all. Looked like it wasn't there. [00:37:33] Jill (Host): So was this indicating that their blood vessels had not hung on to the norepinephrine? [00:37:40] Dr. Raj (Guest): It indicates that there may be a problem. So I think it indicates potential NET deficiency in some of those folks, even though the gene coating was okay. So when you're on the DNA it was normal, but if you looked at the protein level in the blood, in some of the folks, it was okay. In some of the folks, it really wasn't. And so what would the effect of that be? Well, effectively it's it's NET deficiency. So, effectively it's the same problem that those two patients that were reported in the New England Journal in back in 2000 would've had where they're not able to clear it, right? So, what we're saying now is it's not that the protein's there and it doesn't work, we're saying the actual transporter's not there. And so, then you'd expect them to be hyperadrenergic, and that was, that's what they were getting at. So what that spoke to was a whole issue of the translation to the protein, and then is there gene silencing. There have been a few other papers that they came out with, but they did a nice little study looking at gene silencing and, and found a mechanism of how that gene was silenced. So there, there's the gene to make the, from transporter, but it wasn't then getting converted to RNA and then ultimately getting converted to protein. And there are different mechanisms of doing that. So the, a common one is called methylation. [00:38:54] Jill (Host): Mm-hmm. [00:38:54] Dr. Raj (Guest): Um, but that wasn't the case. It actually had to do acetylation of histones, uh, and were getting deep enough into genetic science that I probably will sound silly if I try to say anything more detailed about it, but different mechanisms of silencing. And they found a mechanism that, that existed in that group. And at one point there was talk about using some forms of chemotherapy because these mechanisms are found in some forms of cancer and stuff, and using some forms of chemotherapy to see if you could reverse that. But I think that was deemed to be too risky and so that that never really went anywhere. But the point is it sort of resuscitated, at least in my mind, I'm not sure worldwide, but interest in fact, that there may still be something about this norepinephrine transporter. There may be something that varies in different individuals with POTS that may be causative or certainly heavily contributory in some where they're more predisposed because they're not able to get rid of the norepinephrine when it is released quite as well. [00:39:49] Jill (Host): That's fascinating. Yeah. [00:39:50] Dr. Raj (Guest): So story's still playing out. Again, this is another area where I think there's smoke, but I can't point to the fire and I can't say for sure because people have done bits and bits and bobs. But you know, for this to really be impactful at a patient care level, we would need an easy way to measure it, and ideally a way that can be measured more than once. So, I don't see thousands of POTS patients rushing to have a part of their vein taken out of their arm to sort of look at this. And even if people were willing to do that, you can only do that so many times. It's not like a blood test you could go and do before and after a treatment or a blood test you could do every six months or annually. I mean, this is, there's a limited amount of your vein that you're gonna be willing to give up for this. And so, so we need a, a different way of looking at it. And we've certainly been trying, but it hasn't been easy to sort of find sort of robust ways of doing it, right? The vein, as I said, maybe uniquely suitable because there are so many sympathetic nerve endings there. So that's limiting the ability to sort of fully sort of look at the potential and understand what's happening there. [00:40:54] Jill (Host): Mm-hmm. [00:40:55] Dr. Raj (Guest): So, and I was just gonna say, I think the norepinephrine transporter story is important, and I think it turned out to be important, not for the reasons that they originally thought, like the, the gene silencing part may part of the same story that's still playing out. But even if none of that comes to bear, even if none of that, at the end of the works out, I think the insights it gave us about how to use pharmacology I think are important, to know that at least in a good chunk of POTS patients, the drugs that block in this transporter are particularly gonna be a problem, it comes from that original genetic study. [00:41:28] Jill (Host): So you're making me realize that, that there are puzzle pieces to this that I had not even ever heard of. And my question, and I know I only have you for a couple more minutes, but my question is, when you look at all of the puzzle pieces we have now about POTS, do you think we're looking at 10% of the whole picture or 90% of the whole picture? Do you think we're close or do you think we have not yet barely even begun to understand POTS? And my other question is, is there any burning question that keeps you awake at night about POTS where you're just so curious, oh, if we just knew this one thing. It's kind of the bigger question about the the future of POTS. How much is there left to know? [00:42:08] Dr. Raj (Guest): There's a lot left to. I will say that trying to find a way to actually assay and understand peoples' level of norepinephrine transporter does excite me. It may be without foundation, but you know, I actually still believe that 1), it may be a diagnostic test for POTS in some patients. It may serve as a, a way to decide on pharmacological treatment for some patients. So, maybe not everyone with POTS needs to avoid these drugs. Maybe it's just the people with really low levels, right? If you have good normal levels, maybe you don't need it. And, and some of that could apply to disorders other than POTS as well. But I think there's a, there's a lot that's. There's a lot of, as I say, a lot of interest in autoimmunity, but we don't fundamentally understand it. There's a lot of interest in small fiber neuropathy, and I know some people believe that small fiber neuropathy and autoimmunity are inexorably linked, not as clear to me. Clearly a lot of POTS patients, there's certain comorbidities that seem to be a lot more common, so Ehlers-Danlos syndrome, how does that fit in? What I will say is that many patients that have POTS and Ehlers Danlos syndrome seem very convinced that their Ehlers Danlos syndrome is causing their POTS. I don't think the data's there for that. I mean, we have two syndromes. Syndromes by definition means we have clinical features that make you look like this other group of people, and that may be a starting point for treatment or starting point for investigations, but it doesn't speak to why. And I think that's true of Ehlers-Danlos syndrome, especially when we recognize that I think there are 13 or 14 subtypes, 14 subtypes of Ehlers-Danlos syndrome right now, most have a gene mutation and a protein mutation except for the hypermobile type. And unfortunately that's by far overwhelmingly the most common type, both I think in general in the Ehlers-Danlos universe, but, but certainly among the patients that we see with POTS. So, how we get from here to there, I mean, I can make up reasons for why it could do it and it's possible, but, but that hasn't been shown. And I think we don't know if that's the case or if there's some other common underlying causative agent that's not one cause than the other, but some other common agent, and I think that needs to be understood. So, there needs to be more work on really understanding what causes them, but but also physiologically, if people are arguing well, the problem with Ehlers-Danlos is the vessels are stretchy, some of those things can be tested.. Not, you know, in the whole, but you can test compliance of vessels in patients with and without it, and maybe that should be done. The MCAS group is interesting. We're finding that that seems to be enriched in the patients with POTS and EDS versus say the patients with POTS without EDS. And again, how they all fit in, is it the autoimmune component or the allergy component, the inflammatory component? Is that the link to neuropathy? I mean, I think there's a lot of it that we don't know and it's, it's hard for any one person to get your arms around everything 'cause there's so many different things that move in so many different directions. If you were to ask what are the burning things that we desperately need answers for that we do a really crappy job of right now, you know, I, I would say that, you know, I, while we could do better, uh, you know, I think I do a pretty good job of managing what I'll call cardiovascular symptoms in POTS, right? I can get the symptoms related to the excessive heart rates and the volume regulation. I think we do a good job of that, and I think that does make a difference in people's quality of life. But often people are still left with issues related to profound fatigue. Whether we want to call it chronic fatigue syndrome or not is a different thing based on sort of older criteria. When we were Vanderbilt, Luis Okamoto looked at the cohort of inpatients we have with POTS, and about 60% met the prior CDC criteria, 40% didn't, right? But a hundred percent of them were chronically fatigued. But whether you met the criteria or not is a bit different, but that's one issue. And the other issue that I think is really poorly understood and probably the most disabling symptom is the cognitive impairment. So often referred to as brain fog by patients, fundamentally we need to get a better understanding of, of what that is, at least sort of quantifying it. I come back to sort of a saying that one of my mentors has layered at me for for years on and off, and that is if you can't measure it, you can't treat it. And so, we need to find a way to actually quantify that in some way to try and understand what's actually contributing to the symptom and how do we figure out better or worse, and then maybe then we can sort of look at the path of physiology. There are obviously tools like fMRI that might be interesting and I think there's some folks that have been trying to look at that. We've used modafinil at times off label. Some people respond, others don't. But I think understanding and trying to treat that would make a huge difference in, in people's lives if we were able to do so. But understanding how these overlapping disorders interact is, is important. These other disorders are important. I'm a often a low hanging fruit guy. I know everyone wants to find out what the underlying issue is and hit the home run. I guess I'm a little more cynical about cure-alls. I go back to the patient with a norepinephrine transporter deficiency, and one of the things I remember she said to me was that patients would sometimes come up to her and say, "you're so lucky, you know what caused your POTS because she had that gene mutation and, and we can't figure it out for me." And she said, "well, yeah, I, I know that this is what's caused it, but I still have all these other symptoms I still have to deal with. That knowledge didn't make those symptoms better. I still have to sort of do these other things." Right? And I think that's actually often the truth. You know, even when you find a cause like that, there's not necessarily magic bullet that goes and reverses everything. Often we're left with doing the same things, dealing with the different symptoms as best we can. And that still needs to be done. And to that end, what I would say is that in the search for the home run, I think there's a risk that we miss getting the singles and the doubles. I dunno if you're a baseball fan or your audience is, but you know, the, the home runs are the sexy part of baseball. But you can score a lot of runs by getting a hit here and there at the right time. And, you know, there are a lot of things that we do to try and treat patients for which there's very little or almost no data compared to, from a cardiac point of view, how we treat heart attacks and heart failure and understanding of that. I mean, hypertension, these are disorders where people study hundreds or thousands of people to sort of figure out if A or B works. You know, in POTS, if we can study 30 people, that's a big study. I think there are a lot of things that people think help, and maybe they do, maybe they don't and they may have access to it, but it would be, I think that there is value in determining what works and what doesn't work so people don't waste their time and effort on things that maybe purported to work that, that don't. And that takes effort, structure, organization, money to not just look for the esoteric, but sometimes study the mundane and see if the mundane works or. Study aspirin after heart attack, not the sexiest thing. It turns out it makes a pretty big difference. Could people have taken aspirin without the study, because it's available? Absolutely. But what we've learned is that aspirin after heart attack, useful in some groups, but aspirin, if you have atrial fibrillation for example, and another rhythm problem that we see and don't have enough reason to go on more potent anticoagulants. We used to put people on aspirin as a alternative, sort of a parting gift, if you will. But we've changed that because it turns out the aspirin has its own risks, not huge risks, but if you're now talking instead of one person and you're talking about a hundred thousand people, those risks actually you can count up and find there's enough risk that you shouldn't do it. And that's I think, what we're missing as well in the POTS world. As we mature as a field, we need to actually try and get more structured studies. ideally with multiple centers, sometimes looking at the mundane things, sometimes looking at exciting things, but sometimes the mundane things, to figure out what works and what doesn't, so we can standardize our practice and optimize it for the patients that that do come to us. [00:49:52] Jill (Host): Well, we cannot thank you enough for all of your brain power and your commitment and your compassion doing this work because there is so much work to be done. But I think a big reason we are as far as we are with having answers is largely thanks to you. So, Dr. Raj, thank you so much for speaking with us today. I know that I speak for the entire community when I say we owe you a huge debt of gratitude and that we hope you will keep doing this for another 30 years. So thanks for all that you do and for joining us today. [00:50:25] Dr. Raj (Guest): I appreciate you having me and uh, I'm not sure I have 30 years in me, but we'll keep going for a while. [00:50:30] Jill (Host): Excellent. Okay, listeners, that's all for now. We hope you enjoyed this episode. We'll be back next week with more. In the meantime, thank you for listening. Remember, you're not alone, and please join us again soon. [00:50:58] Announcer: As a reminder, anything you hear on this podcast is not medical advice. Consult your healthcare team about what's right for you. This show is a production of Standing Up to POTS, which is a 501(c)(3) non-profit organization. You can send us feedback or make a tax-deductible donation at www.StandingUptoPOTS.org. You can also engage with us on social media at the handle, @standinguptopots. If you like what you heard today, please consider subscribing to our podcast and sharing it with your friends and family. You can find us wherever you get your podcasts or at www.thepotscast.com. Thanks for listening. © 2022 Standing Up to POTS, Inc. All rights reserved. [Transcriber’s note: if you would like a copy of this transcript or the transcript for any episode of the POTScast, please send an email to [email protected]]