Strategies for POTS Relief with Dr. Satish Raj

[00:42] Dr. Linda Bluestein: Welcome back, every bendy body, to the Bendy Bodies Podcast with your host and founder, Dr. Linda Bluestein, the Hypermobility MD. This is going to be a really exciting conversation. I know so many of you have had questions about POTS and other forms of dysautonomia, and we are going to be talking to Dr. Raj about this incredibly important topic today. This has touched me personally as I had dysautonomia in both of my pregnancies, which I understand we're going to talk about is not a specific diagnosis in and of itself, but literally that's what they put on my paperwork was dysautonomia of pregnancy, and both times I was started on beta blockers.
[01:17] I do want to give you a brief little warning that we recorded this early in the morning and I must have still been half asleep. I forgot to turn on my good microphone, so the actual interview was recorded using my computer microphone, so if you notice a difference in sound quality, that's why.
[01:36] Okay, let's talk about Dr. Satish Raj. He is a heart rhythm cardiologist. He spent 12 years working at the Vanderbilt Autonomic Dysfunction Center in Nashville, Tennessee. He then moved back to Canada and founded the Calgary Autonomic Investigation and Management Clinic. His primary research interests relate to the understanding and better treatment of POTS, vasovagal syncope, and orthostatic hypotension. Dr. Raj is a former president of the American Autonomic Society, and he also serves as a medical advisor to many POTS patient groups, and he is a part of the EDS Comorbidity Coalition Working Group.
[02:14] I am so excited to have this conversation with Dr. Raj because I know that so many of you have had so many questions about POTS. As always, this information is for educational purposes only and is not a substitute for personalized medical advice. Be sure to stick around until the very end so you don't miss any of our special hypermobility hacks. Let's get going.
[02:37] Well, I am here with Dr. Satish Raj, and I'm so excited to finally get to chat with you about POTS, dysautonomia, vasovagal syncope, so many of the things that you treat and that are so important for this population of people. We are doing this fairly early in the morning, at least where I live. Hopefully you're a little bit more awake than I am this morning.

[03:00] Dr. Satish Raj: Well, I have an hour on you. I'm in the Mountain Time Zone, the forgotten time zone, as I like to call it.

[03:04] Dr. Linda Bluestein: I didn't realize that you were on Mountain Time. I'm on Mountain Time also.

[03:08] Dr. Satish Raj: So there you go.

[03:08] Dr. Linda Bluestein: Wonderful. Let's start out by talking about what is dysautonomia, and if that's a good umbrella term to use, and why is this topic so crucially important for people with bendy bodies?

[03:22] Dr. Satish Raj: It's a term that's useful as a concept, but perhaps not as a diagnosis. Dysautonomia is a shorthand way of saying that there's a dysfunction in the autonomic nervous system. Dys and auto from the autonomic nervous system. And it's one of those things that's actually at some level fairly common. There's a spectrum obviously of things that can be wrong and the spectrum of severity of how badly things can be wrong.
[03:50] But one of the challenges, I guess, first is trying to understand what is the autonomic nervous system. One of my colleagues in Los Angeles actually has described it as the human equivalent of the Internet of Things. It's a term I heard a lot more a few years ago than now, but the whole concept that your house, your life will be wired so that you can control everything from your room, the lights downstairs, the garage. We're seeing some of this right now, but it's the wiring, and that's what the autonomic nervous system does. It's the wiring that takes care of the background life functions throughout. I'm a cardiologist by training. Our focus is on cardiovascular manifestations, heart rate and blood pressure regulation, but this affects much more broadly. It affects breathing, it affects gut function, it affects bladder function. It affects sweating — all the things that are really useful for living. If one of those things doesn't work, life becomes very difficult and sometimes unsustainable. But these are things you don't want to have to think about to do, right? There are certainly fables in mythology where people have to think to breathe, and that doesn't go well. So that's what the autonomic nervous system is, and dysautonomia or autonomic dysfunction is saying there's something wrong with it.
[05:09] Now, the problem with dysautonomia as a label or as a diagnosis is that it's hard to disprove. It's hard to say there's nothing wrong with any of those things because we can test for some of those things and many of the things don't have brilliant tests, ways to sort of say yay or nay. But the other issue is that things can be true and unhelpful. For example, when I was at Vanderbilt, my autonomic clinic was in a building that we call the Vanderbilt Heart and Vascular Institute, and it's probably true that every patient that was seen in that clinic could be said to have heart and vascular disease — we'll shorten it to heart disease. But if we gave every patient the diagnosis of heart disease, while technically correct, it's totally unhelpful. Within the spectrum of heart disease, you could have a myocardial infarction, or what is commonly called a heart attack, and that has its own set of risks and treatments and prognosis. You could have heart rhythm problems, and even heart rhythm problems isn't a single thing — you have atrial rhythm problems, ventricular rhythm problems, different types that have different prognoses. You could have valve problems. These all have different natural histories, different courses, different treatments. And so just labeling someone with "I have heart disease" doesn't really help communicate what the issues are, what's likely to happen to them, or even what treatments might be helpful. So it means something's not quite right, but we need to get a bit more specific.
[06:51] Certainly in the spectrum, we have traditionally seen patients with, say, late-stage diabetes, as a complication, or with Parkinson's disease — older patients that can get profound orthostatic hypotension because some of these autonomic nerves, in particular ones in the sympathetic nervous system, are shot. They're not able to squish vessels properly and they're not able to maintain their blood pressure. That's sort of at one end of the spectrum, but there can be problems with regulation, problems with the reflexes that help control heart rate and blood pressure regulation in response to different stresses. Those are more common, I think, in the younger populations — patients under the age of 60 or 70 years old, and certainly in patients with Ehlers-Danlos syndrome, joint hypermobility, things in that spectrum.
[07:46] One of the more common specific manifestations that I see is an overlap with POTS, or postural orthostatic tachycardia syndrome. But certainly patients can be prone to issues of orthostatic intolerance where they feel unwell when they're vertical, when they're upright, and may not fully have the excessive tachycardia to meet the criteria for POTS. We define criteria where you have to meet A, B, and C. That's helpful because if you want to start understanding why things are happening, you need a group that's somewhat homogeneous. But that doesn't mean that everyone who just falls short of the criteria doesn't have something along that spectrum and may still benefit from some of the treatments that we learn about.

[08:33] Dr. Linda Bluestein: I'm really glad that you brought up orthostatic intolerance and POTS. If somebody has orthostatic intolerance but they don't meet the criteria for POTS, I honestly keep trying to figure out what the correct ICD-10 code is for that. Do you happen to know offhand?

[08:53] Dr. Satish Raj: The short answer is that there's not a great answer. But the longer answer is, even outside of ICD-10 codes, there actually wasn't a term for it until a few years ago. If a physician were being strict about the criteria and someone came in and didn't quite meet the criteria for POTS, they would say, "You don't meet the criteria for POTS." What they might be saying is, yes, you have something, it just doesn't meet these criteria. But I think a lot of times what the patient hears is, it's another doctor telling me there's nothing wrong with me.

[09:29] Dr. Linda Bluestein: Correct, right?

[09:29] Dr. Satish Raj: And so there's a challenge between what was said and what was heard, even if everything was said correctly. Sometimes what would happen is physicians would diagnose people with POTS anyway, and that gets confusing because now the label is communicating something to other people, including other physicians, that may not be correct, and that adds confusion.
[09:51] A few years ago, the Canadian Cardiovascular Society put out a statement on orthostatic intolerance. Originally it was supposed to be focused on POTS. As we were discussing it and trying to figure out what to do, what was clear is that everyone on the writing committee had confronted this issue — people being misdiagnosed and also the communication issue of wanting to acknowledge that there was something even if it wasn't meeting the criteria for POTS. We came up with an ecosystem, I guess, of other diagnoses to try and address this issue of "don't quite meet the heart rate criteria but have symptoms," and also to address the issue of people that do meet the criteria — or don't — if they have significant other comorbidities outside of orthostatic intolerance. Their prognosis and response to treatments for orthostatic intolerance may be different. If you have major GI issues and we treat the orthostatic intolerance well, if you try and track quality of life and say, how well did my treatment work, the quality of life may not improve a lot if their main problem is actually their gut.
[11:02] We came up with a nomenclature to try and convey that as well. The term we came up with for patients with a lot of orthostatic intolerance symptoms but not enough heart rate is "postural symptoms without tachycardia." I grant you, it really needs marketing — that wasn't a roll-off-the-tongue sort of phrase. We acknowledged that this was a first effort at trying to describe this group, to acknowledge there clearly is something. It's not that we don't believe the patients, but it's without the tachycardia criteria. We're certainly open to better names, but the concept is important: there can be something there without that tachycardia.

[11:41] Dr. Linda Bluestein: Yeah, I think it's really important. And I think you hit the nail on the head. I definitely have had patients that have gone to some different places, and I'm thinking of one particular patient that was diagnosed with POTS and then went back to this center and had the tilt table test again, and they told her, "You no longer have POTS." And her symptoms were no different — in fact, she was still really miserable. I explained, and tell me if I'm wrong about this, that that's a snapshot in time. That's how your cardiovascular and autonomic system was behaving on that particular day. And I feel like it can be challenging because people probably vary a lot day to day as well.

[12:22] Dr. Satish Raj: Yeah, there's absolutely day-to-day variability, there's time-of-day variability. We've published a couple of papers — well, we published a paper and there's another abstract being presented next week at the American Autonomic Society meeting with data from our autonomic lab — where we know that there's time-of-day variability. In the morning, first thing, the standing heart rates are a bit higher, the supine or lying heart rates are not. And so the orthostatic tachycardia, the difference, tends to be higher in the morning, and that decreases by late morning and certainly into the afternoon. Being assessed first thing in the morning is worth a few beats per minute compared to if your clinic is in the afternoon.
[13:04] Now, what I would say about your patient situation — one of the questions is what was the diagnosis of POTS based upon. If it was, "We took your history and we think this sounds like POTS, let's get the test," the patient may not have met the criteria for POTS to begin with. It was more, we think this should be looked into. Versus, we did orthostatic vital signs in clinic. And I want to be clear, a tilt table test is not an absolute necessity for POTS diagnosis in everyone. A good lying and 10-minute standing test — if you shoot over the bar of heart rate, if you will — that's good enough. But one of the other abstracts we're presenting is a more detailed comparison of tilting versus standing in the same cohort of patients. It's worth a few beats per minute. If someone on a stand test has their heart rate go up only 10 or 15 beats per minute, it's very unlikely that they'd come back a few weeks later for a tilt and suddenly have an increase of 35 or 40 beats per minute, unless something has fundamentally changed in their physiology. But if someone on a stand test is at 28 or 29 beats per minute increase, it's quite possible that because of day-to-day variability, on a different day they may be just over that threshold. And obviously lots of things affect this — hydration status, time from medications, medications in general.
[14:38] So I think we have to be a bit flexible about it. If someone meets POTS criteria based on symptoms and heart rate, and on a different day, on a different assessment — especially if they've been engaging in some non-pharmacological treatments, which we can get into — their heart rate is just below that threshold, I don't think the diagnosis disappears. But it does depend on how the diagnosis was made in the first place.

[14:58] Dr. Linda Bluestein: Yeah. The diagnosis was definitely made based on the clinical picture and then doing a tilt table test, and then upon return to the same center, still having the same clinical picture. And I wasn't there when they had this conversation, so like you said, there are sometimes things that are said one way but heard another way. That's definitely another challenge. I want to make sure that we talk about causes of POTS, because it's my understanding that there are different ways that people can get to this final common pathway of postural orthostatic tachycardia syndrome. Are there multiple different causes of POTS?

[15:38] Dr. Satish Raj: I think so. One of the challenges is that in most people, it's hard to determine the exact cause. We have sort of inferences. But I think most people that treat a lot of patients would argue that it's not one very specific thing, but a heterogeneous mixture of different pathophysiologic mechanisms.
[15:59] There are two sisters, twin sisters, that have a genetic mutation in a norepinephrine transporter gene that causes their POTS. Those are perhaps the only two people where I can be 100% sure that we know what caused their POTS. In most people, it's tougher. Post-viral seems to be a common descriptor. We've done a study that we've often colloquially referred to as the Big POTS Survey. It's an ethics-approved study out of Vanderbilt, something that I started shortly before I left there, and it's still ongoing. It's been done in partnership with Dysautonomia International and distributed largely through their social media platforms. Right now we've had well over 10,000 patients touch it. It has challenges — we don't know who the patients are necessarily, we're taking their word for everything they tell us because it's not something we verified in clinic. But it has strengths as well. The main strength is it's much more democratic than data we collected at Vanderbilt or data that my colleagues at Mayo would collect at Mayo, because obviously not everyone can get to Mayo or get to Vanderbilt. There are a lot of barriers and challenges depending on where you live and your insurance and things like that.
[17:20] When we looked — and this was probably when there were about 5,000 people, the first paper — we looked at what people said about what happened. One of the questions was, in the 3 months before the onset of your symptoms, did something happen? We had a laundry list of things they could choose, and the most common answer was no, which isn't to say nothing happened — it's that nothing jumped out at them as being unusual. But of the people that said yes, 40% reported a viral illness in the 3 months before the onset. I still remember one patient early in my time at Vanderbilt that insisted she could tell me almost to the minute when she developed her POTS — she was at a picnic, feeling well, and all of a sudden became really ill and was never the same since. I suspect that even pre-COVID, this was a dominant cause of this type of illness.
But there are certainly other triggers. People have found different bits of pathology in different cohorts, not necessarily in everyone. Some people have had issues with peripheral neuropathies. There was a very elegant and hard-to-do study published in the late '90s by Jieroas Jacob and colleagues out of Vanderbilt, before I was there, where they actually used segmental norepinephrine spillover techniques — techniques to look at sympathetic nerve release of norepinephrine. They looked at different parts of the body as opposed to just the whole body and showed that in some of the POTS patients there seemed to be less release of this neurotransmitter from the sympathetic nerves in the legs, suggesting there may be less sympathetic squeezing of the legs, and that may be part of the problem. That's the basis of what's often referred to as neuropathic POTS.
[19:20] There are some people — and I think it's a fairly small group — that just release a lot of sympathetic activity; their sympathetic nerves fire like crazy, like their brainstem is just causing it to fire. There's obviously a reason somewhere, but not an obvious reason that we can pick up. Some of the work we did at Vanderbilt was really focused on blood volume and blood volume regulation. We found that a majority of patients, when we formally assessed their blood volume, seemed to have a low blood volume. That's actually the basis of some of the treatments that we use. One of the consequences of that is that it secondarily increases sympathetic tone as a response mechanism, and that can contribute.
[20:01] So there are different physiologic or pathophysiologic mechanisms. The challenge is that some people want to say, "I have this type of POTS or that type of POTS," but the truth is these mechanisms overlap in the same individual. I'm a big fan of Venn diagrams. People think of these as discrete things, but they're actually a series of overlapping Venn diagrams. These are features, and if you can figure out that your patient has this feature or that feature, there may be treatments you'd be more likely to use that may be helpful. Although that's largely clinical experience-based — we don't have trials on, you know, you have this feature, so we're going to test this drug. That may be where we want to go, but we need some more basic trials. We're starting to see some initial treatment trials, but we're way behind things like myocardial infarction or stroke or hypertension in terms of having big trials and good data to say this works.

[21:03] Dr. Linda Bluestein: And what about structural causes? When I was doing some reading, I came across some papers about problems with pelvic veins, upper cervical instability. Do you think there are structural causes of POTS?

[21:18] Dr. Satish Raj: Probably. There's increasing interest in venous structures. The person that put me onto that years ago was a guy named Peter Rowe, a pediatrician at Johns Hopkins who's been in the chronic fatigue syndrome, ME/CFS space for 30 years. He and his colleagues had found some patients with what he described as pelvic veins that look like Medusa's head — they're just all over the place. That can certainly lead to a lot more venous pooling. There's a small case series suggesting that embolization, where you get rid of some of these excess ectatic veins, helps. The truth is I'm not entirely sure how common that is. We've actually embolized on a couple of occasions, and in the patient I remember best, some of the pelvic pain she had improved, but her orthostatic intolerance didn't improve that much. But there's probably a spectrum in terms of what gets better and how much.
[22:27] It's worth noting that a not-insignificant number of patients I see have a diagnosis of endometriosis. These are young women, typically our patient population, and they certainly do get endometriosis. But the other possibility is that the pain attributed to endometriosis could be from pelvic congestion, and there's potentially a different treatment.
[22:57] More recently, there's been more interest in things like May-Thurner syndrome, where you can get venous compression on one side. I've heard a recent talk from Peter Rowe, and one of the things that may contribute is that it can actually lead to ectatic veins because you develop collaterals to deal with the venous obstruction, and that may be part of the problem. In the pediatric group, they talk a lot about median arcuate ligament syndrome, or MALS, which involves a compression further up in the gut. How much that's a venous issue versus a nerve issue — like the celiac ganglion itself is getting compressed — is less clear, because if it's nerve damage, that's less likely to be responsive to things that alter the flow issue. I've seen that a lot less in the adult world, and I'm not sure if that's a growth issue or whether they present at an earlier stage.
Craniocervical instability is another interesting issue, and it's obviously important in the hypermobile world. There's no doubt that some people can have bones that slide. I've certainly seen X-ray images showing more movement than there should be. Where the data is less clear is on what symptoms that's contributing to. Is it contributing to autonomic symptoms? Should there be other neurological symptoms if you're actually having significant compression? And the most important question is: if you were to try and stabilize it, does that improve the symptoms? Fixing craniocervical instability — now we're talking neurosurgery, it's not a trivial matter. And that's where I think the data is lacking.
[25:23] It's certainly an area of interest. People are doing it — not widespread, but some neurosurgeons are doing it. I think it's critical that when things like this are being done, they be done in the context of research studies or at minimum registries where we can get follow-up information to try and figure out what gets better. Does anything get better? And if so, what gets better? If you have paresthesias, does that get better? Does your heart rate regulation get better? That's the challenge in terms of saying, yes, you should go and try and get this stabilized. Obviously, if it's so unstable that someone's concerned it's going to slide and transect your spine, that's a clear neurosurgical indication. But the issues we're dealing with are usually more subtle. The patients clearly have a lot of symptoms, and there's some instability at the critical junction. The question is, is one causing the other? And if we fix the one, will that help the other?

[26:32] Dr. Linda Bluestein: Definitely. And we've discussed upper cervical instability a lot on the podcast. Just so people don't panic, there are a lot of people that have mild upper cervical instability that can improve through physical therapy and a variety of other techniques. But if you're on that end of the spectrum where you need a surgical intervention, now you're talking a much bigger procedure. And I agree with you 100% that a registry would be so beneficial to really be able to tell how beneficial or not these surgeries are and for individual symptoms, because it is such a massive undertaking. So that would be very, very helpful.
[27:21] What about hyperadrenergic POTS? You hear people talk about that a lot. There are maybe different takes on that, but of course that would also change the treatment approach if a person's blood pressure, for example, is high as compared to if it's on the lower end of things.

[27:37] Dr. Satish Raj: Absolutely. I'll take a step back and just say I dislike subtyping, as I mentioned earlier, because depending on how you define it, these can often overlap. I still remember one of my earlier American Autonomic Society meetings, and there was a session on POTS. The group out of Mayo in Rochester — a very highly productive research group — had two abstracts back to back on POTS. One was on hyperadrenergic POTS and the other was on neuropathic POTS. When chatting with the people that presented the abstracts afterwards, there were some patients that were in both studies. What they did was perfectly honest — they described who they studied and the criteria were based on certain specific test results. Hyperadrenergic POTS was probably based on standing norepinephrine levels and maybe based on blood pressure response from lying to standing. Neuropathic POTS was probably based on abnormal sweat testing, which is mediated by the sympathetic peripheral nerves. What it points out is that these aren't mutually exclusive terms.
[29:00] But I do think the features are important and can guide treatment. The challenge with these terms is that there's not a generally accepted definition of what they mean. For example, orthostatic hypotension has a clear definition: a drop in your systolic blood pressure by 20 millimeters of mercury, or a drop in the diastolic by 10, with a caveat that if you have a lot of baseline hypertension, the threshold rises to 30 over 15 millimeters of mercury. But for hyperadrenergic POTS, if you look at different papers, everyone uses a slightly different way of deciding. Some people focus on plasma norepinephrine levels on standing — norepinephrine is the neurotransmitter in the sympathetic nervous system, and it's a biochemical marker you can infer from, assuming someone didn't have a vasovagal reaction when they were standing, because if that happens, your adrenal gland sends out a bolus of norepinephrine and epinephrine. Other people focus on blood pressure — if it goes up more than 10 millimeters of mercury from lying to standing rather than dropping, some say that's a marker of a hyperadrenergic state; some say it should be 20 millimeters. So we don't actually have widely accepted criteria.
[31:15] Having said that, in clinic there are some people that I do think are very clearly hyperadrenergic, where it's severe enough that I would actually try to target that directly with central sympatholytic drugs — drugs that work at the brain or brainstem level to decrease sympathetic outflow. And I want to be clear, this is a minority of my patients. The reason it's a minority is that these drugs have all been on the market forever; they all started life as antihypertensive agents and are hardly used now, mainly because there are much better-tolerated antihypertensive drugs. These drugs are clunky — they work mechanistically in a specific targeted way, which is why we want to use them, but they're blunt instruments. If I give them to the wrong patient, or if I give too much even to the right patient, they'll feel miserable because they work at the brainstem level. I can flatten someone out like a pancake if I give too much. So you have to be very judicious about who you're giving it to.
[32:27] What I've come up with — and this is largely unpublished in terms of the approach, though we're actually trying to put together a small case series — is that there are some key features that cluster together and seem to identify people that respond. One of them is patients that wake up at night with their heart racing. Fundamentally, the P and the O in POTS are postural and orthostatic — these are people that usually have their heart rates jump up when they're vertical and certainly when they're exerting themselves. But if they're asleep, none of those things should really be true. Yet there are people who will say they go to bed and a few hours later they wake up with their heart racing — not that they wake up to go to the bathroom and start thinking about things, but they wake up and their heart is already racing.
Another feature that a lot of these people will have is what they describe as a hair-trigger temper. They'll often couch it by saying, "I'm really a nice person, but things will just set me off." Often their partner or other family member will verify that as well. And some will actually just describe feeling revved up all the time, like they can't seem to get calm. Not surprisingly, many of these people have been diagnosed or treated for anxiety, with or without success, based on some of these symptoms. All of those in my mind are consistent with something not peripheral — something that just rapidly increases their sympathetic tone. And so my go-to drug for that constellation, after warning patients that this could make them feel horrible, is methyldopa.
[34:24] This is a very old-school antihypertensive drug. It's still a correct internal medicine board exam answer for drugs you can safely give pregnant women with hypertension. In most centers it's not very commonly used anymore, and in fact many of my U.S. colleagues are telling me they're having trouble getting it now and have switched to other central sympatholytics. The key with methyldopa is it's blunt. I start at a low dose. I start it at night because fatigue is the main side effect — if you're going to be tired, better at night than during the day. We start low and sometimes have to titrate up at night, and sometimes we only need to use it at night. Just by settling things down at night and improving sleep, that helps enough during the day. But then I have other patients who tell me that at some specific time in the morning, their symptoms come back with a vengeance, and that's usually a trigger that they need another daily dose. It's typically a twice-a-day drug. I've occasionally had to dose it three times a day, but sometimes the nighttime dose alone is enough.
[35:41] I will always tell people this is the Marmite of drugs. You know what Marmite is? My wife is British — it's a yeast-based savory spread that's popular in England. There's a cousin of it in Australia called Vegemite that's a little bit different.

[36:00] Dr. Linda Bluestein: Yes, I have heard of that.

[36:06] Dr. Satish Raj: Their entire ad campaign for several years is entirely based on the fact that lots of people hate it — it's a niche thing, and the punchline is either you love it or you hate it. I was giving a talk last week and I was trying to pull in a little video clip. The one my wife told me not to use was of a woman who was breastfeeding a baby, and toast had popped up and she put it on a plate and then used a little squeezy Marmite bottle — it was actually advertising the squeezy bottles — and with one hand she put the Marmite on and took a bite, and all of a sudden the baby stopped feeding, pulled away, looked at her, and then projectile vomited at her for about 10 seconds.

[36:49] Dr. Linda Bluestein: Oh no.

[36:51] Dr. Satish Raj: And remember, these are the people trying to sell you Marmite that are putting this ad out.

[36:54] Dr. Linda Bluestein: Right.

[36:55] Dr. Satish Raj: But the whole point is that methyldopa — and I think most of the central sympatholytic drugs are like this. The people that respond to it, I've had more of them tell me this is the best drug they've ever been on for anything. But if you're not in that right group, you will hate it. So this is where there's a lot of things we do generically for POTS, but this is one of those more subtle, personalized characteristic things. And it's not based on the label of hyperadrenergic POTS, but it's based on specific characteristics that do seem to predict response to treatment.
Let me say that everything I've said over the last several minutes has no objective trial data — this is a clinical experience thing. At some point we'd probably want to study this, but this gets into the difficulties of arranging studies in subtypes of disorders where the initial studies are difficult to begin with. But hopefully we'll get there.

[37:57] Dr. Linda Bluestein: Yeah, that absolutely makes sense. We are going to take a quick break and when we come back, we are going to dig into one of the things I've been really dying to ask you about. I think I've heard you say that people with POTS feel faint, but people with POTS usually don't faint. And I want to ask you about vasovagal syncope or neurocardiogenic syncope. I know they're not the same thing, but we want to talk about that. And we're going to talk more about treatment options. So we'll be right back.

[40:05] Dr. Linda Bluestein: Okay, we are back with Dr. Raj talking about POTS and other forms of dysautonomia. I believe I've heard you say this at a conference, but I just want to clarify — if people with POTS feel faint, or if they do faint, or if they can do both. What are your thoughts on that?

[40:24] Dr. Satish Raj: The point I've tried to make at several meetings is that POTS is fundamentally not a fainting disorder. It's fundamentally a feeling-faint disorder. One of the things that really drove this home was one of my first studies at Vanderbilt. We were looking at blood volume regulation and fluid shifting in response to tilts. We were doing 30-minute tilts and we had a cohort of patients with POTS and healthy controls — Vanderbilt grad students at the time. The POTS patients had a symptom rating every few minutes where we'd ask a series of symptoms. That was actually the very origin of what eventually became the Vanderbilt Orthostatic Symptom Score, to simply track orthostatic symptoms.
[41:08] One of the things that was interesting is that the healthy control subjects were pretty much asymptomatic. Every once in a while someone would get a little bit symptomatic, then they'd faint, and then be censored out of the data, and the group was largely asymptomatic again. In contrast, the POTS patients were symptomatic almost from the beginning, and they would tell you they were going to faint, and they kept telling you for almost 30 minutes. When we looked at the data, actually a higher percentage of the healthy control subjects did not complete the 30-minute tilt than the POTS patients. So more POTS patients made it through the 30-minute tilt even though they felt miserable that whole time. That's the point — it's a mistake to think of POTS as a fainting disorder.
[41:49] Having said that, probably about 20 to 30 percent, depending on the series you're looking at, of POTS patients will faint, and the mechanism is usually a reflex faint or vasovagal syncope. Does fainting mean you don't have POTS? Well, the fainting wasn't necessarily from the POTS — it gets a little more complicated because one can actually contribute to the other. But most POTS patients don't faint.

[42:16] Dr. Linda Bluestein: And I want to clarify — what you were saying is that if the control subject fainted, then you removed their data. When you say they didn't survive, you don't mean that they died.

[42:24] Dr. Satish Raj: They didn't survive the tilt — they didn't make it through the 30 minutes. Everyone, I promise you, was alive at the end of the study. Tilt table tests do not kill people.

[42:26] Dr. Linda Bluestein: I'm glad we clarified that. Although I imagine tilt table tests are pretty miserable, especially for 30 minutes if you feel like you're going to faint the whole time. That's definitely tough.
[42:53] I want to make sure that we spend plenty of time on treatment options. You mentioned methyldopa, and I think it was really valuable how you were sharing how you might start with a bedtime dose and that you may or may not add in daytime dosing, and that you start low. Are you able to share a number for the average patient — how low you would typically start?

[43:23] Dr. Satish Raj: Every patient I start on methyldopa gets 125 milligrams at bedtime, which is either one pill or half a pill depending on how your pills are constructed. It's a pretty low dose. In theory you can actually go down to half of that if you don't tolerate it. But usually the problem is that's not enough. I'd rather start at the not-enough and go up than hit people with so much that they feel miserable for a different reason.

[43:51] Dr. Linda Bluestein: Sure. And could that waking up with a racing heart rate be caused by sleep apnea?

[43:59] Dr. Satish Raj: Less likely sleep apnea. When I was at Vanderbilt, we actually did a series of studies trying to understand the sleep issues in POTS. Starting with questionnaires where lots of people describe sleep problems, we did actigraphy-based studies where clearly their sleep wasn't as good. And in a cohort of, I think, 18 or 19 people, we put them through formal sleep studies. I think one person had some apnea. Most of what we saw was insomnia. And there are actually two types of insomnia — there's the "I can't get to sleep" and there's the "I wake up after several hours and I can't get back to sleep." Some patients have one or the other, and some have both. But that's actually the main problem. There may be restless leg syndrome seen in some folks as well, and that has some treatment approaches.
[44:50] The challenge is understanding the cause of this insomnia. If you have obstructive sleep apnea, absolutely I recommend using CPAP and other treatments for it. I used to wonder whether this was related to a REM cycle issue. In older patients with some of the neurogenic disorders, such as multiple system atrophy — a very different demographic than my typical audience — they can get something called REM sleep behavioral disorder, where during REM sleep, when your brain is active but things are supposed to be quiescent, there's a breakdown. Some people can have very vivid dreams, act out in their dreams, sometimes physically hit their partners — not intentionally — while asleep. Sympathetic tone can increase with that, so heart rates and blood pressures can change. Maybe that's still relevant here, but we've taken a more pragmatic approach of trying to target the sympathetic tone directly, and that seems to help other things as well.

[46:14] Dr. Linda Bluestein: So let's talk about some other treatment options. Let's say there are some physicians who listen to this podcast, and an internal medicine physician wants to help treat a patient's POTS — especially with COVID, we know that there are more people now with POTS than there have been before. Can you go through the different steps of treatment options that you would approach in that kind of a patient?

[46:37] Dr. Satish Raj: The foundation of treatment is non-pharmacological, and then we layer on pharmacological therapies on top of that. It's rarely a "this or that" situation — usually it's a "this and that" situation.
Our non-pharmacological treatments are largely based on what we think is the underlying problem. In most people, the heart rate is a response. One of the common features that has been seen by different groups — Mayo has reported it, UT Southwestern has reported it, we've had data at Vanderbilt and now in Calgary, and it's been reported in other disorders as well — is that patients seem to have a low stroke volume. For the patients out there, stroke volume is a fancy way of saying that every time your heart beats, a certain amount of blood leaves — it pumps a certain amount of blood with every beat. Add that up for a whole minute and we call that cardiac output, which is largely made up of stroke volume and heart rate. If you need more blood, your muscles are requiring more blood in a minute, and if your stroke volume is low and you can't increase it, the only way to increase cardiac output is by increasing the heart rate. That's how these two things are related.
[47:56] We found that the stroke volume is low in POTS patient cohorts, measured repeatedly by many groups. Part of the assumption has been that maybe that's the underlying issue and the heart rate is a response to it through the sympathetic nervous system. So strategies have been aimed at trying to improve that.
[48:19] One of them is to try to increase the blood volume — the liquid part in particular. This was one of the interests at Vanderbilt. When we objectively measured blood volume, about 70% had a low blood volume. But this is hard to measure precisely, and it generally involves nuclear medicine tests that aren't always easily accessible. It's common enough, though, that we try to treat it non-pharmacologically in everyone by trying to get people to hold on to more fluid.
[48:54] So the first part of the strategy is to drink more water. I try to get all my patients to drink at least 3 liters of water per day. Almost all my patients can do this. The ones that can't are a minority with major gut issues that limits them, but most patients can do it. But you have to try — if you're drinking when you're thirsty, you're not going to get there. The approach I've taken is to get patients to have a water bottle. By a water bottle, I'd analogize to NFL football teams — there's a saying that if you have 3 quarterbacks, you don't have a quarterback. I don't want people to have a drawer full of water bottles. I want them to have a dedicated water bottle that they love. When there's a family portrait, I want the water bottle in the picture. I want people to think it's been surgically sutured onto their hand because it's always there. If they come to clinic and I ask them if they have a water bottle and they say yes, my next question is, where is it? And if they say they left it in the car, that's a fail — I want that water bottle to be so important to them that they keep it with them all the time. When I go see my doctor, I don't leave my glasses in the car. I want the water bottle to have that same status. With that, honestly, most of our patients can do it. And 3 liters is a floor, not an aspirational target. In the summer when it's hot and their requirements go up, that might increase. But 3 liters is what I've said.
[50:26] The other advantage of having one water bottle is that it has one size. You can figure out how many of those bottles you need to get through the day, and you don't have to add up a little bit of this and a little bit of that. So that's fine — you're going to pee out most of that water, but the idea is it's probably good for you. It flushes out the kidneys a bit and allows them to hold on to whatever they want to hold on to. But one of the big predictors of what the kidney holds on to is the sodium load. So we want people to take in more sodium so their kidneys hold on to more sodium, and the water will follow and they'll retain the fluid.
[51:03] And until fairly recently, there wasn't good data that this worked, even though doctors had been giving this advice for a long time. But we actually did a study at Vanderbilt — one of the last big studies before I left, NIH-funded — where we brought patients with POTS and healthy control subjects into the research unit at Vanderbilt for 7 days, twice. During one phase, we fed them a very low sodium diet — we targeted 10 milliequivalents. During the other phase, we put them on a high sodium diet. For 6 of those 7 days, we did nothing besides let them eat because we wanted to get them into sodium balance. Then at the end, we analyzed a bunch of things. We formally measured blood volume in both phases. We looked at the standing norepinephrine levels. We looked at the orthostatic tachycardia. And we tried to track symptoms.
[52:22] What we found is that increasing the dietary salt intake did what we thought it would do — it increased the plasma volume, the liquid part of blood. We only did this for a week, and the red cell volume didn't change, not surprisingly. But the blood volume increased, and it was all because of the liquid part. We noted that the norepinephrine level on standing decreased — it went from ridiculously high to just high. It didn't normalize fully, but it improved a lot. And one of the important things about that is that I sometimes get told, "I don't think I should be doing that because I have hyperadrenergic POTS." These norepinephrine levels were high enough that in some studies these people would be considered hyperadrenergic POTS, and they improved — their norepinephrine went down when we gave them salt. It didn't go up. And the orthostatic tachycardia, the heart rate increase, also decreased. We didn't normalize people — there's more to it than blood volume and salt — but we made them better, and the symptoms seemed to improve as well.
[53:29] So from a practical point of view, using the combination of the Heart Rhythm Society position statement on POTS from 2015 and the Canadian Cardiovascular Society guidance, about 10 grams of sodium is recommended. We don't have great data on the exact amount, but 10 grams is in the range of what people are recommending. The challenge is, how do you figure out what 10 grams is? I can't figure out myself how to add up all the little bits of sodium I'm eating, so I can't teach my patients to do it that way either. The approach I take is to say, a teaspoon of salt is about 5 grams. So basically we're trying to get people to take an extra 2 teaspoons of salt a day. You could take it all at once and just chomp on it, but that's really the hard way to do it.
[54:22] What I ask people to do is take a couple of teaspoons of salt, put it into a container — a small bag, doesn't matter what it is — and instead of shaking salt on from whatever random source you have, add it from that container. That way you roughly know how much you're getting in. Someone could argue about how big a teaspoon is, because while teaspoon is a formal measurement, most of us use whatever we have in the kitchen. But the truth is it doesn't really matter — this is a horseshoes and hand grenades sort of thing. If you're close, we want to get you close. You don't have to be really precise. The whole idea is get the sodium in, pull in the fluid. This amount of sodium doesn't typically affect the plasma sodium much — it may go up by a point or two, but I've never seen someone get hypernatremia from this because the whole idea is that you're trying to bring the fluid in with it, so the concentration shouldn't change much.
[55:20] If someone does this properly and they were on a low sodium diet to begin with, they will retain fluid. We want that in the bloodstream, but it's not just in the bloodstream — it's throughout their body. So they may actually feel a little bit of tissue edema. That may not be a pleasant thing, but it's a good thing. And they may gain a little weight — by a little, I mean a few pounds, not 20. If you retain a liter of water, that's a kilogram, a couple of pounds. All of that is par for what we're trying to get done here.
[55:50] The truth is I'm very prescriptive about how I get people to take their salt and water. But I've had many patients come back and tell me with sometimes surprise how noticeably better they feel. And the thing is, everyone I see has probably already been told to take more salt and water. But when I tell it to them in this more prescriptive way, they still notice a benefit. How you do it, with the practical "do it this way," actually can make a difference as opposed to just saying, "Try and do better." Telling people to do better doesn't help unless you give them a practical strategy.
[56:26] So that's all about increasing the blood volume, filling up the tank more, and hoping more blood gets back to the heart. But the next part of the issue is that our patients typically, with the exception of those with tachycardia at night, aren't that symptomatic with their lightheadedness or palpitations when they're lying down — it's when they're standing up. What happens when we stand up is that fluid shifts. Fluid that sits in the chest where your heart is, some of it shifts down to below your chest where your heart isn't. That's probably a big contributor to the low stroke volume, because the heart can't pump out blood that doesn't come in. So the strategy is to get less of that blood shifting, and that's where compression garments come in.
[57:06] I've had a graduate student — who's now graduated and is now a medical student — named Kate Bourne, who's done some excellent studies looking at compression in POTS. Her first set of studies, published a few years ago in the Journal of the American College of Cardiology, was in our research lab where we got a neoprene and Velcro segmental compression suit and brought in patients and tilted them 4 times in one morning — 4 ten-minute tilts. These were heroic patients to put up with that. In each tilt we had a different compression configuration. The extremes were no compression versus full lower body compression — abdomen, thighs, legs. What we found was a beautiful dose response. Full compression blunted the heart rate increase on tilt and improved symptoms compared to no compression. Abdominal compression was almost as good as full compression, and calf compression was almost as useless as no compression.
[58:02] So when people say "get compression garments," the gap is that I think doctors say compression garments, and patients go and get DVT socks.

[58:11] Dr. Linda Bluestein: Right.

[58:11] Dr. Satish Raj: And most say it did nothing. But that's because that's not where the fluid goes. There are some very elegant studies using segmental bioelectrical impedance to look at fluid shifts, and probably about 70% of the fluid is actually in your abdomen and pelvis. In those with pelvic congestion, probably more. About a little under 20% is probably in your thighs, and a little under 10% is in your calves. So the problem is you're squishing in the wrong place. It's like the old story about the bank robber: why do you rob banks? That's where the money is. If you're squishing but there's nothing to squish out of there, it's not going to help.
[59:00] So we actually recommend ideally full-on tights — high-waisted tights. You want to get that whole area compressed. I used to prescribe a lot of medical-grade compression tights. What I now tell people is to go to a sporting goods store and purchase high-end athletic wear like triathlon tights or high-end runner stockings. The trade-off is that they're not as tight and maybe not quite as effective, but they're more comfortable for that reason. And the added thing I never considered earlier in my career is that they're more fashionable. I am of a generation where tights were considered underwear. My daughter disagrees — that's what she will wear. And if you're going to wear tights, you might as well wear something that's not unattractive. The truth is my daughter is closer to the demographic of my POTS patients than I am — a lot of the POTS patients I see are teenagers, early 20s, early 30s, people that grew up wearing tights. And the best tights in the world don't work if you don't wear them.
[1:00:06] The challenge is that even in Calgary, where we're known for cold weather, patients complain that in the summer they overheat and don't tolerate heat well, and so they have trouble with the tights. Our backup plan, which until very recently was based on no evidence, has been to use body-shaping garments like Spanx or compression bicycle shorts. If you can't compress fully, target it to the area of most benefit — the abdomen and pelvis — and leave the legs with more skin exposed so you can regulate your temperature better, but you still get some of the benefits of compression.
The data hadn't been there until Kate did follow-up studies during COVID looking at commercial compression garments. We designed a study where we sent monitors to people's homes with instructions on how to do orthostatic vital signs themselves and send us the data. We did it before and after putting the garment on in the morning, and before and after taking it off in the afternoon. What we've shown is that commercial tights help lower the upright heart rate — it's worse in the morning, but there's a significant effect that persists for hours, working into the afternoon. That paper has just been accepted for publication and will be coming out in the next few weeks, showing that commercial garments work, not just the study garments we used in the lab.
And maybe more exciting, we actually have a study that has just been submitted for publication looking at abdominal-focused compression — body-shaping garments, bicycle shorts, things like that. That works too, not as effectively as full tights, but if you just look at whether it works compared to when you take it off, the answer is yes. We actually have data now that these practical commercial garments can be helpful for POTS patients in terms of heart rate response and symptoms.
So the non-pharmacological pillars so far: salt, water, compression garments. And then the fourth non-pharmacological piece is the toughest, and that's exercise. There is reasonably good data — not perfectly randomized controlled data, but the best data is probably out of Dallas, published about 15 years ago, where they did a fairly large before-and-after study of patients with a 3-to-6-month exercise program for POTS patients. They measured almost everything before and after. It was a physiologically heroic study, and what they showed was that patients that went through the program — everyone that completed it, which in fairness is not the same as everyone that started it — improved. They did cardiac MRIs, echoes, put central venous catheters in to measure pressures.

[1:03:01] Dr. Linda Bluestein: Oh wow.

[1:03:01] Dr. Satish Raj: They did micro-neurography for nerve recordings of sympathetic traffic. As a human physiology person, it was great. Most patients don't care about any of that, but they did measure the orthostatic heart rate change — patients care somewhat about that because they can sometimes measure it themselves. And they looked at the SF-36, a generic quality of life scale, and showed that everyone improved. Some a tiny bit and some a lot — I don't want to make it sound like this is the cure-all — but there was improvement, and the improvement largely related to the fact that the cardiac mass increased. So the stroke volume went up, which comes back to what we think is part of the underlying problem.
[1:03:45] Now, one of the things they did that was really clever — and I'm still a little bitter that I didn't think of it before they did — is that they noted we'd always told people to go and exercise and they came back and said they couldn't. We never told them how. And they said, okay, these patients feel miserable when they're standing up, so we probably shouldn't have them standing up and exercising. If you're a physician and you tell people to exercise, ask what they heard, what they think that means. Most people will say something along the lines of walking, running, treadmills, elliptical machines — all vertical exercise. People think of exercise as vertical. So these researchers said, no, not in the beginning. They wanted people to use a rowing machine — besides the gravity issue, you're sitting and you're low to the ground from a gravity point of view. If you couldn't use a rowing machine, and this is an issue especially with the hypermobile folks if your hips or shoulders are involved — I certainly recommend testing it out in a gym before you buy equipment, because a few people can't tolerate it. But I would say most of my patients can. Just because you have hypermobile joints that sometimes sublux, it doesn't mean it will happen on the rowing machine. But if it does every time, that's not the exercise for you. The backup plans are recumbent cycles or swimming. Now, they were in Texas where every other person has a pool in their backyard. I live in Calgary — we call outdoor pools ice rinks, and there aren't enough indoor pools. So for most of my patients, we're really talking about recumbent cycles or rowing machines.
[1:05:29] What I tell people from a practical point of view is that time and duration matter. Everyone has modified what they did in the Dallas Protocol — they call it the modified Levine Protocol, after Ben Levine, the senior scientist and cardiologist that ran that study. Everyone modifies it differently. There's a CHOP protocol from the Children's Hospital of Philadelphia on different websites, recommending starting with like 2 minutes, then going to 3 minutes and 4 minutes. The approach we've taken is to say, get to 30 minutes — which is what they ultimately recommend — but keep the load low and build up the load over time. Frequency and duration matter. They make a big point that patients need to exercise every other day to get into an aerobic training mode to really get that heart growing. I actually ask people to try for 5 or 6 days a week — not because they absolutely need that, but because life will get in the way. A lot of people have kids. If you try for 5 or 6 and miss a couple of days, you're still around 3 or 4, which is enough to get into training mode.
[1:06:40] Fairly quickly you should get to 30 minutes. But I've had people come back and say they can do 12 minutes and then feel like they're about to die. If you feel like you're about to die, stop for that day — that's not a matter of pushing through. But you messed up. What I mean by that is with the rowing machines and recumbent cycles, there's a resistance dial, and I tell everyone to turn it all the way down, make it as easy as possible. If you're burned out at 12 minutes, that means you went out too quickly. Next time, go more slowly. And the challenge is that a lot of patients are competing — against their partner, their kids, their former selves. "I used to be able to do this." I tell them to stop. It's not about pace. Get to 30 minutes. Don't worry about how slow you are. Then over time, as they keep doing this, they may want to add resistance or duration — but that's all for later. In the beginning, the focus is no resistance, get to 30 minutes, get into that habit.
[1:08:06] The challenge is that the benefits don't happen right away. When I first started doing this after the paper came out about 15 years ago, patients would come back and say, "That exercise thing wasn't for me, I didn't start getting any better." I actually called up Dr. Chi-Fu, who was leading the study, and said, what am I doing wrong? She said, well, we said everyone got better — we didn't say it happened right away. It was a 3-to-6-month study, and it can take a while. She's right. If you told me to exercise and said you'll feel better, I'd give it a couple of weeks. But the truth is it can take up to 6 weeks before patients notice any improvement. And in that time they may well feel worse. I believe that a lot of POTS patients have post-exertional malaise, and I believe a lot of them train out of it — but not right away. You have to warn patients that it's going to take 6 weeks. This is an investment.
[1:08:59] Part of that is also thinking about when to start. If you're a student, you don't want to start at the beginning of December as you're about to hit finals. You want to start maybe after finals, where if you're feeling extra miserable for a few weeks, it's not the worst time for that to happen.
[1:09:16] So exercise is the fourth pillar, and it's the one that takes the most time, but in terms of sustainability, it's important. In the beginning, we're asking patients to do things that make them feel worse. But around that 4-to-6-week point, when they start to notice improvement, I've had patients tell me they feel worse when they miss a day of exercise. Something switches. But it's a long tunnel to get there. We're asking people to do stuff without reward right away. There are lots of patients that would swear by that approach, but it's the toughest of all the things we've talked about.
So that's the non-pharmacological foundation for everyone. Obviously some people have specific challenges and aren't able to tolerate all of those things. For example, some people have so much pain sensitivity in the abdomen they can't wear compression garments. But you work with what you can work with. Most people can get the salt and water. The salt is generally best tolerated with food. Some people hate the taste of salt in food, so they have to come up with different approaches. There are certainly buffered salt tablets that can help, though I don't tend to use them as much because of cost. People can sometimes add salt water to their water bottles and drink it, or add it to hot water and lemon juice. Some young patients even do salt water shots — that's sort of like a margarita without the really good stuff. The point is there's not a right way or a wrong way to do it, but what we're asking patients to do is not to do this once, but daily. They need to find the way that works for them.
[1:11:03] And then the final layer of treatment is drugs. Depending on how severe the symptoms were and how high the heart rates were, some people want to try the non-pharmacological approach for a while and see how they do before deciding if they want to take drugs. Others say, I feel miserable, let's do both at the same time. If their heart rates are really, really high — say on standing, their heart rates are getting into the 130 to 140 beats per minute range — I've found that lowering the heart rate a little bit, taking the edge off the heart rate increase, usually has significant symptomatic benefits.
[1:11:41] Historically, I've been a big proponent of low doses of propranolol. Each pill works for about 4 hours at a time. It's a non-selective beta blocker, short-acting, and our typical starting dose would be 10 milligrams 4 times a day. If someone needs more, we can go higher, but I rarely go higher than 20 milligrams 4 times a day. The goal is not to fix the heart rate or normalize it — it's to prevent it from going as high. If instead of peaking at 130 it peaks at 115, still high, still abnormal, but patients can feel a lot better if their heart rates aren't as high.
[1:12:14] The other option — the newer, shinier option — is ivabradine. Some people prefer that. We're actually doing a study comparing the two right now to see if one is better than the other as a group. Ivabradine has some insurance and cost challenges in both Canada and the US — it's a bit more expensive — but it's certainly available, and it's an off-label use but a reasonable thing to use. There's some data out of UC San Diego that it actually is helpful in POTS compared to placebo, just like there's some data that propranolol is helpful compared to placebo. We just don't know which is better.
[1:12:45] If the blood pressure is really low — some people have low blood pressures with POTS and vasovagal syncope — propranolol or ivabradine, by taking the edge off the heart rate, can make the blood pressure a bit worse. In those patients, we may use a drug that squeezes the vessels a little bit, like midodrine. This is a short-acting pressor drug that squeezes arteries and veins, and it too works for about 4 hours at a time. We'd only dose that 3 times a day because we don't really want patients taking it at bedtime when they're supposed to be lying down. So we may individualize the drugs a little based on characteristics, but the non-pharmacological foundation is pretty universal.

[1:13:29] Dr. Linda Bluestein: And what about drugs like pyridostigmine? That seems to be more commonly prescribed these days.

[1:13:37] Dr. Satish Raj: When we were at Vanderbilt, we actually looked at this in POTS. We had an acute 4-hour study model where on a research unit, we'd give patients a drug in the morning and run the studies from 9 to 11. Pyridostigmine is a drug on the market for a neurologic disorder called myasthenia gravis. What it does is slow down the breakdown of the neurotransmitter acetylcholine, so effectively you get more acetylcholine in the nerve terminals throughout the body. We showed that in a lab-controlled setting, it can lower the heart rate a little bit — going in the right direction. The truth is it's not a very potent drug. A drug like ivabradine or propranolol will have much more potent heart rate lowering effects.
[1:14:16] A colleague in Toledo, Dr. Blair Grubb, actually started using it fairly aggressively in his clinic and then published a data dump — I think he had 300 patients — which wasn't a detailed study, but gave a general sense of liked it or not. About 60% liked it. We don't have a lot of detail about exactly why, but positive response. About 20% had to stop the drug because of diarrhea or abdominal cramping — one of the things acetylcholine does is increase gut motility. So right now, if someone tells me they're prone to diarrhea, I stay away from it. But if someone tells me they're prone to constipation, they have bowel movements every 3 days if they're lucky, this is sometimes the best drug they've had for their constipation. It's not a laxative — it's actually working at the nerve terminals to increase the signals to the gut, and it can be very effective. Generally speaking, it's a really well-tolerated drug. If you try it and get cramping or diarrhea, stop it. It'll go away. It's not going to do any long-term harm to you.

[1:15:37] Dr. Linda Bluestein: Okay, that is a lot of really great information. I want to ask one last question before we get to our hypermobility hack and wrap up. In your clinical experience, or maybe there's a study that can also inform this question — what percentage of people are able to improve their quality of life sufficiently through the non-pharmacologic methods so they don't need medication? Versus the percentage that actually do end up needing medication on top of the non-pharmacologic?

[1:16:08] Dr. Satish Raj: It's a difficult question because obviously my clinic is perhaps not a representative sample of the larger population. The people that put up with a long wait to get in here probably feel a bit more miserable than the average patient. I'd say of the people I see in clinic, the vast majority are on drugs as well — probably somewhere around 70 to 80%, maybe north of that.
Having said that, there are also people that you start on drugs, and then as they really get into the non-pharmacological approach and their exercise routine — because the exercise doesn't work right away, it takes several months and longer — I certainly have had some patients that are able to wean off drugs and are still doing the non-pharmacological treatment alone. That does happen. But I'd say the more common scenario — and I'm always intrigued when people come to me and one of the first things they say is, "I don't want to be on drugs." I actually think that's the wrong way to look at it. What they should be saying is, "I want to function better." And if they can do that without drugs, great. And if they need drugs and in the end they are better for it, then great. Most of my patients do the non-pharmacological things but still need some drugs to help them function better.

[1:17:27] Dr. Linda Bluestein: All right. So last question — do you have a hypermobility hack to share with us? Some kind of quick win for people?

[1:17:36] Dr. Satish Raj: One of the things I was concerned about when starting to see patients with hypermobile Ehlers-Danlos syndrome or joint hypermobility syndrome was that compression tights might be tough to get on and off — and they're not easy for anyone. But what some patients have told me is that they actually found that wearing them helped stabilize their joints. Once they got them on, their hip joints and sometimes their knee joints felt a little more stable with the support from the compression garments. That's not usually why I'm prescribing them, but it might be an added benefit.

[1:18:11] Dr. Linda Bluestein: Okay, very good. And before you go, can you let us know where we can learn more about you?

[1:18:18] Dr. Satish Raj: I fear to say. I avoid searching myself on the internet just because you never know what people are going to say.

[1:18:24] Dr. Linda Bluestein: And you gave us a link that we can share in the show notes too.

[1:18:28] Dr. Satish Raj: Our lab has set up a website through the University of Calgary — our autonomic lab. It lists bios and some patient information brochures that we've created and linked to on the site. And we have hopes and visions of trying to feed back to both our patient participants, our patient partners, as well as patients at large, some of the results from our studies. As abstracts and papers get published, we want to be able to put links to those there so that it can serve as a broader patient education forum as well.

[1:19:08] Dr. Linda Bluestein: That's great. So we will have the link in the show notes so that people can go there. And are there abstracts and papers there now, or is this something that's being worked on?

[1:19:17] Dr. Satish Raj: If there are, not enough. This is in the work-in-progress section at the moment. I will harass our students to try and rush that.

[1:19:24] Dr. Linda Bluestein: Okay, no problem. Well, Dr. Raj, thank you again so very much for coming and chatting with me today. I know that your schedule is very, very busy, and I really appreciate you taking the time to share your incredible knowledge and wisdom with us.

[1:19:41] Dr. Satish Raj: Well, thank you for having me.

[1:20:45] Dr. Linda Bluestein: Well, I am so glad we got to chat with Dr. Raj and learn so much about POTS and specifically how he instructs his patients with those non-pharmacologic methods. I feel like those very specific portions of those instructions are going to help a lot of people. Because while a lot of people have heard, increase your salt, increase your water, increase your exercise, the devil is definitely in the details. So I hope a lot of you found that really beneficial.
[1:21:13] And I want to thank you so very much for listening to this week's episode of the Bendy Bodies with the Hypermobility MD podcast. Help us spread the word about joint hypermobility and related disorders by leaving a review and sharing the podcast. This really helps raise awareness about these complex conditions. If you would like to dig deeper, you can meet with me one-on-one. Please check out the available options on the services page on my website at hypermobilitymd.com. You can also find me, Dr. Linda Bluestein, on Instagram, Facebook, TikTok, Twitter, or LinkedIn @hypermobilitymd. You can find Human Content, my producing team, at Human Content Pods on TikTok and Instagram. You can also find full video episodes up every week on YouTube at Bendy Bodies Podcast. To learn about the Bendy Bodies program disclaimer and ethics policy, submission verification and licensing terms, and HIPAA release terms, or to reach out with any questions, please visit bendybodiespodcast.com. Bendy Bodies Podcast is a Human Content production. Thank you for being a part of our community, and we'll catch you next time on The Bendy Bodies Podcast.