Good morning, I'm James Daniels, I work at UT Southwestern in Dallas, and I'm grateful to the organizers for giving me the chance to be here and speak this morning. So I'm going to be talking about POTS. I am a clinical electrophysiologist, so I'm going to be approaching it from that standpoint as someone who sees patients in clinic, does procedures, certainly not as a POTS expert as there are on our panel today. But I hope that this will be kind of a practical talk for those of you who see these patients. So nothing relevant to disclose financially for this presentation. Any pharmacologic agents will be off-label because everything's off-label. Probably the biggest disclosure is that I work with Ben Levine, who is well-published in this area, and so he's been a major influence on how I think about POTS and how I treat POTS. So we'll talk a little bit about the diagnosis and the physiology, spend some time talking about the treatment, and then go through some take-home points today. So people throw the word POTS around all the time, at least here in the U.S. We use that word for lots of things. I have lots of patients that come to me in the clinic with this diagnosis of POTS, but oftentimes no one really knows exactly what that means. So I think it is important to start with some definitions. So the Heart Rhythm Society put out this document about 10 years ago. Of note, the website says that it will be revised at some point this year, so keep an eye out for that. But this is a very good document from a heart rhythm standpoint. They define POTS as frequent symptoms that occur with standing, such as lightheadedness, palpitations, tremulousness, generalized fatigue, blurred vision, exercise intolerance and fatigue, an increase of heart rate of greater than 30 beats a minute when moving from recumbent to standing position held for more than 30 seconds, so pay attention to that number. Or if, for adolescents, it's got to be greater than 40 beats a minute. And then the absence of orthostatic hypotension, so greater than a, sorry, it should have been greater than 20 millimeter drop in systolic blood pressure. A couple years before this, there was a statement from the Association of Autonomic Neurologists has a very similar definition, however, they say 10 minutes of standing or head up tilt, which is a fairly consistent definition, because there is a normal increase in heart rate upon standing in the first couple of minutes, and so you wouldn't want to diagnose someone with POTS based on that. So generally it's, you know, at the five or 10 minute mark after the head up tilt table test. Again, absence of orthostatic hypotension, and these can be, again, accompanied by those symptoms. And then Dr. Raj was the chair of this writing group that published the Canadian Cardiovascular Society Position Statement on POTS a few years ago. Very similar definition to the Association of Autonomic Neurologists, again, absence of orthostatic hypotension. But then they did a really nice job of specifically clarifying what symptoms would kind of fall into the category, and also differentiating the fact that these patients often have orthostatic intolerance symptoms, but they can have a lot of other symptoms that are not necessarily associated or that are not associated with changes in position, such as sleep disturbance, headaches, chronic fatigue, and these others that you see here, the brain fog and the POTS feet are somewhat common as well. And so many of these patients kind of feel like this, and we really ought to try as best we can to take the time to listen and go through their review system so that we can have a full understanding of what symptoms they have. This group also came up with kind of a POTS framework, so there's POTS as described, and then they identified some other syndromes that can sort of confuse the picture, and we don't have time to go through them all today, but this POTS Plus, I think, was a helpful group because these are patients who not only have POTS, but then they have these other symptoms and are often associated with these other systemic illnesses. And so these can be somewhat complicated patients. So based on that 2015 document in Heart Rhythm published, the prevalence is around .2%, at least in the U.S. Over 75% of the patients are female, some even estimate 90% of the patients are female, and most patients present between the ages of 15 and 25 years old. So typically the kind of the classic POTS patient is a young woman. The physiology, this is from an article published by Ben Levine and Meredith Brierley, who's actually an autonomic neurologist at our institution, along with Steve Vernino, and this is, I think, a helpful way of thinking of the physiology, at least for someone who is not a physiologist per se, but at least from an electrophysiology standpoint. So it kind of starts with a susceptible individual, whether there's a genetic predisposition. Sometimes they're a very highly active person, tend to be kind of smaller in stature. And then many patients will have some sort of inciting event where their activity level somewhat abruptly decreased. That could be an infection, a surgery, injury, just lots of pain upon movement, or for whatever reason they have to lay in bed for some prolonged period of time. And that starts this process by which they develop some orthostatic intolerance. They diminish their activity further, because every time they try to do something, they feel bad. They develop some cardiovascular deconditioning that's associated with decreased overall blood volume, decreased stroke volume, cardiac atrophy, and then I think some would add decreased venous return to this slide. That activates the sympathetic, the autonomic sympathetic system, resulting in increased heart rate, decreased GI motility, and often headaches. Maybe the arrow should be going this direction as well, which results then in worsening orthostatic intolerance. And so then this cycle continues, and patients can actually become quite debilitated, sometimes even bedbound or have to get around in a recumbent wheelchair. So how do we treat these patients? First of all, like most things we deal with, if there's anything that's exacerbating it, we should remove it. Some common triggers for POTS tend to be large, heavy meals, alcohol, or excessive heat exposure and dehydration, so we want to remove those. And then the second thing I tell the patients to do is exercise, and the third thing I tell them to do is exercise, and the fourth thing I tell them to do is exercise. And herein lies Ben Levine's influence on me. There's lots of good data. This is from his group that shows that training protocol, you see their supine heart rate here in yellow, and in the increase with standing, and then after training, the POTS patients had a significant decrease in their standing heart rate as well as their supine heart rate. Now it didn't normalize it, but certainly significant improvement, and in their study, they found that 68% were in remission. So Ben prescribes this three-month training program, starts with 30 minutes, three days a week of moderate intensity cardio. In his mind, the key is to start semi-recumbent because that helps with the orthostatic symptoms. He really likes rowing. He does a lot of work with elite athletes, and rowers tend to have the largest physiologically hypertrophied hearts, and so a lot of patients will start out rowing. The recumbent bike or swimming are certainly good options. And then as time goes on, you progressively increase to 40 to 60 minutes, three to six days a week, which is actually, you know, now what the American Heart Association recommends for everyone, somewhere in this range. And then you add more upright exercise, so just a regular bike or treadmill. And then one day a week, add higher intensity, and then strength training two days a week towards the end of the three-month protocol. All along, of course, we're going to have patients take increased salt and water. Recommendations vary a little bit, but generally three to four liters of fluid per day, eight to ten grams of salt per day. That's actually a fair bit of salt and can be very challenging, especially for patients nowadays who have, you know, appropriately been told their whole life that you shouldn't eat a lot of salt. And so it really takes some effort to add that. Compression of the abdomen or lower extremities can also help with the symptoms. This is a study from Dr. Bourne, Dr. Raj, a few years ago that showed this kind of full compression suit does reduce the standing heart rate during head up tilt test. And then earlier this year, another article was published by the same group that showed that whether you were taking medicines or, so this is without medication, patients were taken off their medicines. They had a reduction in heart rate with these commercially available compression garments in morning and at night. And then even if they were on, stayed on their medicines, they also had a similar reduction in standing heart rate and improvement in symptoms. So you can see that, you know, way down the list is the pharmacologic therapy. So it's not necessarily that you have to do all of these things first. There are some patients that really do need some medications to help get them to where they need to be. I'm not going to go through much of the data here because there's not a whole lot, but there was a study a couple of years ago with Evabredine that showed that it significantly reduced their heart rate and their quality of life measures were improved as well. At this point, you know, especially if you're getting beyond the Evabredine and the beta blockers, by the way, propranolol tends to be the preferred beta blocker for these patients, I would consider a referral to a center that has a lot of expertise in this area. There are some novel areas of research, non-invasive vagus nerve stimulation on the tragus has shown reduction in heart rate. And then also stellate ganglion block, we may hear about that a little bit later, has in post-COVID patients showed improvement in symptoms as well. So take-home points, POTS is characterized by an increase in heart rate of at least 30 beats a minute or 40 for adolescents within 10 minutes of changing from supine to standing and associated with symptoms known as orthostatic intolerance. POTS treatment always involves lifestyle modification, including exercise, increased salt and fluid intake, abdominal lower extremity compression, and POTS treatment sometimes includes medications that may be most helpful if they're directed at treating the predominant symptom that the patient's experiencing. And so with that, I will conclude and take any questions. Thank you very much. We have microphones for questions, and of course you can also go on the, use that or use your Q&A in your app to put in a question. We should be able to see them here on our little monitor. Yes. I'm John Papagiannis from Greece. I just want to know if there's any role for tilt training in these patients, and also what do you do about their psychological issues, and how do you manage that? Yeah, that's a great question. I'll answer the second one first. So sometimes I think, especially those of us who have a busy clinical practice, sometimes these patients, we see them on our schedule and we may not be super excited because they often do come along with psychological issues. And so for a lot of patients, it is actually helpful to refer them to a counselor for cognitive behavioral therapy. There is data showing improvement in that, and Ben Levine in that review article from 2019 made that point. As far as tilt training, I think there can be a role for that. There is benefit to that. For me personally, I think it's much more practical to try these other things first, and then so that would be a little bit further down the list of things that I might try. So, if I may, a couple of, first of all, a very nice presentation. Thank you. It's a little complicated subject. Very. But the notion of a patient presenting with all those symptoms, I think one element that might have to be emphasized is they don't drop their blood pressure. They maintain their blood pressure. That's a great point, yeah. That's just an element in the, I think, the one only thing that you might have emphasized. Yes. The other piece of the puzzle, though, that mystifies me is how we came up with these numbers. The 10 minutes, the 30 beats. I don't think we know if, we don't have 10,000 healthy people in that age group that have given us heart rates and standing rates. Maybe Satish can, where did that number, where did these numbers come from, just a bunch of gray hair people sitting around a table and? Well, they didn't all have gray hair at the time. So, the 30 beats actually was from, as you say, a study of healthy volunteers on tilt. Definitely not 10,000. I suspect somewhere in the low to mid-double digits at Mayo. And so this was defined, and this would have been in the early 90s, right, because the criteria first came out in 93, and this was based on two standard deviations above what they found for the upper limit of normal. The other, where I thought it, and that was from Ron Schondorf, who was one of the authors on the original paper. Where I thought they took it from was before that, David Streeton, in one of his treaties, had looked at standing tests in healthy volunteers, and two standard deviations above the upper limit of normal for that was 27 beats, and I thought they just rounded to 30, but apparently they recollected tilt data and came up with that. Yeah, so Streeton's work is landmark, no question. But there is a difference between if you did a tilt and if you just do active standing. So I don't think we can use tilt table data, even though that's what is said, right, in the guidelines. So I'm not sure if you're setting me up for this, but just this week, actually, an article from our center comparing the hemodynamics of active tilt and stand in POTS patients has been published, Autonomic Neurosciences, open access for everyone. Okay, I wasn't setting you up, I'm grateful for the information, thank you. We're pretty much at the end of our time, but I would like to, well, hopefully we can circle back and ask a few more of these questions. One has to do with differences in post-COVID patients versus the patient who simply had a bed rest due to an injury. Yeah, I think we're going to hear about that in the later session. Thank you for this elegant talk. Our next speaker is John Lee from St. Luke's Mid-America Heart Institute. Good morning, I'm John Lee. I'm from the Mid-America Heart Institute in Kansas City. I'm an electrophysiologist, but my practice now concentrates on patients with autonomic dysfunction, whether it be POTS and orthostatic hypertension. So that's my bulk of my practice, as well as syncope. So I wanted to give you some highlights regarding orthostatic hypertension with respect to definitions and treatment. So these are the objectives of the talk. To define classic orthostatic hypertension and its variants, these include entities such as initial OH, postprandial orthostatic hypertension, and delayed OH. I want to highlight some treatment strategies for OH and raise awareness about supine hypertension and its ability to hamper treatment for OH in these patients. Classic orthostatic hypertension is defined as a sustained reduction of systolic blood pressure of 20 millimeters of mercury and a decrease of 10 millimeters of diastolic blood pressure within three minutes of standing up, usually measured on a head upright tilt table test, but it can also be measured in the office with an active stand test. Delayed orthostatic hypertension is a rather newer entity, and it's defined as a sustained reduction in systolic blood pressures occurring later, that is, after three minutes in the upright position. And this is just a little cartoon highlighting the drop in blood pressure in classic orthostatic hypertension with maintenance of hypotension as long as the patient's standing up. People with orthostatic hypertension develop symptoms, whether it be lightheadedness, dizziness, due to declines in cerebral blood flow associated with hypotension. So in the top here, we can see transcranial dopplers of the middle cerebral artery, and these are blood pressures recorded during, continuous blood pressures recorded during standing. So as you can see, with a drop in blood pressure, you can see a concomitant, a simultaneous drop in cerebral blood flow resulting in symptoms, potentially syncope. For all intents and purposes, when you measure orthostatic hypertension, you can actually just use systolic blood pressures. In this one study by Artur Fedorovsky, he looked at all comers with orthostatic hypertension, and 95% of them had systolic blood pressure drops. So isolated diastolic orthostatic hypertension is a very rare condition. These are the various presentations for patients with OH. We all know that they can faint, but they can also have other subtle symptoms that you may not recognize as due to orthostatic hypertension. These include things like lightheadedness, spots in their vision, fatigue, weakness, cognitive slowing, brain fog, coat hanger pain, and orthostatic dyspnea. Essentially, all these symptoms are derivatives of the fact that you have reduction in your cardiac output to these various organs and leading to these specific symptoms. Now, in general, the causes of classic OH can be divided into non-neurogenic and neurogenic causes. Non-neurogenic causes are generally reversible, and they include things like volume loss, whether it be due to hemorrhage, diarrhea, excessive sweating, drug-induced factors like diuretics, SGL-2 inhibitors, or physical deconditioning. Whereas neurogenic causes are primarily due to impairment in baroremediated vasoconstriction. There could be damage in the central or peripheral sites of the baroreflexed efferent pathway. And basically, with these defects, you get a reduction in norepinephrine secretion from sympathetic postganglionic neurons. And the poster child for these diseases are the alpha-c-nucleopathies, basically diseases like Parkinson's, MSA, dementia of Lewy body, and pure autonomic failure. Other disease entities can also cause this as well, too, like diabetes, which is a very common cause, amyloid neuropathies, and autoimmune ganglionopathies as well. I wanted to highlight this so-called change in heart rate over change in blood pressure ratio, which was discovered by the NYU group. And basically, this ratio can potentially distinguish a patient, whether they have neurogenic versus non-neurogenic causes of OH. And a change in heart rate to change in BP ratio of less than 0.5 beats per minute per millimeter mercuries would signify a neurogenic cause for OH. And this is just a cartoon highlighting the pathophysiology of neurogenic OH. Again, a decrease in norepinephrine secretion, resulting in impaired vasoconstriction, and it's impairment in the efferent pathway of the baroreflex, whether it be central or peripheral. Initial orthocyte hypotension is a unique entity, and it's an exaggerated and transient fall in systolic blood pressures of 40 millimeters of mercury or a diastolic blood pressure drop of 20 within 15 seconds of standing. So it's very immediate. And this is obviously associated with symptoms of orthostatic intolerance, lightheadedness, presyncope, or syncope. The prevalence of this is actually quite high. It's out there. It's about 32% in longitudinal study of Irish individuals by Finucane. But the caveat of this is that it can only be detected by continuous beat-to-beat BP monitoring with a Finipress device, and it has to be an active stand test. And as you can see here, this is the difference. You have initial orthostatic blood pressure drops with initial OH within 15 seconds with a recovery within 30 seconds. And this is classic OH where you see the blood pressure drops within the first three minutes with persistence of the orthostatic hypotension throughout. And the pathophysiology of initial OH is thought to be a temporal mismatch between cardiac output and vascular resistance. There is a decrease in systemic vascular resistance induced by muscle contraction, and standing up causes an initial increase in venous return through the effects of contraction of leg and abdominal muscles. And the sudden increase in right aorta pressure may also contribute to a fall in SVR through a reflex effect. And this is another cartoon highlighting this. This is measurements of the blood pressure changes with active stand compared to tilt. As you can see, during the tilt table study, you may miss initial OH because it's not recognized as opposed to an active stand test where you see this. And again, you'll need continuous beat-to-beat blood pressure monitoring to pick this up because it occurs within the first 15 minutes. Postprandial hypotension is defined as a fall in systolic blood pressure of at least 10 milliliters of mercury within two hours of eating. It's very common in diabetics and in different forms of autonomic failure and quite common with an incidence of about 24 to 36%. Patients with this problem can have their symptoms even in the lying and supine positions. This is just ambulatory blood pressure monitoring for 24 hours highlighting these changes in blood pressure. So you can see every time a patient has a meal, they have drops in their blood pressures, lunch, dinner. And I wanted to highlight that these individuals with orthostatic hypertension will often have supine hypertension, which is a problem. It leads to pressure diuresis in the evening so the patients will wake up at night urinating frequently and this can cause worsening of orthostatic hypertension in the morning. So I think something to remember in these patients. And the pathophysiology of postprandial hypertension is vasodilatation, secondary to vasoactive gastrointestinal peptides. There's an inadequate sympathetic compensation to this vasodilatation, thus a drop in blood pressure. And there's an impaired maintenance of cardiac output and SVR. And as mentioned earlier, there is a possible role of incretin hormones like GLP-1s and GIPs in the pathogenesis of this condition. And just to highlight treatment, general principles include attenuation of symptoms. You won't be able to completely rid these patients of their symptoms, but you want to reduce symptom burden. You will never really normalize blood pressures because this is not possible. It's very difficult. These patients will send you reams of blood pressures every time through various ways and they're really fixated on the fact that their blood pressures never get better. You really have to educate these patients and let them know that we're trying to mitigate your symptoms. Other things include identifying patients with supine hypertension, correcting aggravating factors, and employing non-pharmacological therapies and drug therapies. Correcting aggravating factors, meaning adjusting medications, whether it be antihypertensives that promote hypertension and correction of anemia. And these are potential drugs that can cause or make your orthostatic hypertension worse, including diuretics, alpha adrenergic blockers for prostate issues. Tizanidine is a very common drug, a muscle relaxant that's given that can cause potentiation of OH. Antihypertensives and SSRIs and SGL-2 inhibitors are other drugs. Non-pharmacological treatments are utilized like liberalization of salt intake, increasing water, water boluses the first thing you wake up in the morning, raising your head up 30 degrees when you go to bed at night, recumbent exercises to improve your core muscle strength, counterpressure maneuvers, and the use of the abdominal binder. Usually waist-high compressions is the best. I don't think knee-high or thigh-high are helpful. And treatment of supine hypertension, I think you have to treat this first before you employ pressure agents because some of these patients will have blood pressures in the 180 millimeters of mercury range, so it will limit your ability to use these pressure agents. So we use short-acting agents like Lusartan, nabivolol or nifedipine or clonidine at night. Pharmacological treatments would include agents such as mitrogen or droxedopa. Just to highlight, for pyrodistigmine, which we also use, which improves neural conduction through sympathetic neurons. And I may be running out of time, but some initial management strategies for initial O.H. include rising more slowly from supine to standing and counterpressure maneuvers. And some highlights for the management of postprandial hypertension include eating small but frequent meals, avoiding alcohol, taking mitrogen before meals and the use of octreotide. And finally, Acarbose has also been shown to be helpful for postprandial hypertension. It's an alpha-glucosidase inhibitor and it decreases GI absorption from the GI tract and it's been shown to attenuate the fall in blood pressure by about 17 millimeters of mercury in studies. And to conclude, orthostatic hypertension can have varying clinical presentations leading to syncope. Their treatment includes both non-pharmacological and pharmacological strategies and complications. Complicating the treatment is that of supine hypertension, which needs to be managed. It can be very challenging to manage and it has to be treated before you actually manage the O.H. Finally, O.H. is a chronic condition and it has a really profound impact on quality of life. These patients are chronically ill, debilitated, and are quite frustrated by their treatments. Thank you. APPLAUSE Thank you very much. This is a difficult problem that we encounter frequently and we're at a loss. I found that very helpful. I'm afraid we need to move on because we are... You have an urgent question. My duty is to ask questions. Elizabeth. Just a simple point, though, because you raised the issue of supine hypertension. The audience needs to be aware that if you treat patients with short-acting antihypertensives at bedtime, warn them if they get, especially old men, get up at night to go to the bathroom, they may crash and burn. They need to have walkers or other protective gear. We do ask them to get up gradually at night because they often have to go to the bathroom because of the pressure diuresis. So we really ask them to get up gradually or maybe have a bedside commode when you have to do that. And I've had a patient who actually fainted with a sublingual nitroglycerin patch, for instance. So it's a challenging problem, managing both hypertension and hypotension together. Very nice. Thank you. Thank you very much. So moving on to our next speaker, that will be Dr. Raj. And speaking about drugs for vasovagal syncope, what is known, what is coming? So thank you all for joining us this morning, and thanks to Dr. Kaufman and Dr. Bendit for having me. So vasovagal syncope is something that I think we're all familiar with. Some of you will know that we've already had an episode at this meeting in the very first session, actually, a couple of days ago, right? So it's something that actually affects us all, either professionally, personally, and sometimes both. My disclosures are listed here. None actually have anything to do with what I'm going to say. So I've been asked specifically to talk about the pharmacological treatments for vasovagal syncope. And a lot of what we do is still based, at least loosely, on a physiologic model developed, I think almost 70 years ago now, known as the Sharpie-Schaeffer model, right? And it's certainly not perfect. We could all sit here and pump holes in it, but it actually has been useful despite its imperfections. And the fundamental premise is related to the fact that most patients with vasovagal syncope do it in an upright posture, right? And so it's a posture where there's fluid shifts, from the chest to below the chest, some central volume depletion. Part of the physiology of adaptation is that the sympathetic nervous system kicks in a little more aggressively. Catecholamines increase. But ultimately, something goes wrong. It's often thought to relate to an underfilled ventricle and the septum and the lateral wall whacking against each other, triggering nerve fibers in the myocardium that send signals up, right, to the brainstem level, triggering or de-triggering baroreceptors causing a CNS reflex, but the net result being what we see, which is either you get an excess of vagal stimulation leading to bradycardia or asystole, or sympathetic withdrawal, which can also actually lead to bradycardia, but often can have other effects, more vascular effects on dropping resistance. And so what I have here in red are different treatments that people have looked at historically to try and target different aspects of this pathway. And we'll touch on data on a few of these. And the one I'm going to touch on first is in green, and that's the use of Flornap or flutocortisone to try to target or address volume depletion. So like a lot of things, you know, things have been used for years, but it wasn't until just a few years ago, less than a decade ago, that the first large paper, by large I mean like a multicenter study of any sort, of flutocortisone vasovagal syncope was published. So this was the second prevention of syncope trial or the post-two trial led by Bob Sheldon and as you can see you know this these data actually are a Rorschach test of your view of the world so if you're a physiologist you look at these curves that have separated and say well it looks like it's doing something if you're a clinical trialist you look down below at the p-value and see that the p-value is above 0.05 and you say it's crap it doesn't work let's move on but I would point out that actually the problem and maybe you know to the credit of our excellent trialists you know they think about these things but the problem with doing trials is that there are a lot of ways things can go wrong and in fact with flutocortisone it's a hormone that actually takes time to work and this was built in this was baked into the protocol because the protocol involves starting at a dose of 0.1 milligrams waiting a week doing an assessment checking the potassium to make sure the patients didn't get hypokalemic and if not there was a forced titration up to 0.2 milligrams which was the target dose and then we repeated that one week later so really there was a two-week loading baked into this if you look closely at the first figure I'm not sure if these arrows they don't show on the left there was a high event rate in that first one to two weeks when the drug presumably wasn't fully effective and in fact if you censor those first two weeks which you know I see the trial is rolling around and you know distress at the moment but if you censor those first two weeks and just pretend they didn't happen and start with events after that it turns out florence seems to work or at least it reached a p-value of less than 0.05 now if you want to cheat a little more and do an on a full-on treatment analysis and only look at those patients that reached and were able to tolerate the target dose of 0.2 milligrams per day it was even more effective with about a 50% reduction right so again whether you believe this or want to use this or not really is a function of your view of the world when it comes to you know how you deal with trial evidence but it certainly is an option for some folks so practically speaking I'd start at 0.1 milligrams per day the target dose is 0.2 I would caution you against the more is better philosophy right but you know this stores or retains sodium at the expense of potassium and you can start getting into more side effects with hypokalemia at higher doses but more concerning is this this is a modified version of cortisol at low doses it doesn't tend to affect the glucocorticoid receptor that's why we can use it if you're going to give a gram of or sorry a milligram of fluted cortisone you might as well just give cortisol because you're going to start getting HPA suppression right so don't go too high I'm gonna get you to look down to the bottom right so the issue is that we know that there's sympathetic withdrawal in everyone some people get a lot of you know vasodilation some get a little bit at the end the end right before someone faints this physiologically happens and so in the post for study the fourth prevention of syncope trial we tested mitodrine and so mitodrine is a has been discussed briefly it's a short-acting presser agent is actually a pro drug of an alpha-1 agonist right so it's a blood pressure drug that actually raises it's a squisher it squishes arteries it squishes veins it done right it may raise blood pressure a little bit and the right folks it only works for about four hours at a time so you have to take it multiple times per day which is a bit of a nuisance for some of our patients but it works right so what I will say is this is the first drug in a large randomized trial for syncope that a trialist would accept actually works right the p-value is on the correct side of 0.05 and interestingly it decreased both full syncope but it also decreased presyncopal symptoms which are rated during the study right so it improved broadly symptom benefit and one of the questions when you have a treatment like this is are there some responders and some non responders or does it work a little bit in everyone and the answer is mitodrine works a little bit in everyone and so if you fainted a ton you're probably still gonna faint but a little less if you fainted a little bit we may be able to move you into the no fainting and this was in a 12-month follow-up what about SSRI so this is targeting a little further upstream the CNS reflex argument and I will say this has never caught on some of these studies have been around in this field longer than I have but over the years there have been multiple studies of SSRIs to prevent fainting and and people can have different philosophies as to why that is you know some may say well it's treating anxiety or depression that's triggering syncope and it's absolutely true that some syncope can be triggered that way there's also a whole serotonin hypothesis in response to hypotension and at the brain or brainstem level regardless three different SSRIs have been studied and this is a meta-analysis that was published a couple of years ago showing a fairly consistent benefit so this isn't to say rush out and put all your vasovagal syncope patients on an SSRI for it but it's certainly not an unreasonable thought especially as you're moving down the list of therapies and other things aren't working it's not a crazy thing to consider and and you know sertraline has been looked at fluvoxamine has been looked at and I forget what the third one was but it seems to be a class effect each of these studies was a different drug and then getting to novel stuff we come back to the bottom right and the issue of sympathetic withdrawal and I'm just going to say a few words about adamoxetine it was mentioned in the previous slide when John was talking about orthostatic hypotension but adamoxetine for those that of you who don't know what it is it's it's marketed in the US and Canada as stratera it's a drug marketed for the treatment of attention deficit disorder but it's the way it works it's the most potent inhibitor of the norepinephrine transporter and so this is a cartoon of a sympathetic neuron with the presynaptic terminal on top and the postsynaptic terminal on the bottom you see all these little vesicles with red dots of norepinephrine you know in the presynaptic area and those little tubular things are meant to be alpha and beta receptors postsynaptically different receptors and usually when you get a sympathetic nerves firing the norepinephrine gets released some of it attacks the alpha and beta receptors and then you know when you release stuff into a synapse if you want to do it more than once in your life you have to have a way to get rid of it and the way this neuron gets rid of it is by this thing called net or the norepinephrine transporter it's a clearance transport it's a vacuum cleaner that getting rid of the norepinephrine but if you block the norepinephrine and then you know you release it unfortunately some of it gets taken up but some of it can't get taken up and so more of it goes back to the alpha and beta receptors and you get more bang for your buck and so the net effect of these drugs is an increase in sympathetic nervous system tone right so we thought maybe you know if you're a sympathetic withdrawal maybe that would be useful and so Bob Sheldon first looked at this years ago off-label with a drug called subutramine and I don't know how many of you remember this medication it was a weight loss drug I believe a sympathomimetic so he was using it off-label in his worst of the worst fainters there were calstrin fainters and he found that in a dose dependent manner it decreased the recurrence of syncope and just so you get an idea these numbers are episodes per month right so these are people in the beginning that basically were fainting every day and sometimes multiple times per day and you know as you increase the dose of subutramine it decreased and then but it was actually not being marketed for syncope it was being marketed for weight loss they did a big cardiovascular study called the scout study turns out it knocked off a few more people than it should have and it got pulled from the market right so all of a sudden Bob's great syncope treatment disappeared so then we actually went back to adamoxetine and so we did a tilt based randomized study so this was a randomized trial of patients put on tilt for 60 minutes drug-free where they got two doses of either adamoxetine or placebo night before morning up so it's an acute study and what we found was the adamoxetine decreased syncope on tilt interestingly unlike the mitogen it didn't decrease the presyncope right so there's an equal amount of presyncope but what it did is that right at the end right when they were trying to faint it prevented the different things that happened and I can you know for sake of time I'm not gonna go through the painful details but I was wrong about why I thought it would work I thought it would decrease the drop in vascular resistance or preserve vascular resistance it did nothing for that I thought it would squish the vessels and improve stroke volume it did nothing for that what it did if you look at the top right is it prevented the bradycardia at the end it acted like a pharmacological pacemaker right when you needed it for a few minutes and the interesting thing is that so shifted the reason for those that fainted and and prevented people from fainting and I don't have the slide here but it's actually quite interesting some people around 17 minutes they became but hypotensive felt like they're about to faint and if you could ride that out for a few minutes their pressure recovered and they were fine for the rest of the 60 minutes and that's what it did so that's being tested right now in a clinical trial the post 7 study if you guys are interested send them to Calgary or other places we can sign you up even as a placebo controlled study so to summarize the emerging and sort of maybe more novel approaches or fluted cortisone don't go above 0.2 mitodrine 5 to 10 milligrams up to 3 times a day not at bedtime SSRIs and potentially atomoxetine although the clinical data on its efficacy is still pending for those that like flow diagrams this is from the 2017 ACC AHA guidance document guideline document atomoxetine of course is not there but but if the study works out maybe in the next iteration thank you any hard questions thank you very much that's always hard to know where to move forward with these folks and that's a nice framework we'll move on to the final speaker in this session and hopefully my colleagues can stay around for any last-minute questions that occur at the end of the session our next speaker is dr. Samir Jamal from Hackensack University Medical Center post-covid dysautonomia is it here to stay I think there'll be a lot of questions okay I want to thank the presenters and the chairs and HRS for giving me the opportunity to present post-covid dysautonomia is it here to stay it's always a challenge to be the last speaker following such great presenters and presentations but I will do my best to meet the bar that's been set so yeah no relevant disclosures so like all of you in the audience I've been intently listening to our speakers because they're so knowledgeable and I have covered a fair amount of you know what we consider cardiovascular autonomic dysfunction including POTS orthostatic hypotension and initial or immediate orthostatic hypotension as well as vasovagal or neurocardiogenic syncope so these among others right are types of cardiovascular autonomic dysfunction that we see in post-covid as well now with what frequency several studies have tried to compile the data on this Fedorowski Dr. Fedorowski and his group has sort of I think done the most comprehensive work in terms of putting this together and have suggested that both immediate orthostatic hypotension as well as POTS tends to make up the highest frequency in these patients again these are estimates and ranges now what we've learned in the post-covid setting is that this initial orthostatic hypotension often serves as a precursor to the POTS that we see in these individuals as a result we'll talk more about POTS usually specifically in this talk but to take a step back in terms of post-covid dysautonomia for those of us who treat the you know these disorders in the room it's a bit perplexing because was COVID something that unmasked patients who are already predisposed to it or did it actually induce these types of issues in these patients and so it is a bit of a chicken and egg but an issue that we're still grappling with and we don't have the answer for yet now I'm not going to elaborate on the mechanism because we have people who are clearly experts in the field here but just quite quickly in terms of orthostatic intolerance that we sometimes see post-covid there are factors that lead to a few important things one is a decrease in circulating volume others lead to the sympathetic surge that Satish talked about in terms of the increase in heart rate and still others that decrease the vascular tone so these three things together can lead to some of these clinical presentations that we see in our patients post-covid so let's think about things as a matter of perspective and look at the incidence rates of POTS before March of 2020 so data suggested that patients with POTS incident rate was about one to two cases per a million person years now post-march 2020 I think we're all familiar with this graphic in this curve the incredible and overwhelming you know surge in COVID cases the hundreds of millions of patients on the y-axis over the time that's on the X and not you know so long after these initial diagnoses started coming in we started seeing case reports right individuals who were being described as having postural tachycardia syndrome maybe not POTS exactly but something kind of like it and more and more cases yeah I work with some individuals we found individuals that sort of had the bona fide diagnosis of POTS but POTS POTS like something was awry right something was wrong in some of these patients in the post-COVID setting so other groups took notice and this is a global survey of about 2,000 patient from Larson and colleagues that looked at generic dysautonomic function dysautonomia using the compass 31 score and noted that in these individuals about two-thirds of them demonstrated moderate to severe autonomic dysfunction and this was independent in the severity of the acute initial COVID infection interestingly about 90% of these patients had at least one cardiovascular symptom right so signs of cardiovascular autonomic dysfunction including lightheadedness palpitations tachycardia presyncope a graying of vision etc so our group identified individuals who were post-COVID and had signs and symptoms suggestive orthostatic intolerance and performed head-up tilt table testing and so out of 24 patients we noticed that four met bona fide criteria for POTS but many others sort of had this almost POTS right POTS like and still others had neurocardiogenic syncope orthostatic hypotension etc and we also demonstrated that COVID severity did not seem to influence the development of this long COVID orthostatic intolerance Satish and his group looked at this as well in Canada and took 70 long COVID patients and I believe this was a 10-minute stand I think and in these patients about 70 percent or so or even more demonstrated cardiovascular autonomic abnormalities again we talked a little bit about the initial orthostatic hypotension that was the most frequent but POTS was close behind in addition to that was orthostatic hypotension inappropriate sinus tachycardia and they too suggested that COVID severity did not seem to influence the development of long COVID orthostatic intolerance so the natural question is we know this curve we've seen this curve how many of these individuals with COVID went on to develop dysautonomia and the numbers based on the data suggest that within six to eight months of infection these are ranges but two to fourteen percent of COVID-19 survivors develop POTS and a very broad range of individuals develop this sort of POTS-like symptom. And so let's look at comparative values. So the incidence rate of POTS previously has been established pre-COVID and then post-COVID, this is data from Blair Grubb's lab, is dramatically higher. Okay, is it this high? Well, it's hard to say definitively. Dr. Fedorovsky looked at it as well and suggested that maybe it's a five-fold increase regardless, I think we can all agree that there's been an increase pre-COVID compared to post-COVID. Now, the mechanism is a real question, right? And this is a bit of an oversimplification alert because I'm gonna fit it all in one slide, which is really impossible. This could be an entire lecture series, I would imagine. But in terms of the mechanism, there are three sort of putative mechanisms that are suggested. One is autoimmunity, another is inflammation, and then also a predilection for neural tissue and propagation along neural tissue. These can all lead in various forms to dysautonomia, which can then lead to what we feel is likely the most frequent, the most prevalent form, which is POTS. So what have we established thus far? The incidence rate pre-COVID compared to post-COVID of dysautonomia has increased. COVID severity does not seem to influence dysautonomia development, and several mechanisms seem to contribute to the development of this type of dysautonomia. And so the natural next question is, how long does it last and is it here to stay? So again, let's look at reference in terms of recovery rates of pre-COVID POTS. Limited data on this, but I'll give you a few studies that are out there. So one study evaluated patients by mail response and suggested that 20% of patients with pre-COVID POTS had full recovery within five years, and 50% of them had partial recovery at five years. And still other studies demonstrate about half of the patients will recover between one to three years. So it takes time pre-COVID POTS, right? And not everybody recovers, which is what accounts for the fact that many of us see these patients in our offices and in our practices. Let's look at post-COVID, right? Big question, right? And I am sorry to say, but there may be more questions than answers unfortunately. But some of that has to do with the fact that there are variable definitions in the data, right? Is it POTS? Is it POTS-like? There are different forms of autonomic dysfunction that are cardiovascular in nature that may get lumped together. So that's a question. There are fewer longitudinal studies and even fewer objective metrics that we can follow. But that said, here's some of the data that we know. So recovery rate of post-COVID syndrome, okay? So this is not specific to dysautonomia, but the largest study looking at post-COVID syndrome recovery is a national study out of Israel. 300,000 patients, again, not specific to dysautonomia, but demonstrated that the majority with this post-COVID syndrome have recovery within one year. If we look specifically at dysautonomia, another study of about 110 patients, evaluating patients by both compass and quality of life metrics, demonstrated that about half will have resolution of their autonomic dysfunction at one year. Looking specifically at post-COVID autonomic dysfunction and POTS, again, not a lot of longitudinal studies, but one study of 32 patients diagnosing things by 10-minute stand suggested that 94% have full recovery within six months. Our group, in our progressive fashion, looked at the 24 patients with head-up tilt table testing and noted that the majority of these patients with the mild orthostatic intolerance recovered within a year, but those with bona fide POTS didn't really see much improvement in a year. What's the take-home point? In general, it seems that individuals with post-COVID autonomic dysfunction fare better than their counterparts who had it pre-COVID, but again, some will recover, some won't, and so it depends on how you look at this glass, right? Half full or is it half empty? And even if individuals do recover, you must describe this to your patients that their recovery course is oftentimes uneven. They'll relapse and they'll remit, certainly with counter-current illnesses and other things, this is something that needs to be stressed. Now, what I don't want to do is leave everyone feeling disheartened, and so I have a bit of good news in the sense that the number of individuals, this is from the CDC, being diagnosed with long COVID as a percentage of those who actually have COVID is going down, so that's good, right? The decrease is great. And some of the putative mechanisms for this change are that long COVID may have been more prominent with some of the earlier strains. Perhaps immunization is helping, and some of the viral treatment may also be helping reduce some of these diagnoses of long COVID. So just to summarize, the incidence rate of dysautonomia has increased pre-COVID compared to post-COVID. There's no question about that. COVID severity does not seem to influence dysautonomia development. There are several mechanisms that contribute to dysautonomia development that we discussed. The duration depends on initial severity, but some seem to recover within a year. And long COVID rates overall appear to be decreasing. Thank you for your time. Thank you. Very nice presentation. Difficult subject. Just curious, did you think about other viral illnesses that might have comparable post-infection events? Do we have sort of applicants? We do. So if you look at SARS and MERS, again, smaller numbers, but what we know is that the rates for COVID look to be higher than they are for those particular viruses. Now, again, some of this might just be data collection, and that's even the challenge of the post-COVID patient population is that we are all aware of it, but data collection definitions vary, and that makes some of the summarizing and the synthesis of it a little bit murky. It appears to be higher rates than what it has been in some of the other pandemics. The publications, I just never looked. I did review a few. I think there's one in particular that sort of describe this. It's a pre-COVID paper, but when you do that comparative, it looks as if based on the way that Dr. Grubb and Dr. Fedorovsky have sort of suggested that increase, it seems to be higher than what it is in other pandemics. Thank you. I have another question about this for any of our colleagues here. It seems like if a patient has an injury and they end up on bed rest, then they have POTS, which they can recover from with an exercise program, uncomplicated POTS, and their elevated heart rate is autonomic success since their stroke volume is decreased and they need to increase their cardiac output. It feels to me in these post-COVID patients as though it truly is an autonomic dysfunction and that the usual attempts to use exercise have been much more difficult. Patients seem to tolerate it for even worse than your traditional POTS patients. Have you encountered that? And do you have any cautions about modifying the exercise protocol for these people? You know, I think it's interesting. In our experience, and I wonder if other people can attest to this on the panel, that when people feel better, they stop seeing you. And so I think there's a bit of selection bias with this. And even in our own investigation, for the patients that we did all the head-up tilt table testing for, within nine months, many of the patients with milder symptoms just felt better and they didn't really want to see us anymore. And so we are left with some of these individuals for whom, again, maybe it's sort of, you know, becomes more of the chronic process and some of the processes that we've heard about earlier today. Again, were these individuals who were susceptible to it beforehand and this was the second hit? It's hard to say. Now, in terms of the exercise, I mean, I still tend to give them the same, I didn't go into therapeutics today because I think that it was covered pretty extensively. And I sort of rely on some of the other experts on the panel in terms of what they have recommended. And I stick with those same recommendations. I don't know if you guys have any different experiences. Just an observation. I think there's gonna be this subset of patients with long-haul COVID and who have autonomic dysfunction who have a chronic fatigue variant, which is kind of unique. Their fatigue will get worse with exercise. So their chronic fatigue is akin to chronic fatigue syndrome. So in those instances, I think exercise might be detrimental for that subset. They develop a lot of post-exertion malaise and so you get to exercise more, they actually get worse. So maybe in that specific group of patients, we may have to modify the exercise recommendation a bit in those individuals. I think they're the most difficult to treat as well. So there's an overlap between ME-CFS and this, right? So those are patients that are a subset. There's a huge overlap, right? I mean, I don't know if you guys like Venn diagrams, I love them, right? I mean, but POTS is a Venn diagram of a bunch of things that end up with a phenotype and ME-CFS is a much larger circle in the Venn diagram. I would say that most of my POTS patients actually have post-exertion malaise. We don't always label it that way, but they give you the history that, you know, doc, you don't understand if I try and go and exercise, I can't get out of bed for two days. And exercise can help. I mean, I guess I wouldn't take it as far as Ben in terms of you can cure, like Ben will say, I can cure all POTS with it. I actually don't think that's true, but there's an element of deconditioning that sets in when you were doing stuff and then you get sick and you aren't, and you can improve that as part of the treatment. To your point, Dr. Kaufman, I'm not sure that there's anyone that decides they're gonna go on prolonged bed rest, right? Usually there's an acute insult, often a viral infection, which isn't that different than COVID, although we didn't know the name of it before in POTS, or a concussion or stuff. And so there's, I think fixing the bed rest and exercise fixes a part of it, but there's usually still another part of the acute insult that that's not treating, whether it be a viral infection, whether it be a bad post-concussion syndrome. We should probably, go ahead. I don't know if this is on. So Greg Marcus from UCSF. Thanks everyone for your fantastic talks, very clinically helpful. I have a case that I have assumed is a unique kind of anecdote, presumably not applicable, but thought I'd leverage the expertise of the panel to see if this resonates or fits with any of your experience. So young, very active athlete, 15 year old woman, girl, who classic POTS, developed a infection attributed to, with some sort of atypical organism, had a little bit of maybe atypical pneumonia, chronic sinusitis, got a Z-PAC, got a little bit better, but then developed classic POTS, presyncope, brain fog, chronic fatigue, kind of wiped out, everything that you all have described to a T. Fairly refractory to usual therapies, having difficulty exercising, started on Fluorinef, waxed and waned for months, and really had to stop playing travel softball, had to leave school frequently. And then several months later, developed a fever, got another Z-PAC, and all her symptoms went away, after the Z-PAC. So in retrospect, I wondered, did she just have an indolent infection all this time? And I wonder, and we talk about the insult that leads to the bed rest, that can be an infection. I'm just curious, have any of you seen this before? Is this a completely unique case? Might this be operative in other patients? Thanks. I can admit that I've never tried Z-PAC for a POTS patient. So in my view, it's a unique case, but others? Yeah, I haven't seen people miraculously get better. Again, I don't see 15 year olds, so maybe they're a different breed. I will say that in the long COVID space, there's lots of hypotheses and little data, but one of the hypotheses is that long COVID is a persistence of infection. And you've seen this in post Lyme syndrome or chronic Lyme, where people have argued this, and Lyme, they've actually tried antibiotics. My summary of that literature is that those treatments, at least in the patients of mine that have tried it, have never worked. And certainly in larger data sets, haven't worked consistently. But certainly the way you describe it, it does sound like there's an infectious source that was cleared. And just getting back to the exercise business, your patient, obviously, with an infection, probably not a good candidate for exercise. But the other groups, it's a very, I think one of the problems that physicians have is this is a very intense kind of group of people to treat, right? I mean, it takes a lot of resources. Even the exercise component to convince somebody, you can start small, just do something small and build it up. But that takes a lot. I mean, you need APPs involved who are contacting the patient, being like their champions or whatever. This is a very expensive form of medical care. And with rather dubious outcomes so far, unfortunately. Yeah, we're certainly, our center certainly doesn't have the expertise that say, UT Southwestern does with exercise. I mean, I've taken Ben's approach and my low touch, low cost approach, because I don't actually even have a nurse practitioner or a nurse clinician, it's me, is to basically tell them what to do. And that means non-upright, I think that's key. Frequency and duration are important, that it's aerobic, right? So one of the things I try to emphasize I try to emphasize is it's mainly about aerobic reconditioning. So Pilates, great for core strengthening, not gonna help your POTS, right, by itself. It's an and, if you wanna do that and the aerobic stuff, that's great, but it's not gonna help otherwise. And then everyone has a modified Levine protocol, but everyone modifies it differently. Our approach is to say, get to 30 minutes on a recumbent cycle or with a rowing machine, turn the resistance all the way down and go in super slow-mo. Go as slow as you need to go to get into that habit and then build up resistance, build up speed, build up other duration later. The CHOP protocol, Children's Hospital of Pennsylvania, is you start doing whatever you're gonna do for two minutes and then three minutes and then four minutes and build up in that way. But you do need to have a build-up strategy. You have to warn them. The main thing that I learned over the first few years was when I started doing this, my patients would come back to me and say, this isn't for me, this works for someone else. And I actually called up Chi Fu, who worked with Ben on the study, and said, what am I doing wrong? And she said, we said everyone got better that completed the protocol. We didn't say it happened right away. And in fact, it can take up to six weeks before people notice any improvement. And in that time, they often will feel worse because of the post-exertional malaise. And I don't know about you guys, I probably wouldn't do anything for six weeks unless I knew I was supposed to take that long. I would assume that I was a non-responder. And that was one of the big changes for us was managing the expectations, warning them that they were gonna feel like crap for a while doing it. But my patients have told me it's almost like a light switch flips at some point where they then feel worse when they miss a day of exercise rather than when they do the exercise. And then compliance is easier. But that first bit is a long slog. If they're teachers, they should do this in the summer. If they're students, you don't wanna start this before finals, right? So that's the other part of it is managing the when. It's not just go out and do it whenever. Well, thank you all for your patience. And it was an extended session because there were a lot of good questions. I'm so sorry we didn't get to all of them. Very nice.

POTS

cardiovascular autonomic dysfunction

post-COVID-19

diagnosis

treatment options

sympathetic nervous system

orthostatic hypotension

vasovagal syncope

dysautonomia

pharmacologic interventions

individualized care