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Jill Brook: Hello, fellow POTS patients, and marvelous people who care about POTS patients. I'm Jill Brook, your hyper adrenergic host, and today we are interviewing the always so knowledgeable, so amazing physician researcher Dr. Jeffrey Boris about his recent publication on the genetic landscape of POTS in pediatric patients.

You may recall Dr. Boris from his previous episodes. He is a pediatric cardiologist and a general pediatrician practicing since 1997 and caring for patients with POTS and related conditions since 2002. He has a long, long history of impressive academic appointments, accomplishments, awards, including being named the physician of the year

by DI in 2016. He is always publishing and participating in the really important projects, like the expert consensus statements, and he is such a wealth of information about POTS and related conditions. He now has a private practice where he [00:01:00] does consulting and medical advocacy for helping get children back to school, work, and life.

Dr. Boris, thank you so much for being here today.

Dr. Jeff Boris: Hi, Jill. It's great to talk to you again.

Jill Brook: So a genetic study. What made you decide to do a study on genetics of POTS?

Dr. Jeff Boris: You know, I've always wanted to look into this and I was talking with one of our families about doing research and, and actually talking with multiple families really when I was at Children's Hospital of Philadelphia and, one of the families said, you know, what about genetic research? And I said, we have the Center for Advanced Genomics here at the Children's Hospital of Philadelphia, and I think we could probably make something work.

And so the Esther Feigenbaum foundation was amazingly generous, gave us a, a, a huge grant upfront, and I [00:02:00] went ahead and spoke with the head of the Center for Advanced Genomics, Dr. Hakon Hakonarson. And he said we could definitely do something and you know, make it, make it probably make something work.

I had seen almost 950 patients from the time that I had been at CHOP from November of 2007 through February of 2018. And so we were able to look at, we were able to recruit patients from my clinic, and then there were also a bunch of patients from my clinic who'd already had blood drawn for other reasons,

and whose blood was in the the Center for Applied Genomics biobank. So we could already go ahead and go through those data as well, which was kind of cool.

Jill Brook: Wow. That's amazing. Okay, so what is the methodology for something like this? I don't know if you're able to explain it at a level [00:03:00] that we would understand it, but...

Dr. Jeff Boris: Well, I mean, so for starting out, I mean, what you want to do is you want to look at the genetic evaluation of the patients and what's called the, the trios, right, so the patient and their parents. And then if you also can get siblings and then if there's other potentially affected patients like cousins or aunts or uncles or whatnot who have POTS, getting them in the mix too is kind of, you know, bonus, right?

But, but at least getting the trios is super important from that standpoint.

Jill Brook: Okay, so you, you would start with a POTS patient and then get a parent or two and a sibling. Well, both parents, maybe a sibling, and then maybe somebody like a cousin, if that person also had POTS.

Dr. Jeff Boris: Correct. But at minimum, trying to, as much as we could get the trios, because you wanna look at mom, dad, and kid, affected [00:04:00] patient. Right. And so, like I said, I mean we were able to recruit families from my clinic and and then like, and there were also a number of samples that were already in the biobank, about 185 actually already in the biobank, which was really interesting.

So in the end, I think we had, we had like 400 trios, which was, which was pretty amazing. I mean, I think in the, and, and then what we did was we narrowed it down to, I think about a hundred. A hundred complete families. And what we did was we did several types of assessments and, and I will

freely admit, I am not a geneticist. And so all of these things are try trying to explain all these things is a little bit foreign into me. But we did genotyping and what's called whole exome sequencing. And [00:05:00] you look at the trios, the families, and then you look at a cohort of what's called a case control cohort of 207,

in this case unrelated patients who were of European descent because you want to, because all the patients who were, all the patients whose family, patients and families were were evaluated, were of European descent. And then they also had over 4,000 ethnicity matched control subjects. And we did that for both genotyping and the whole exome sequencing portion.

Jill Brook: Oh, cool. Okay. So is it, is it something like you look at what genes are different in the people who have POTS versus the people who are the same ethnicity but don't have POTS or the same family but don't have POTS.

Dr. Jeff Boris: I think that's right. I think, and, and really what we're looking for is not just the genes, but like the specific mutations in those genes. Because you know, these genes can have multiple [00:06:00] different mutations and many of them, we don't know what they mean. Many of them have been affiliated with other, other disorders, other medical conditions, or other just findings that have been seen.

And so we could sort of look at all this, look at all that together.

Jill Brook: Right. I remember, you know, kind of going through my own genetic testing, looking at things, for example, like, Ehlers-Danlos Syndrome type things, and you get a lot of results back where they say well, you have some funky mutation here and we can give it a score for whether it's likely to make a difference or not to your life,

but we've never seen it before. We don't know exactly what it means. And there's like kind of a lot of that still that comes back so...

Dr. Jeff Boris: No question. I mean, in 2025, we know a lot more about the human genome than we did five and 10 and 15 years ago. But, but there's [00:07:00] so many genes and so many mutations that it's gonna, it's still gonna take a while, right? So you get these, these VUSs, these variants of unknown significance. And, and we don't know what it, what it means.

We need more, you know, as we say in research, in research lingo, we need more data. And I think a lot of that is observational over time and then we kind of collect affected patients and we can say, oh, this specific gene mutation does X, Y, and Z. And we're able to pretty much say that this happens most of the time, all the time, some of the time, right,

'cause just 'cause you have a gene mutation does not mean that anything's going to happen. Case in point, we all have 10 to 15 lethal mutations. That doesn't mean that anything, any of those is gonna actually cause us to die anytime soon or later, they may do nothing, right. So it's just, it's, you know, I mean, I, I, it's [00:08:00] very hard for us to be able to look at these data now and have a really good context for them and into which to put them.

Jill Brook: Okay, so we might not have, you know, definitive meanings from these yet, but, but what did stand out? What was unique about the POTS genes?

Dr. Jeff Boris: Yeah, so what we can say is that you know, we found a bunch of potential mutations over, over 5,600 mutations. But those were really not felt to be significant. But there were definitely some some variants of interest. And there were 55 genes that had what's called genome-wide significance, which means that from a statistical standpoint, it was really, really strong,

much stronger than chance that we would do this. And then there were also what's called pathogenic or likely pathogenic variants. And there were 99 of those confirmed over the two databases, but [00:09:00] there was sort of wide we call it heterogeneity, meaning just wide variability in there. So what we've found

was some, a few things. One was a collection of different kinds of gene mutations that acted on how the, how cells work. And those, and that includes how those cells join together what's called a cell cell junction, the membrane of the cell, the cell body, how they do transporter stuff, that transporter complex, which means that there are proteins within cells that move

proteins and other waste products and other important products through the cell. Adhesion molecule binding, how they stick together. Motor activity, right, so abnormal activity from that standpoint. And also some binding in what's called actin. Actin is a is a, component [00:10:00] of muscle, muscle tissue.

And so, you know, what, what does that mean? What, what could that do? We found some other mutations in what's called early estrogen response, and that's really kind of interesting, right? Because if we, if we know that female patients are way overrepresented in, in POTS. You know, in our series in our demographic series of 708 patients that was published about a decade ago it it was a three and a half to one female to male ratio.

But you know, I've seen four to one, I've seen five to one female to male. So we know that females are overrepresented. In our long-term outcome survey, our first paper that was published last summer, we also know that female patients have more symptoms for longer duration, and more severity, right. And, and then also another paper that I published a few years ago on transgender [00:11:00] patients who are transitioning from female to male, once they had the addition of testosterone as part of their transition, their POTS symptoms improved,

right. And so there, there's definitely something about sex hormones that play into this. We know that actually a, a paper that just got accepted for publication just the other day is the second paper in our long-term outcome survey, and it's our gynecologic findings. So we know that 72% of the girls and women have worsening POTS symptoms around their periods, around their menses.

And so again, hormonal changes definitely, or, or hormonal content, definitely play a role in this as well. And then some of the more specific findings, I mentioned there were 55 genes of, of interest there, and a lot of those had to do with function or dysfunction of how muscles work. So [00:12:00] contraction of the, of the fibers, the membrane

of the cells, the cellular components, the extracellular matrix, the junction of the cells, how microtubules or microtubules are these little scaffolds that, that cells build. And and both the cells themselves as well as their contents move are, are moved along like a conveyor belt. So, so all of those have been, have some initial findings that suggest that there might, that there might be some abnormal involvement from that standpoint. There's some other genes that were associated with muscular dysfunction, specifically with blood pressure regulation. Okay. And also with heart rate. Alright, so, I mean, obviously we know that that

POTS patients have abnormal blood pressure and heart rate maintenance. And so that's, that's certainly an issue from that standpoint, right. And then there were some, and then some other abnormal gene findings include a [00:13:00] whole, include a whole subset of genes associated with autism spectrum disorder,

which I find fascinating. I have some preliminary data that suggests that about probably six to 10% of the patients in my present clinic have autism spectrum disorder, which is really interesting. And I think you know, there may be some data associated with joint hypermobility and and autism as well, right?

Jill Brook: When you say six to 10% of your patients have autism, are you saying your just pediatric patients or your POTS patients?

Dr. Jeff Boris: My POTS patients. So, so my present clinic is a telemedicine only clinic. I see patients who have autonomic disorders, so I'm not doing general pediatrics. I am a pediatric cardiologist, but really I'm functioning as a pediatric autonomic specialist, and I'm seeing patients up through age 23 years.

And it's, it's [00:14:00] telemedicine. I have licenses in I think like 18 states across the US. For telemedicine, you have to be licensed in the state where the patient is physically located. So either they're, either they're in that state or they drive to that state across state lines, and then it's okay.

And so of those patients, I have seen 272 patients so far who have POTS and with, with autism the total percentage of patients is 8.8%. And really, I'm, I'm looking at my data right now and really, it's probably higher because it just makes me wonder, I have a lot of patients who have, not necessarily been diagnosed with autism spectrum disorder, but have, for example, a lot of sensory issues,

right. So, you talk about using an abdominal binder or compression stockings [00:15:00] in a patient who you know, is a, it's a, it's a non-pharmacologic approach to the management of POTS that can help to reduce venous pooling and, and help to improve blood pressure. And patients are like, oh no, I can't do that.

I don't like the way that feels. And, and it's, and it's truly a sensory thing. It's not just 'cause it makes me too hot. It's a, it's a sensory issue. And so, you know, I, I wonder do those patients have some aspect of autism spectrum disorder as well.

Jill Brook: So, okay, so my mind is just spinning here thinking that, okay, I think the autism rate is something like one in 30 some people, but it's way higher in males than females. And you probably have more females than males 'cause you have POTS patients. So this sounds like a really high rate of autism.

Dr. Jeff Boris: So, I actually have my data broken out into males and females. 6.3% of my POTS patients who are male, have autism [00:16:00] spectrum disorder. 9.2% of my patients who have POTS who are female have autism spectrum disorder.

Jill Brook: That's that's phenomenal. And so you are saying that to some extent maybe there's some sort of genetic connection because in your genetic results, you are seeing genetic mutations that are associated with autism in your POTS patients.

Dr. Jeff Boris: Absolutely. And then there's another single mutation that I also found, or that we also found that is specifically related to vestibular dysfunction, right? So, you know, we have three ways that we maintain our balance. We have these tissues in our joints that tell us where we are in space. We use our eyes to scan the horizon to make sure that the horizon is stable, right?

So visual input. And then we have our vestibular system, which is part of our inner ear. [00:17:00] And if there is mismatch between two of those systems, you can get vertigo, right. So, so when we talk about dizziness, dizziness is an umbrella term. It includes lightheadedness. Lightheadedness, is that feeling like you're gonna pass out.

Right. And, and obviously POTS patients have that. But vertigo is that feeling where you're sitting still and the room is spinning around you, or the feeling like you're on the deck of a boat and the boat is pitching side to side or back to front. And that's different from lightheadedness, right? And so vestibular dysfunction can also be seen.

And I actually have data in my patients for vestibular dysfunction as well. Vestibular dysfunction can occur after a concussion, right? So there's something called post-concussion syndrome where if you get a concussion and you feel awful for the first one to three days, but then things kind of tend to calm down [00:18:00] and, and get better.

But then you realize that you still have sort of these, this residual vestibular dysfunction. And there's also something called convergence insufficiency, where the eyes have a, have difficulty in tracking. And so, patients can, especially when they bring objects close in to read, it looks like the words are moving back and forth on the page without them trying.

And so I have data in my clinic for patients who have no history of head trauma or concussion who still have either vertigo and or convergence insufficiency, which is really interesting, right? So, so, you know, could these patients potentially have this vestibular dysfunction associated gene?

Jill Brook: Right, right, right. They don't need a concussion to get it. They were just born with it.

Dr. Jeff Boris: So, so it's, it's really, I mean, there's, there it is just kind of cool. And then there were, there were some mentioned also some pathologic [00:19:00] and likely pathologic variants. And there was one that was a subunit of a mitochondrial DNA enzyme, and there was another one that was a subunit of cardiac myosin and slow twitch skeletal muscle.

So I mentioned actin before as a component of skeletal muscle. Myosin is also a component of muscle as well, right? And so if we think about this, we know that these patients have difficulty maintaining blood pressure, and so if you have difficulty maintaining blood pressure, you have difficulty getting blood up to your brain.

If the, the brain doesn't get enough blood, the hypothalamus puts out norepinephrine and tries to crank up your heart rate and blood pressure to improve that blood flow. But if you can't squeeze your blood vessels appropriately then, you know, is this contributing as well? So I, I think [00:20:00] what these findings say to us is it's not a definitive answer, right?

It's not this is what causes POTS. These are the genetic things that we need to be looking for in every patient, end of statement. That's, that's not the way this works. What this is saying is, this is giving us a window into these are potential gene markers and now we need to look more closely

in, in the bigger picture at patients and see how many of them, number one, how many of them potentially have these gene markers? Number two, how do these genes work in these patients? What proteins come out of them that are different? And to remind your listeners right, the way genetics works, the DNA works, is

you have DNA that codes for the creation of a protein, and that protein gets [00:21:00] pieced together like box cars of a train, and then that train gets let go, and that protein does its function, whether it's locally or it's transported to somewhere else, and it does its function somewhere else. And so if you have a mutation

in a gene that causes the box car, one of the box cars in the train to be, to have a faulty axle, or the door doesn't close right then that protein's not gonna function, may or may not function correctly. I mean, you can still have a box card that the door doesn't close right,

but the protein still might work.

Jill Brook: Right.

Dr. Jeff Boris: And so what we need to do is we need to find out how these proteins work downstream. And so that's sort of the next round of of research I think that needs to be done, to prove that these various gene mutations really are mutations that are valid as potential causes from [00:22:00] a POTS standpoint.

One of the things I found really also very interesting is there were a number of collagen mutations, collagen 27, collagen seven, collagen 12, and with those, you know, don't forget a lot of hypermobile Ehlers-Danlos Syndrome or hypermobility spectrum disorder patients are represented as patients, you know, who have POTS as well.

Jill Brook: Okay, so the findings of this study are a little bit to me feeling like the findings of, did you see that study by Dr.

Artur Fedorowski and his group? It was the protein proteomics profiling where they looked at different proteins in the blood and what was different in POTS patients about the rest of the healthy controls. And just like this, some interesting things stood out. And I think in that one, the biggest difference they saw

was in [00:23:00] proteins that had to do with blood clotting, but then also some things that had to do with the heart. And it kind of seemed like such foundational work, like it's gonna be a little while till we know what this means, but it at least suggests that at the most basic level in the genes or in the proteins in the blood, you can see differences, that POTS patients are different.

Dr. Jeff Boris: Yeah, I think, I think that's, I think that's a fair statement. And you know, so it's interesting Artur Fedorowski and I actually just wrote a book chapter on pediatric POTS and inappropriate sinus tachycardia. So he and I have talked a fair bit, and I think it's funny that he looked at the proteins, the downstream proteins, right, in these where we were looking at the, at the genetic stuff.

So, you know, can we, and, and I actually, I actually sent a copy of uh, Artur's paper to Dr. Hakonarson and I said, hey, you know, this, this could totally cross link, right? And so I mean, I, I think it gives us [00:24:00] ideas and I think it gives us certainly an approach. But I think we also have to keep in mind the bigger picture.

Just because you have these proteins or these genes, how do they fit into what we think is going on in POTS, right? And so we think that many, if not most, if not all POTS patients have probably some aspect of an autoimmune cause or an autoimmune etiology. And so how do these cellular, for example, these cell cell junction, these cellular interactions, how does that relate?

What does that mean? How do a subset of autistic patients, how does that relate from an autoimmune standpoint? And actually as I talk this out, you know, I think it would be really interesting to see is there increased autoimmune disease in patients with autism spectrum disorder? Right. I, I mean, I don't know [00:25:00] the answer to that.

But we can probably look in the medical literature and sort of see if that's a thing. So, you know, I, I think we, we come at this from multiple different angles and we're sort of shining flashlights through different windows of this thing and trying to come up with what does it look like in the center.

And hopefully we'll be able, you know, and I, I'm, I'm sure in the next 10 to 20 years we'll be able to turn on the lights inside so we can see what's going on better.

Jill Brook: Yeah. Yeah. So I am, I'm guessing that a lot of people listening are saying, okay, so does this mean that POTS is a genetic disease? Does this mean that if I have POTS and I have kids, they're more likely to have POTS? Do you know the answer to that?

Dr. Jeff Boris: We published a paper several years ago on family history in POTS patients, and what we found is that in POTS patients, 14% had a family [00:26:00] member with POTS. Now, let's think about that for a second, right? If we say that pre pandemic, the estimated number of POTS patients in the United States was about one to 3 million. Post pandemic, it's three to 8 million.

So even if it's 8 million, right, if we say there's 330 million people in the United States, we're at two and a half percent ish, two and a half, almost 3%, right? And so 14% is much greater, right? 14% is much greater percentile or percentage. We also found that about 20% of POTS patients had a family member with joint hypermobility

unless they had joint hypermobility, then it was like 26%. And then 45% of POTS patients had at least one family member with an autoimmune disorder.

Jill Brook: Did you say 45%.

Dr. Jeff Boris: I did.

Jill Brook: [00:27:00] Whoa.

Dr. Jeff Boris: Right. That's huge. That's huge. Now we have to be careful here, right? Because there are, depending on, depending on what source you use, there's any from anywhere from 85 to about a hundred different autoimmune diseases. But so, so, so almost anything could be included. But if you're, if we're saying that there's that much going on, you know, that's a lot.

The, the other thing too is again, what is the background prevalence of of autoimmune disease in the general population? I doubt it's 45%. There is some thought, however, that especially now with a lot of our exposures to all kinds of chemicals in that, that have been released in one way, shape, or form, into our environment, that that in and of itself could be lowering our threshold to [00:28:00] have, for example, autoimmune disease.

Jill Brook: You know, I was, I was thinking about that. And is it that our genetics have not changed, it's just that now some genes are more prone to this because of the worse exposures? Or is it that some of these toxic exposures are actually causing some of the genetic mutations or both maybe?

Dr. Jeff Boris: So I would, I would go with the former, right? If you are a child or an adult and you're exposed to something and you have a mutation, just because you have that mutation, one of a couple things happens.

Either, either that cell is removed, right, or it dies, or it's limited in its ability to, to expand, right? All the other cells, all the other cells still have normal genetic content.

Jill Brook: Right, right, right.

Dr. Jeff Boris: Unless we're talking about exposure [00:29:00] to a, to an early, early fetus, where a, where a large amount of those cells can be exposed to that to that mutation

it's hard to believe that you know, an environmental exposure would, would necessarily make a system wide or even, even not system wide, even just an organ wide change.

Jill Brook: Yeah, that makes absolute sense. But I have to laugh 'cause sometimes when I hear about some of these genetic studies, especially when they talk about like, oh, the genetics of autism or something where it's really steeply on the rise, I feel like it's not fair to blame the gene if that gene wasn't a problem a couple generations ago.

Like clearly something, whatever, whatever we're doing in the last a hundred years with all these chemicals or something is making a difference to genetics that weren't a problem very, very long ago.

Dr. Jeff Boris: I mean, I think that's fair. But by the same token, if you, if you want to use autism spectrum [00:30:00] disorder and the prevalence of autism, autism is increasing. Part of that, honestly, is just, we're asking the questions. The pediatricians are looking for it now. The pediatricians are, are going through various questionnaires and, and, and various protocols to look for it, whereas it wasn't looked for before.

And so here's the, you know, if you don't look for it, if you don't ask, you won't find it. And now that we're looking more, sure, we're finding it more, but the numbers are higher because, because we're asking about it.

Jill Brook: And do you think that that's playing a big role in all the new POTS that's being found too? I guess it's hard to know because it seems like with COVID there legitimately is more.

Dr. Jeff Boris: I think there is, I think there is. So I, I think there's a combination, right? I think that that, you know, the SARS Cov2 to two virus is what was one of the most dastardly viruses around, just did all kinds of bizarre and strange and awful stuff to people. [00:31:00] Do I think there's more recognition. I do. Do I think there's more people who, more prov clinicians out there who have, who, who do recognize POTS or, or admit that it exists,

acknowledge that it exists. Yes. In, in fact, I would say it might even be going in some cases in the opposite direction. I would say that there are probably patients who go see a doctor and they're like oh, I'm dizzy when I stand up. And so the doctor, not knowing enough about POTS, but having heard of POTS goes, okay, we'll do simple orthostatic testing.

So have you lie down, have you sit up, have you stand up, and measure your heart rate at the one minute mark for each of those? And yeah, their blood, their heart rate increases, you know, significant amount, be it 30 points or 40 points or whatever threshold you want to use. And in the first minute, that's not [00:32:00] POTS. At minimum, that's immediate orthostatic hypotension, right. Used to be called initial orthostatic hypotension. Now immediate orthostatic hypotension.

Jill Brook: So it could actually be overdiagnosed at some point.

Dr. Jeff Boris: Correct. And so, you know, I mean, I think there's probably float in both directions. I think, you know, I, I can tell you even now

in, in, in patients in my present clinic now who they see their local physicians and their local physicians are like, nah, POTS isn't a thing, it's just anxiety. It's just the, you know, the usual garbage. And so there's those, and then there's the ones who are overdoing it, right? So, yeah, I mean, the, the good news is as of September of 2022, we have a, an ICD 10 code.

Jill Brook: Yes. I know you were part of the team that worked so hard to get that.

Dr. Jeff Boris: Yes.

Jill Brook: Yeah. So thank you.

Dr. Jeff Boris: Yeah, absolutely. Absolutely. No, I'm glad we could do that and make that happen. You know, that was, that was me and Lauren [00:33:00] Styles and, and basically made, finally, finally separated out and ICD 10 code. There was an ICD 10 code that was sort of a non-specific code for atrial arrhythmias that had included POTS.

And we were like, nope. Split it up.

Jill Brook: So now we can get good data.

Dr. Jeff Boris: Correct. So we can, we can get the data. The question is, we know, we know it's being diagnosed. The question is, is it, is it accurate? Right. And by the way I also helped make the, the code for ICD 11. So when we, when we transition to ICD 11, it'll already be there.

Jill Brook: Oh, great.

Dr. Jeff Boris: Yeah.

Jill Brook: Excellent. So, so, I know that we don't have much more of your time, but before we started recording, you had mentioned a little something about hormones that I think could be so useful for people to hear. Are you allowed to talk about your next paper yet? And what you're finding in your patients helps some of them for the for the people who have worse POTS around the time of their menstrual periods.

Dr. Jeff Boris: [00:34:00] So, sure. So, as I mentioned before our second long-term outcome survey paper was just accepted for publication and it's specifically on gynecologic findings, and it talks about a bunch of aspects of gynecologic issues in women with POTS, girls and women with POTS. So the average age of the patients in that study was about 22.

The average duration of symptoms was about nine and a half, 10 years, right? So they'd had symptoms for a long time. And what we found was 72% of the POTS patients had worsening of their, of of the female POTS patients, had a worsening of their POTS symptoms around their period. Of the ones who had worsening of their symptoms around their period, 98% of them had them either in the 10 days prior to or the five days during their menses.

Okay. And so, about 50% of our patients were [00:35:00] taking a hormonal contraceptive to help try to reduce the severity of their POTS symptoms. We don't have data as to which specific contraceptive they were taking or, or they, they were using. The use of a low estrogen containing hormonal contraceptive like Loestrin, or the use of a low estrogen containing intrauterine device IUD, like a Kyleena or a Mirena, has been helpful for a fair number of patients to reduce the severity of their symptoms around their periods.

Now that doesn't work for everybody, and I have absolutely had patients who don't tolerate the low estrogen or the very low estrogen containing contraceptive therapies. And so there are some patients who have had to go on a progesterone only or progestin only hormonal contraceptive therapy, and that does also help for those patients as well.

Again, I mean, I think that the, the thing to keep in [00:36:00] mind is that my patients were younger patients, right? The average age was about 22 and the range was probably about, you know, go, go, went up to about 30 ish. You know, would that, would that carry over to older POTS patients? Maybe.

But but at least I think, I think at least we have anecdotal experience to say that patients really do do better with the addition of hormonal contraceptives as long as the estrogen content is either low or absent.

Jill Brook: Okay. Okay, so kind of smoothing out the estrogen over the month seems

to be the

thing that helps.

Dr. Jeff Boris: I I, guess. I, I think so. I mean, obviously estrogen levels change over the monthly cycle. And we know that menarchy onset of menses or a growth spurt during adolescence, both of those are known described triggers for POTS as well. So there's, you know, and, and, and again, from our long-term outcome survey from last summer, [00:37:00] female patients have more severe, longer symptomatology than male patients.

So there's, there's definitely something to the fact that female hormones play a role in one way, shape, or form. And that again, then we go back to the genetic thing, right? And this early estrogen response is one of the subset of mutations that was found. What does that mean? I don't know. But, you know, hopefully that'll point us in a direction as well.

Jill Brook: Well, that is a wonderful, wonderful clinical nugget for, for everybody who hadn't maybe tried that trick yet. If, if they suffer from worse, worse symptoms around their period. Thank you so much. Is there anything else you're currently excited about in the world of POTS?

Dr. Jeff Boris: You know, so we have, so we have another, another paper or the third of our long-term outcomes survey papers, which is educational employment and social outcomes. And one of the things I think is just so cool [00:38:00] about these POTS patients is, and this has been described multiple times in the literature, that, that POTS patients are high achieving either academically or athletically.

And what we found, one, one of the little tidbits that we found was by age 21, 98% of the POTS patients either had their high school diploma or their GED. Now, mind you, mind you, this is in the setting of having at least one, if not multiple chronic illnesses, right? And these people just kick butt and take names, right?

I mean, they go ahead and get their high school diploma, 80% go off to college. I mean, it's huge.

Jill Brook: Yeah. I don't know the baseline statistics are on that, but I bet that, I bet 98% of the average teenage population out there doesn't get there.

Dr. Jeff Boris: Number one, and number two. Then look at it with a chronic illness, right? I mean, how many people with a chronic illness, 98, you know, get, you know, get, get their high school diploma, their GED. Oh, that's amazing, right?

Jill Brook: That's so amazing that you quantified it though, because like I feel like we've all [00:39:00] been talking about this for a long time because everybody notices this, but we've never had any data to back it up, and so maybe we were all just imagining it, but no.

Dr. Jeff Boris: No, it's, it's the, it's the real deal. So, so there's, there's that. Another thing that I think is really interesting to me in the, in the, in the setting of POTS patients is this whole vagus nerve stimulator device utilization and increasing data. Dr. Stavrakis has had a couple of papers come out with that. And then there's some preliminary data from one of the companies from from Europe that has a VNS device as well that really show not only a good benefit, but a lasting benefit.

And if we think about how these VNS devices, we think they work now, the original VNS device research was done in surgically implanted vagus nerve stimulators. Right? And what they found was that it reduced [00:40:00] two inflammatory mediators, interleukin-6 and tumor necrosis factor alpha from spleen specifically.

Okay. And so people were like, well, you know, the vagus nerve has this branch in the ear, so what if we do it externally, right? And so we're stimulating the vagus nerve externally. And if we again, go back to postulating that, you know that POTS is autoimmune and that a lot of patients have, a lot of patients probably also have co comorbid disorders, including an the autoinflammatory disorder, Mast Cell Activation Syndrome. If we modulate their immune system

by reducing IL-6 and TNF alpha, you know, is that sort of indirectly proving again that that is that that is an autoimmune disorder. The other thing that I was gonna say is I have data in my present clinic, clinical practice right now over [00:41:00] 270 patients whom I've seen in the last four and a half years.

And what I've found is 71% probably have Mast Cell Activation Syndrome and about 78 ish percent have joint hypermobility. Right? And so these are much higher numbers. I, there, there was actually there, I think there, there has been another paper that is, was published that talked about a really high number of POTS patients having MCAS. I think that made it come outta Stanford in the last year or two.

But, but this is sort of another, you know, another source that could that could do this. And so, you know, historically we used to think, eh, 10, 15% of POTS patients maybe have MCAS. Probably more. Probably more, and certainly there may be some ascertainment bias in, in the patients who are coming to see me through my clinic, obviously.

Jill Brook: But yours are also young, so they still have time to develop MCAS if they don't have it yet.

Dr. Jeff Boris: Sure, sure.

Jill Brook: Wow. Wow. Well, this is phenomenal data. I [00:42:00] mean, we so appreciate just how how you seem to always be thinking toward an eye of collecting data and, you know, getting down to the, the quantitative numbers and, and you just contribute so much to the, to the POTS literature. Thank you so, so much.

Dr. Jeff Boris: Thanks. No, I, I, I'm, it's, it's, it's gotten to the point where it's really getting, it just gets fun to sort of say, this is what we're finding, this is what is going on in these patients. And you know, I, I had to do research as a cardiology fellow, when I was a teenager and also when I was in college, I worked at the National Institutes of Health for a couple of summers and I was like, oh God, this is so boring.

This is not my thing. I wanna be a clinician. I wanna take care of patients. And once I started getting data on my POTS patients, I was like, ooh, I, I turned into a big data [00:43:00] nerd. And then the other thing, and the other thing is that I really felt like, because there were so many clinicians out there who didn't get it about POTS, that I had to put stuff out there and say, this is what we're seeing.

This is what these patients have. They've got better things to do than hang out in my clinic or anyone else's as well. This is their problem, and it's not necessarily that I'm doing specific interventions, right. I mean, there's a lot of research out there that looks at intervention, you know? There was the study that came out a little over a year ago looking at IVIG.

There was a study a few years ago that looked at Ivabradine, right. And those are interventional studies. Mine is basically with what we refer to as a cross-sectional survey or cross-sectional study, where we just look at what do these patients have going on with them and, and let's get that information out there

so that can help guide people smarter than me to figure out, okay, well how do [00:44:00] we put these together? And figure out what the heck is going on in POTS.

Jill Brook: Well, we love that we have your brain power on your, on our side, and we love that you, you keep on seemingly doing study after study. So, I know we need to let you go and get back to your patients, but Dr. Boris, thank you so much for being here. And I feel like I already need to listen to this over again and digest everything you said, but all these wonderful nuggets, all this research.

Thanks a million.

Dr. Jeff Boris: It is my pleasure, Jill. It's great talking with you as always, and I hope to talk with you again.

Jill Brook: Okay, listeners, that's all for today. We'll be back again next week, but until then, thank you for listening, remember you're not alone, and please join us again soon.