Dr. Blair Grubb - Postural Orthostatic Tachycardia Syndrome (POTS)

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Transcript

Voiceover:
Welcome to Prescribed Listening from the University of Toledo Medical Center. Each week, UTMC providers sharing insight into their medical specialty. This week, Dr. Blair Grubb.

Dr. Blair Grubb:
My name is Blair Grubb. I am a professor of medicine and pediatrics at the University of Toledo Medical Center. I also am director of the cardiac electrophysiology program and also the autonomic disorders clinic here at the University of Toledo Medical Center.

Dr. Blair Grubb:
POTS stands for postural orthostatic tachycardia syndrome, and it's a disturbance in what is referred to as the autonomic nervous system. You have two nervous systems in your body. One is called somatic, and that's the one you're used to thinking about, and it controls muscle activity and voluntary motion. And the other is called autonomic, and it controls the things you don't have volitional control over. It's from the same root as the word automatic. And is the part of the system that controls heart rate, blood pressure, body temperature, bowel motility, skin turgor, sweating, all the things that happen automatically. To understand it, you have to understand how things work normally.

Dr. Blair Grubb:
And when a normal individual stands, gravity will try to displace downward roughly a third of your body's blood volume, and that displacement occurs instantly upon standing. And so the reaction to it has to be instant. Your brain senses the displacement and then reacts to it by telling your heart to beat faster, by telling it to beat more forcibly, and by telling all blood vessels in the lower half of your body to become three times tighter than what they were. And those three factors working immediately together will push blood from the bottom part of you up to your head. It is just instant. So a normal individual can jump out of bed, jump out of a chair, do double backflips, and your pressure will stay the same.

Dr. Blair Grubb:
Once you're upright, you must maintain it. If you can't maintain it, blood will be pulled downward by gravity, more and more and more, and how you feel will be dependent on the degree of displacement and its rapidity. So if it's a small displacement of blood downward, you'll just feel kind of tired. If it's more, you'll feel like you can't think, can't focus, can't concentrate. If it's more still, you'll feel lightheaded, dizzy. More still, you'll start seeing black spots, get tunnel vision. More still, you'll pass out.

Dr. Blair Grubb:
There are a variety of ways the autonomic system can be disrupted. In postural tachycardia syndrome, something is inhibiting the ability of the blood vessels in the lower part of the body to adequately tighten. Therefore, the blood tends to pool downward.

Dr. Blair Grubb:
The brain will then respond to that by telling your heart to beat harder and faster as a type of compensation. The problem is that mechanism evolved in mammals to treat dehydration, where it works. However, here, the heart can only pump the blood it receives. And if the blood is sitting in the lower half of the body, making your heart go harder and faster is not going to be helpful. Indeed, it's going to get in the way. As it goes faster and faster, actually, the cardiac output begins to decline. You don't tend to see this phenomena while you're laying down because there's no gravitational stress and it's only while you're sitting or standing. And that's where the term comes from, postural orthostatic tachycardia syndrome. The name was actually first used by a gentleman named McClain in 1944 when he was describing these and then was resurrected by Phillip Low at the Mayo Clinic in the early 1990s, which is around the time I started working in these as well.

Dr. Blair Grubb:
So it's a type of regulatory disorder that afflicts mainly women. There's about a five-to-one ratio. They can tend to be younger, although we've seen older patients as well, and our younger patients then become old, and can be very debilitating to them. Many times, when people are afflicted with this, they are bedridden. They can barely function. Minor activities make them extremely short of breath, extremely fatigued. Their hearts will be racing. It's not uncommon for us to see a young person who when they're laying down, their heart rate's 60 or 70, but when they get up and start to walk around, it goes to 180. And at that point, it's really pumping very inefficiently.

Dr. Blair Grubb:
Many of these people feel like they cannot focus. They can't remember things. They can't think clearly. As I said, fatigue is a major one. And also, in the more severe cases, they begin losing consciousness. The compensatory mechanisms are inadequate to maintain adequate cerebral oxygenation and they lose consciousness.

Dr. Blair Grubb:
We started studying these about 30 years ago. From the very beginning, there was a strong feeling that these could be autoimmune in nature. Like most disorders, there are probably multiple causes that can put you in the same place. And if you think about parallel situations like congestive heart failure, in congestive heart failure, instead of losing the ability to maintain vascular resistance, you lose the ability to maintain contractility. And so the brain automatically increases rate and vascular resistance. So if you lose one part of the triad, you increase others.

Dr. Blair Grubb:
So we look at heart failure is a parallel. There are multiple ways to get the heart failure, but the majority are one way. And that's the case here. There are probably multiple ways to end up with POTS, but the majority, we felt, were probably autoimmune. And the reason for this is that a typical history is you'll have a young woman who's 18, 20, way of college, who gets a severe infection, oftentimes with mono, and then everything falls apart. They can't get out of bed. Everything just goes to pieces.

Dr. Blair Grubb:
That's a well-established pattern within autoimmune disorders. My wife, who was perfectly healthy, got a mono infection, and then within a week had full-blown rheumatoid arthritis. So that's a known phenomenon. A young woman poetically said to me, "I awoke in a body that was no longer my own." And also because of blood tests that tended to indicate some kind of autoimmune pathology, we were fairly confident that that was going on. The problem is the technology did not exist to do this kind of research until about a decade ago. And then starting then, several newer technologies became available that made this actually affordable because previously, it was so expensive that it was very difficult to engage in the research of much more affordable, much more easy to do, much more accurate.

Dr. Blair Grubb:
So we started looking at this in detail. In 2019, we published what I would consider a breakthrough paper, where we found that 90% of the post-viral POTS patients that we just tested had extremely high levels of autoantibodies to what are called alpha-1 receptors. These alpha-1 receptors govern tightening of blood vessels in lower extremities. So if they're blocked, they can't tighten. We also found that 50% of those patients had high levels of autoantibodies, what are called muscarinic M4 receptors. The problem with those is we don't know what they do, normally. However, we know that they're heavily in the brain and they govern dopamine release. And that may be part of the pathophysiology of the cognitive problems that people have. Since that time, groups in the University of Oklahoma and in the Lund University in Sweden have published confirmatory data finding the same thing.

Dr. Blair Grubb:
Interestingly, there is a big argument within the research field about there are several different techniques and which one is better. The Swedish group who feels that theirs is better are using human embryonic stem cells as part of the sequence. And I said, "Well, that's very nice, but that's not allowed in the United States." But the point is that no matter what technique is being employed, we're getting the same results. So we're very sure that we're on the right path.

Dr. Blair Grubb:
Now, this is not the mechanism in all POTS patients. As I said, POTS is a heterogeneous group of disorders with similar clinical characteristics, much like other syndromes, as I said, such as congestive heart failure or emphysema or something like that, where there is one cause that seems to be principal, but there are a number of other causes as well.

Dr. Blair Grubb:
And again, to use a parallel in cardiology, we have known that there are people who have hearts that barely contract, called dilated cardiomyopathy, but we also know there's the opposite extreme, where the heart is too thick. And over-contracts, called hypertrophic cardiomyopathy. They will get the same congestive heart failure symptoms. So very early on, we noted there was a small group of people that instead of their blood pressures being very, very low, they were very, very high. They oftentimes were almost a mirror image of the symptoms between them. So in the majority group, which we now call the neurogenic form, they oftentimes were severely constipated, had bowel dysmotility, didn't sweat at all. And this other group whose blood pressure were high that we call the hyperadrenergic group, oftentimes were hypertensive. Both had very high heart rates, but the other group, the small group, was hypertensive, had diarrhea, was over-sweating, was like a mirror image.

Dr. Blair Grubb:
And researchers at Vanderbilt early on discovered that this was a genetic disorder and these people were basically leaking norepinephrine, which is a kind of adrenaline, from the nerves into the bloodstream. So they were getting the same postural tachycardia, but a very different reason. Now those only constitute maybe 10% of the POTS population, if that. And indeed, looking back, we should have actually given them a different name. We should have just said, "This is a different illness. It may look like this, but it's a different illness." However, that time has passed. And so we're stuck with this term, hyperadrenergic postural tachycardia syndrome.

Dr. Blair Grubb:
And it's very important to pick those out because therapeutically, their therapy is the exact opposite of the other group. We've set criteria. I was part of the international committee that set criteria to diagnose it. And we diagnose it as a debilitating illness of usually greater than six months duration in the absence of other conditions. So again, you can't be dehydrated. You can't be taking medications that'll lower your pressures. You can't have had some other problem that's causing this. And then we also have to document the fact that you have a greater than 30 beat per minute increase in heart rate in going from being supine to upright. Now you can do this in the office, or oftentimes, there's another technique that we've employed called head-upright tilt table testing. Head-upright tilt table testing was developed in the mid-1980s at the Westminster Hospital in England by Richard Sutton and Rose Kenney, who were using it to diagnose a related condition called vasovagal or neurocardiogenic syncope.

Dr. Blair Grubb:
The difference with those individuals is their autonomic dysfunction is intermittent. So they'll be perfectly fine, healthy, happy, and suddenly, everything will turn off and their blood pressure will go to zero. Their hearts will stop and they'll fall like a tree. If they don't kill themselves when they hit the floor, then when they get up, they'll be fine until their next episode. So head-upright tilt table testing was initially being used to diagnose those individuals with this different but related condition. And actually, what happened is we... And the term for fainting in medicine is called syncope. So in the early days, we were one of the first centers in the United States to employ head-upright tilt table testing in 1988. We started being sent a lot of patients to undergo this because other people weren't doing it. In the midst of evaluating many individuals with vasovagal syncope or neurocardiogenic syncope, we started seeing these other patterns. Instead of these intermittent, sudden declines in heart rate, we would start to see people whose heart rate were very high.

Dr. Blair Grubb:
A backup mechanism that human beings have is called the skeletal muscle pump. Human beings are the only truly two-legged animals on the planet. And our center of gravity is the furthest away from our brains proportionate to body size of any creature, even a giraffe. A giraffe has a backup kind of heart pump that's higher up in the neck. And so the skeletal muscle pump evolved in humans to allow us the ability to be upright and run. And what happens is when you move, contraction of the leg muscles, and to some extent the abdominal and arm muscles, compress the venous system and propel blood back to the heart. A healthy set of legs can raise your pressure 10 points or more, and many people with autonomic disorders, unknown to them, become very dependent on this mechanism to keep them going. And if you inhibit it, they'll crash.

Dr. Blair Grubb:
Now in you, it's probably just a backup mechanism. It's there if you're up for a very long time, if you're dehydrated, if it's extremely hot out. I mean, think of surgeons who stand for 10 hours doing surgeries or guards who stand all day or whatever. So normal individuals don't need the skeletal muscle pump moment by moment. However, people with autonomic disorders do. And if you're on a table with a footboard meant for weight bearing, and you're inclined upward to between 60 and 70 degrees, the only stress on you in that position is gravity, and you're not even upright. You're at an angle. So normal individuals can stand there perfectly comfortably for hours.

Dr. Blair Grubb:
Our usual time upright is only about 20 or so minutes, but the individuals who are extremely predisposed or afflicted by this, they will experience a dramatic increase in heart rate as a system struggles to maintain their pressure without the skeletal muscle pump. So head-upright tilt table testing is also a somewhat more standardized way to do it, although it's not really necessary in all individuals.

Dr. Blair Grubb:
So if someone is totally deconditioned, let's say they've suffered some kind of injury and they've been bedridden because of that other injury for months, the loss of muscle tone will produce a POTS-like syndrome. And you'll hear people say this, like a POTS-like syndrome, because it technically doesn't meet the criteria.

Dr. Blair Grubb:
Now, one of the things that I take exception to with my colleagues is they act like these definitions, once made, were handed to Moses at Sinai. This is stuff a bunch of guys got together and over a six pack of beer argued about until we got to a consensus. You have to realize these are relative things. But also for example, we will see patients sent to us who are on medications, which unbeknownst to them, are vasodilators.

Dr. Blair Grubb:
So for example, some of the drugs used to treat benign prostatic hypertrophy are very potent vasodilators that will produce a POTS-like syndrome. So you have to make sure they're not doing something that causes that. In addition, there are a number of other conditions that can present first with autonomic problems. So for example, we've shown that patients with multiple sclerosis may first present with postural tachycardia syndrome, and that may precede the diagnosis of MS by years. In multiple sclerosis, you have breakdown of the myelin sheath that it's around nerves, and it can start anywhere in the brain. And the symptoms you'll see first are wherever it's at. And if it's in the frontal areas, you'll get emotional problems. If it's in the motor areas, you get muscle problems. But it can be in the autonomic areas too. And in those individuals, the first thing you'll see are autonomic system dysfunction. So there are other diseases that can affect the autonomic system. And we use the term POTS in a way to distinguish these idiopathic or autoimmune type people from other individuals.

Dr. Blair Grubb:
Interestingly, the ratio of women to men is exactly the same as the ratio of women to men with autoimmune problems. Women are much, much more prone to autoimmune diseases, and it's felt to be due to the differences in reproduction that occur within women. If you think about it, the embryo and fetus is a foreign body that only has half of your genetic material. And so women's immune systems have to deal with much, much more complicated issues than a man's immune system.

Dr. Blair Grubb:
Interestingly, one of the second leading causes of POTS... The first are presumed viral infections or febrile illnesses that we presume are viral. The second leading one is pregnancy, which has been a known trigger for many autoimmune diseases in women. The current theory is that in some women, fetal cells get into the mother's bloodstream through the placenta, and then those foreign bodies, which are different yet similar to the mother's cells, trigger this autoimmune response. And I think the term for that is called crypto chimerism, but those are known ways. So the fact that if this is an autoimmune disorder, that we have many more women, is not inconsistent with what we would expect.

Dr. Blair Grubb:
One of the original investigators in the field, David Streeton, who is at the University, who was at Oxford originally, but then immigrated to University of Syracuse, did a very comprehensive study of the medical literature. And you can find descriptions of these going back a long time. The problem is once you get back beyond say the 1850s, it's very hard to trust the descriptions within literature. But starting in 1874, a gentlemen named [Acosta 00:19:02] published an article called Irritable Heart Syndrome in the American Journal of Medical Sciences, which was the leading journal of that era, and described these patients perfectly, absolutely perfectly. If you read the paper, there's no doubt that he's describing these individuals.

Dr. Blair Grubb:
And then what you see is over the next almost 100 years, that there are intermittent reports of the same condition with different names. In 1919, Sir Thomas Lewis, who's widely considered the father of cardiology, published a paper where he called this the effort syndrome. And he was one of the first investigators who had a blood pressure cuff. It was invented around 1914. And so he was able to measure blood pressures, whereas previously, they could only measure heart rates.

Dr. Blair Grubb:
Again, what astonished me when I read this is he described these people perfectly. He even postulated that the mechanism was increased venous pooling with inadequate return to the heart, in 1919. But again, it just didn't grab a lot of attention. The term postural tachycardia syndrome was first used in a scientific paper by McLean in the Journal of the American Medical Association in 1944, where he, again, published a series of patients that again, if you read it, you know that he's describing these. So I think it's been more a lack of recognition. At the same time, however, I'm coming to the conclusion it's increasing. But I think the current data is that all autoimmune disorders are increasing in frequency and in sometimes severity. So I think this is part of a trend that's going on.

Dr. Blair Grubb:
We noted that many patients would have what are called mast cell activation syndromes. Mast cells contain histamine and they're part of the allergic response in people. And many individuals had these hypersensitivity reactions, and would oftentimes break out in rashes and things. In addition, many children had a condition called eosinophilic esophagitis. Eosinophils, which are a kind of defense cell in the body, would invade the esophagus and stomach and destroy them.

Dr. Blair Grubb:
And we thought this can't be a coincidence. We're seeing too many of these. And we couldn't figure out why it was happening. It then occurred to us that there could be another aspect of the immune system that could be involved. The immune system is divided into two components. One is called innate immunity and the other is called adaptive. The innate immune system is one you're born with, and it uses mast cells, eosinophils, and a group of compounds called interleukins to defend you. The adaptive immune system uses antibodies, T-cells and B-cells. That's the one we're usually thinking about and we're more used to. And indeed, for 50 years, we have known that the adaptive immune system may turn against you. And if that happens, we call them autoimmune disorders.

Dr. Blair Grubb:
Over the last 15 or so years, it's been realized the innate immune system may also turn against you. And then to distinguish those, they're called autoinflammatory disorders. And we postulated that if there was an autoinflammatory component, that would fully explain why we were seeing the mast cell problems, the eosinophil problems, et cetera. And a couple of months ago, we published a study showing good evidence that there's an autoinflammatory component. We have research going on now that's further confirming that, although oftentimes, you can start with an autoinflammatory component that then converts to an autoimmune.

Dr. Blair Grubb:
To give you an example, in COVID patients, which I think we're starting to look at more closely as having a similar kind of problem, the initial cytokine storm is an autoinflammatory response. In between 30 and 50% of those who survive, then that will trigger a continuing autoimmune response. And that's what I think is going on, that there's an autoinflammatory initiator that then converts to an immune process. But again, we're still in the midst of trying to do this research.

Dr. Blair Grubb:
When you start asking like, "So which viruses are triggering this?" I don't think there's one. I think a variety of different ones can do it, which again, would be parallel with what we've seen in other autoimmune disorders. Epstein-Barr virus or mono seems to be the principal one that we encounter the most, but we also know that cytomegalovirus can do it. And I think coronavirus is just another trigger for these kinds of autoimmune processes. In some ways, COVID may prove to be a boon to this research because it's a model showing our hypothesis is probably correct.

Dr. Blair Grubb:
Actually, I'm on a call today to begin to test blood samples of COVID patients to see if we can find levels of the antibody there as well. And I'm seeing increasing numbers of patients who were perfectly fine, got a COVID infection, and then have been left with severe postural tachycardia syndrome, which is exactly what we've seen in the past, except for other viruses.

Dr. Blair Grubb:
At the moment, you treat symptoms, really. You try to correct the things that aren't happening. So we use medications that can try to compensate for what's going on. So if you have an inability to tighten blood vessels, we'll give you medications that can tighten blood vessels. Drugs such as Midodrine, Droxidopa are in that category. Sometimes, these people, because of that vasodilatory effect and its effects on the kidneys, tend to be sort of functionally dehydrated or hypovolemic. So we will use medications to make them retain fluids within them and change the set points of retention in the kidneys and medications such as fludrocortisone or desmopressin.

Dr. Blair Grubb:
We will also use medications to try to slow down the heart rate. As I said, as it gets faster and faster, it becomes a less efficient pump. And so we will use medications to keep the heart rate down in a much more normal range. And the principal drug that we've been using lately is a relatively new one in this country. It's called of [Aberdeen 00:25:36], and it works incredibly well in patients. We will also use medications that enhance nerve conduction, medications such as Prostigmin. So there are ways that we can try to compensate for many of the problems that are going on.

Dr. Blair Grubb:
Ultimately, however, if the research continues to demonstrate the fact that these are probably in many people autoimmune, there is the possibility that we could arrest the process or put it into remission by using immune-modulating agents. And there is currently a study at the University of Texas Dallas Southwestern looking at intravenous gamma globulin as a potential therapy for POTS. We also think that it would be possible to use medications such as Humira and things like that. The problem is when you start using these, there are a number of potentially severe side effects that could happen from their use. And so we're approaching this extremely cautiously.

Dr. Blair Grubb:
Oftentimes, these illnesses are cloaked in mystery and not very many people understand them or have chosen to learn much about them. They're oftentimes dismissed by medical personnel and told that they have some psychologic problem. And I think they should realize it's a real disorder that we are understanding the pathophysiology of, that we have very good ways of diagnosing and very good ways of treating, and that the potential exists... We hope actually for someday actually having just a blood test to tell if you have it much the same as you use it in rheumatoid arthritis, for example. If you suspect a person has rheumatoid arthritis, you check for the presence of antibodies known to cause rheumatoid arthritis.

Dr. Blair Grubb:
And at the same time, the potential promises that we will put these disorders into remission by using some of the same biologic agents that are used in other autoimmune disorders such as rheumatoid arthritis, scleroderma, ankylosing spondylitis, et cetera.

Voiceover:
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