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Management and Treatment of Autonomic Disorders, Including Updates in Post-COVID-19 Syndrome: Part 1

Podcast discussion with Satish R. Raj, MD, MSCI,and Artur Fedorowski, MD, PhD

In this episode of The EP Edit, we are featuring part 1 of our discussion with Drs Satish Raj and Artur Fedorowski about recent updates in dysautonomia, including post-COVID-19 postural orthostatic tachycardia syndrome (POTS). Dr Raj is the medical director of the Calgary Autonomic Investigation & Management Centre and professor of Cardiac Sciences at the Libin Cardiovascular Institute and the University of Calgary’s Cumming School of Medicine in Alberta, Canada. Dr Fedorowski is an associate professor and senior consultant in the department of cardiology at Karolinska University Hospital and Karolinska Institute, in Stockholm, Sweden. To hear part 2 of the conversation, please click here.

Also available to listen on Spotify and Apple Podcasts!

Raj headshot
Dr Satish Raj

Dr Satish Raj:I am a professor of cardiac science at the University of Calgary in Alberta, Canada. I am the chief of the arrhythmia service and the medical director of the Cardiovascular Autonomic Disorders Clinic, or the Calgary Autonomic Investigation & Management Clinic.

Fedorowski headshot
Dr Artur Fedorowski

Dr Artur Fedorowski: I am a senior consultant and associate professor in the department of cardiology at Karolinska University Hospital in Stockholm, Sweden, as well as head of the Syncope and Cardiovascular Dysautonomia unit at the same location.

Raj: There are a lot of challenging issues in the field of managing patients with autonomic presentations in general. The big elephant in the room is obviously COVID-19. There is not a person on this earth who has not been affected in one way or another by the pandemic, either directly by being infected, by having friends or colleagues being infected, or being affected by the restrictions and changes because of the people being infected. But rightly so, I think initially the focus was all on what to do about the initial infection, the initial impact on hospitals, and the initial mortality and how to deal with that. Obviously, vaccines came along and that has helped the course somewhat.

It is fair to say that COVID-19 is not in our rearview mirror, but we are probably over the worst of the acute infections. I think what we are seeing is the wake, if you will, of what is left. All of us that work in the autonomic disorder space, as well as many other spaces, are seeing a large or at least a significant group of patients left with ongoing illness. Maybe it is harder to define than that, and certainly, this thing that has been referred to as post-acute sequelae of COVID-19, which is the definition by the National Institutes of Health (NIH), or more colloquially referred to as long COVID or COVID long haulers, recognize that it is certainly not a singular presentation. There are varied presentations among patients and varying degrees of disability, but regardless of the cause, there is a significant amount of disability in a significant number of patients. Not all of that comes under the responsibility or training of cardiologists or even autonomic specialists. Artur, maybe you could start off by sharing your experience with first, what you are seeing, and second, what you think that we as cardiologists have to be willing to take some responsibility for as far as helping to diagnose and manage.

Fedorowski: This is a huge issue, of course. To some degree, we expected that something might happen in the wake of this pandemic. A few months before we started seeing patients with long COVID, I talked with a friend of mine who is an expert in cardiac arrhythmias, who told me that in a couple of months, we were going to see a wave of POTS patients getting this disorder due to this viral infection. I did not believe him­—I thought maybe he was exaggerating. Then, somewhere in the beginning of September 2020, I started getting calls from Karolinska, from people who were engaged in a post-COVID unit taking care of patients who survived acute COVID-19 infection. They later started seeing patients who were not as sick in the beginning, but began developing symptoms that were similar to POTS. As there are only a few POTS experts in Sweden, they approached me and I was surprised to see that these patients presented exactly like POTS patients.

After seeing so many patients over a period of months, we are now talking about a pre-COVID and post-COVID POTS era. There are a lot of these patients, and one of the main problems is that the doctors in primary care and specialties such as cardiology do not know much about POTS. So many of these patients were misdiagnosed as long-haul post-COVID syndrome, not knowing that a large number of these patients constitute as having a post-acute viral infection, cardiovascular dysautonomia, which we now recognize as post-COVID tachycardia syndrome, POTS, inappropriate sinus tachycardia syndrome, and so on.

My view is that in many cases, even if doctors see the symptoms, they lack diagnostic modalities and knowledge about syndromes, so they do not diagnose it. They call it “post-COVID syndrome.” If you look at a recent paper in Nature Medicine,which summarized post-COVID syndrome, the authors talk about chest pain, palpitations, fatigue, etc. They talk about symptoms of POTS, but do not call it POTS. Then, in the beginning of 2022, there came a paper in the European Heart Journal emphasizing post-acute COVID-19 sequelae in the shape of myocarditis and increasing cardiovascular disease.2 There is one frame in the algorithm showing that there is one complication called POTS. So, POTS was acknowledged in the end. It was not recognized because people did not know about it.

Raj: You raise a couple of interesting issues, the first of which that is worth clarifying is: what is POTS? What does post-COVID POTS look like compared to POTS? Realistically, there are some electrophysiologists that are probably quite familiar with this and others that are not. Do you want to help clarify the presentation of how these symptoms fit together to where a cardiac electrophysiologist might think this is POTS as a first step before deciding what other tests to do or what treatments to offer?

Fedorowski: That is what you have to do with the same disease. If you look back into history, you will see irritable heart syndrome and post-viral fatigue syndrome, etc. It just had different names over the years. In 1993, researchers from Mayo Clinic named it postural orthostatic tachycardia syndrome or idiopathic POTS. They coined the term, but the disease had been with us for a long time. In my opinion, we have now encountered a potent POTS trigger that is widespread. For anyone susceptive to POTS, he or she will likely develop POTS if affected by the virus. In my view, we have a cross-sectional test for POTS susceptibility in the population.

Raj: Not everyone with symptoms after COVID-19, or the long haulers as we call them, have a POTS-like presentation. But I think what you are getting at is that there is a subgroup of those—the exact size of that subgroup which is not yet fully understood—where some of the dominant symptoms include orthostatic intolerance, an inability to function vertically, and profound exercise intolerance in addition to or maybe separate from profound fatigue that is also associated with rapid palpitation, especially when they are active. Of course, we are not talking about a 5K here—we are talking about walking to the kitchen, taking the dog out, or things that most of us would consider regular activities of daily living and not necessarily exercise or exertion. So it is clearly a subgroup within the broader long COVID group. If someone has a patient that meets this criteria, then what? Can you share how your groups in Malmo and Stockholm have been looking into these patients?

Fedorowski: We have learned a lot over these past months on how to deal with this issue. As you mentioned, not everybody has POTS among long haulers. In my opinion and in our clinics, it is about one-third of the population of long haulers that we can diagnose POTS or inappropriate sinus tachycardia or some form of post-COVID tachycardia. So one-third of this population will be diagnosed with a tachycardia disorder or something that we can relate to the cardiovascular system. We have a lot of people who do not meet the criteria of a cardiovascular disorder, but still they are sick and cannot breathe properly or go for a walk with the dog. They are very limited. Usually we are talking about people who are otherwise working every day, so this is a social problem as well. So we are now focusing on the cardiovascular manifestations and this is what we have noticed. In our opinion, this is not only about tachycardia, post-COVID tachycardia, or persistent tachycardia over a 24-hour period. We have seen people with phenomenon such as angina-like chest pain, where in some examinations, you will see a microvascular dysfunction on cardiac magnetic resonance imaging (MRI) using an adenosine test. In others, you cannot see anything, but still they suffer with symptoms that are difficult to explain. These are not people who are stressed or have a history of psychiatric disorder. There is no question of the patient making it all up—this is an individual who is really sick.

Raj: Are you doing cardiac MRIs? This may be stepping back or lead to a broader question. Is your thinking that the patients with this cardiovascular presentation with tachycardia as part of their long COVID or post-acute sequelae presentation are people that may have had myocarditis in the beginning, or are we thinking that it is something different? If it is a myocarditis group, then the cardiac MRI approach would seem to make a lot of sense, but is that who you are seeing or is it a different group?

Fedorowski: It is. You are absolutely right. The reason why we perform a lot of MRI is that we have quite a strong diagnostic center at Karolinska where the MRI group have a lot of protocols for microvascular dysfunction evaluation using adenosine provocation and looking at the perfusion reserve. It was a revelation for us when we saw the restriction of cardiac or coronary perfusion reserve in some of these patients reporting chest pain. Now we knew what was happening. But in 2 similar post-COVID patients with chest pain, one of them may have a profound limitation of perfusion reserve and the other will present with normal perfusion reserve. Still, both of them have the same symptoms of unprovoked chest pain, and some of them may have tachycardia or POTS. Some may not. Still, they are tired and their exercise capacity is limited.

My feeling is that we are only at the beginning of the road. We realize there is an issue now. This issue is not about emotions, a psychiatric disorder, depression, or psychosomatic problems. This is more or less a somatic issue with a lack of appropriate diagnostic modalities to catch the signal of what is wrong in the body. We are just digging a hole in this whole phenotype, getting all the pieces together into some logical hole, but we are still in the beginning. This is my feeling. 

To comment on the workup, we used to start with symptom evaluation and an active standing test. Then we used to perform a Holter ECG, not to detect any arrhythmias, but to see how the heart rate is controlled and to detect inappropriate tachycardia, increased heart rate during the night time, and heart rate spikes during the day. We might move to head-up tilt testing with cardiovascular autonomic testing. In patients with syncope susceptibility, we might perform 24-hour blood pressure monitoring to detect possible low blood pressure phenotype. We also perform laboratory tests.

Raj: Before we take too deep a dive into the management, I want to step back. In your sense of post-COVID POTS or post-COVID tachycardia, do you think that the mechanisms are the same or similar to what we are seeing in pre-COVID POTS, or at least one of the mechanisms? I think most of us agree that the traditional POTS was not due to one thing that had a heterogeneous group of causes in different people. Do you think it is the same? In which case, the issue is that COVID-19 is a virus, there was a significant group that had previously described a post-viral phenomenon, and maybe that is what we are seeing more of? Or, do you think there is something unique about COVID-19?

I think all of society has learned more about angiotensin converting enzyme-2 (ACE2) than probably ever before. The number of ACE2 experts has increased by multiple orders of magnitude compared with the pre-COVID era. But you could make an argument that perhaps there is something about COVID-19 working on ACE2 that has interesting roles, both in the renin-angiotensin-aldosterone system where it resides, but also in regulation of the sympathetic nervous system tone at the brain and brain stem level. So do you think there is something unique about COVID-19? Or, do you think the issue is that while people used to get viruses, we did not know the name of the virus and they occurred at a low rate, and suddenly we were in an era where the viral infection was likely COVID-19 and there was testing for it that did not exist in as meaningful a way for the plethora of viruses that traditionally afflicted us?

Fedorowski: I will revert this question by asking, if we did not know anything about POTS before this pandemic, what would cardiologists call it? Would they look at the POTS signs at all? There are still centers that perform a cross-sectional evaluation of the long COVID population, not really looking at these parameters or investigating the patients in the direction of POTS or inappropriate sinus tachycardia. They care about myocarditis, myocardial infarction, hypertension, kidney function, and so on. There is an obscure side of it called dysautonomia. So that is why people seek out us experts now—because they need us to explain what we are seeing. I would like to emphasize what you said before—that while we are now seeing an increase in cases, this problem was with us before because we have seen it before. What is unique with this pandemic is that the viral trigger is consistent. It was not known in the human population before, and now we are seeing a lot of cases. Why do only one-third of all long COVID patients develop POTS? This is another story. It is probably a question of how we evaluate these patients. If a gastroenterologist or neurologist possessed the modalities to detect date-specific syndromes, they would probably come up with more cases in specific categories. What do you think about this interpretation?

Raj: At the risk of going down a rabbit hole, when you bring up the issue of investigators not assessing this, the most timely version of this that we have seen is the recent release of the study from the Intramural Research Program (IRP) of the NIH, which has had a fairly comprehensive look at patients with long COVID with a battery of tests. They essentially came out with the conclusion that most tests are normal. This just came out in the Annals of Internal Medicine,3 and one criticism has been that there was no attempt to look at anything autonomic, and the truth is that autonomic is a big, fancy, scary-sounding word.

If we were to simplify it, there were no tests looking at orthostatic vitals—just what happens to heart rate and blood pressure on standing, which is a fairly simple test—there are obviously tiered and more complicated tests that could be done. The more controlled way of assessing orthostatic vitals is with a tilt table. But that is a barrier for some people. Some people will not have easy access to a tilt table test, but the point is that we have all used a standing test as a surrogate. In fact, in the position statement on POTS by the Canadian Cardiovascular Society,4 it was made clear that the standing test was perfectly acceptable.

There are subtle differences. The standing test is a little less sensitive for tachycardias than the tilt test. But the flip side is that if someone has excessive orthostatic tachycardia on the stand test, they do not then necessarily need a tilt test to confirm that—the finding is real and a stand test requires a blood pressure cuff and a floor. So it is not something that is out of the range of anyone with a practice or an office or examining room to do. I guess one of the criticisms of the NIH study is that they did not look at that, and one truism in medicine is that you are not going to find something you are not looking for. If you do not ask the question, you are not going to get the answer. That is true on history and on the physical exam. If you do not listen for the murmur, there is almost no way you will hear it. You have to, in some ways, actively seek out some of the information. So the challenge is that we all have a certain expertise. In defense of people running these studies, you cannot test for or be an expert in everything, but it does seem like a fairly glaring omission given that this seems to be a symptom that the majority of patients have, if not a significant minority. You do not have to search hard to find patients with orthostatic intolerance symptoms in long COVID.

Fedorowski: I agree with you. There must be some reason that in some studies, they do not detect these autonomic or dysautonomic abnormalities. Then suddenly you will see one-third of the long COVID population being affected by dysautonomia in some form. Of course, we might be a little biased because we see these patients every day in our clinics, so we are very sensitive to catch that whenever we see patients or hear their story. We are listening to these patients telling us that they feel palpitations or dizziness. I know you do not like the term lightheadedness, which many patients use.

Raj: Just to clarify, you bring up a pet peeve of mine. My peeve is not with the patients using the word dizzy. The truth is, that is a commonly used word. My peeve is when medical professionals, house staff, and referring physicians write that down. While dizzy is certainly a word in the English language, it is not really a proper medical term. Dizzy could refer to lightheadedness, which often has a hemodynamic-related issue and can be addressed in our clinic, or dizzy could refer to vertigo, which tends to be more vestibular and could be brain stem based. The truth is that some people could have both—most fall into one category or the other, but there are some people that have both, and we know the interaction between the vestibular system and sympathetic nervous system.

The point is, if we are going to start using terminology like dizzy or allow that, then we might as well go back to speaking about lumbago. There is some vague problem. We need to be more precise. If we want to try and understand the problem and offer some treatments to help, we need to know what it is that we are supposed to be helping with. That is why I object so much to that term. It leaves us short of being able to properly assess and help patients.

Fedorowski: I agree that we should probably not treat the symptoms, but evaluate them first and find the hemodynamic background for those symptoms. This is exactly what we are promoting. We are talking about autonomic evaluation or cardiovascular autonomic tests, which may seem obscure or not valid for many physicians. We are talking about the renaissance of cardiovascular autonomic testing. We are reclaiming the autonomic territory for cardiologists, because the fact is these post-COVID patients are looking for help. They do not go to neurologists, they go to cardiologists because they feel something is wrong with their heart. They have palpitations and chest pain. They cannot breathe or walk their dog.

They ask their cardiologist about what is wrong with their circulation, their heart, and their breathing. To diagnose it properly, we have to use diagnostic modalities such as an active standing test to interpret it in an appropriate way. You have certainly seen active standing test or Holter ECG protocols being evaluated as normal. It is quite normal when your heart rate increases by 40 or 50 beats per minute (bpm) on standing, and you feel a little bit dizzy or lightheaded. This is what my patients hear. If your heart rate is 110 bpm over a 24-hour period, it is normal—some people have a higher heart rate. Again, this is what they are told. So I think there is a huge need for education as well.

Raj: When you talk about cardiologists reclaiming autonomic disorders, the first thing that popped in my head is there are probably many people that are going to be listening to this who want to return it and who do not necessarily want to make that claim! But it is actually not a new thing. One of the interesting things in a slightly different disorder in dealing with neurogenic orthostatic hypotension was who treats that. There is a drug called droxidopa that has been on the market for a little over a decade, but it is the newest drug developed for this, so it was interesting to watch how and to whom it was promoted. With neurogenic orthostatic hypertension, nerve damage often occurs in the setting of movement disorders, such as Parkinson’s disease and multiple system atrophy. So, perhaps the initial thought was that the target of marketing and education should be movement disorder neurologists. It turns out that while it is absolutely true that movement disorder neurologists see patients with Parkinson’s and multiple system atrophy, it is not as true that they deal with orthostatic hypotension. One of the things that became clear based on data of who was prescribing the drug is that it was mainly cardiologists, or at least a high percentage. So there was a shift toward educating cardiologists about the drug, because I think they realized that when there are problems with heart rate or blood pressure, even if it is due to something else or may belong to another specialty, patients often end up seeing a cardiologist.

So in some ways, we have seen a version of this before. The manifestations are cardiovascular, so these patients are going to end up in our offices. Therefore, it is in our interest to find something to do.

Raj: We have established that there is a large tsunami of patients left in the wake. I may have totally mixed up water-based metaphors that do not necessarily go together, but we will stick with that. These patients are here. They have tachycardic presentations. In many ways, they are functionally disabled and symptomatic. So we have established that they come to see you. Now what?

Fedorowski: It is quite easy. In my view, you have to properly diagnose them and find out what is wrong with their body or circulation. This should start with symptom evaluation and score to see how much they are affected. Then move on to tests. We use cardiovascular autonomic testing, but you can start with active standing tests. You should then record both blood pressure and heart rate. Let them stand for at least 10 minutes to see what is happening. Then you will get some idea about what is wrong with the global circulation. If you are sure about what is going on and can diagnose POTS, then you should implement treatment. There is not much in this area that we can use, based on randomized control studies.

You have contributed a lot in this field, Satish. There are some drugs such as ivabradine or beta blockers for increased heart rate, especially if this is accompanied by inappropriate sinus tachycardia, if the blood pressure is unstable, you can use drugs like midodrine or droxidopa, or fludrocortisone to increase the blood volume and repair the damage in the global circulation. There are also a lot of nonpharmacological measures such as increased volume or fluid intake, compression garments, and rehabilitation training to increase the muscle pump efficacy. There is a lot you can do.

Raj: In broad strokes, the approach you mentioned is what we use for POTS and we have tried to morph that over to our approach for a lot of our long COVID patients with the tachycardia features. Again, I do not think we emphasize enough that long COVID is not one thing—it is a universe of things. If you can figure out a specific underlying cause and treat it, that is great. In many cases, I think we are left trying to treat symptoms or issues that we recognize from other aspects. There is nothing wrong with that or trying to do both. In the short term, patients are going to get more benefit trying to use approaches that we have used in other similar-looking disorders.

So we are very aggressive about nonpharmacological treatments. With water intake, we try to get people to drink at least 3 liters of water a day. That sounds like a lot, and it is a lot, right? But it can be done. Most of our patients with POTS, and now increasingly, long COVID, are able to do this, but it takes a change in mindset. People have to go from drinking water when they are thirsty to drinking water because it is prescribed, almost like a medicine. I tell people that to do this successfully, you almost definitely need a water bottle that you like and that you have with you. It should almost be stitched onto the end of your hand. So if someone comes to clinic and do not have their water bottle, they will tell me they do have one but did not bring it, that is a problem. Because to get the 3 liters in, you almost have to have it with you all the time. I am not good at adding up a little of this, a little of that—you want a simple approach. One of the nice things about water bottles is that they come in all different sizes—some are 500 milliliters, some are 750 milliliters. You just have to figure out how many you need throughout the day. Most patients are able to do that.

We are also very aggressive about salt. One of the differences in our approach vs perhaps what a lot of other physicians are doing is other people will try to eat salty foods to get more salt in. Some people will say to get this many grams of salt because people want to know. But again, I think there are few people in the world that can add up the number of milligrams of sodium that they are getting in everything they eat. The recommendation for POTS is a lot of sodium supplementation. Different guidelines say 8-10 or 10-12 grams, but overall, it is about 10 plus or minus grams extra per day.

We have gone to what we call our “Ziploc bag” method, in which we get patients to take a teaspoon of salt to start—although in many cases, the target dose is 2 teaspoons—and put that into a Ziploc snack bag in the morning and use that to add to their food or other ways of getting it in through the day, as opposed to shaking it on, where it is more uncontrolled and you do not know how much you are getting. The point is, predose it so you know this is how much you have to get in and this is where I am going to take the salt from. I tell my patients, I do not really care how you get it in, because for most patients, I think they find it easiest to add to food. I have some patients that add the salt to hot water and lemon juice, and drink it.

Fedorowski: It sounds awful.

Raj: But this is the point. It does not matter if you or I think it is awful. If that works for the patient, it gets it in. I have some younger patients who will sometimes take a third of a teaspoon of salt and put it in a shot glass with a bit of water and do salt water shots.

Fedorowski: What about tablets and taste?

Raj: I am not a big fan of tablets. If you hate the taste of salt, tablets are better than the stuff you buy in the grocery store. The reason is because you only taste the surface area—the outside—which is less. The challenge with tablets is that you get a high concentration of salt wherever it happens to land in the stomach. So, my sense in talking to patients is that I think the tablets can be associated with more nausea and vomiting risk than the stuff you buy in the store. It is also more expensive. So I am not a big fan of most tablets. Now, if some people really do not tolerate salt at all, there are gel-coated capsules that get absorbed beyond the stomach that tend to be associated with less gut grief. So if people can afford it, they can do that and it is better tolerated. But the vast majority of my patients can find a way to get the 2 teaspoons of salt in.

Does everyone need 2 teaspoons? No. The truth with most medicines is that the lowest dose that gets the job done is ideal. The other truth is that while there are good data that high sodium intakes do things that we think are good in patients with POTS—expand blood volume, decrease the pressure on the sympathetic nervous system when upright, and decrease the upright heart rate and orthostatic tachycardia—we do not know what the long-term effects are. So we need some data on if this can be sustained over 6 months, but the data that are harder to get that we do not know the answer to is the 10-, 15-, and 20-year implications. That is the uncertainty that we have to live with. What I tell my patients is that this is the advice for today. You have done a lot of work on this low blood pressure phenotype, with many of us led by you and a few others. Most of the patients we are seeing are not hypertensive at baseline, they are hypotensive or borderline hypotensive. So, hypertension middle age is not a concern now, but physiology changes as we age, so all advice has to be temporal.

Fedorowski: Can you give me your thoughts about this very important issue? We are talking about salt, fluid, and water intake, but this is just to compensate for something wrong in the body. So why don’t we get to the root of the problem?

Raj: That is a good question. I think a lot of patients would agree with you. That is just treating the symptom and not figuring out the underlying cause. That is fine, if you can tell me what the underlying cause is in most people, and not just what the cause is, but how to fix the underlying cause. There are theories about viral persistence. There are theories that it is an autoimmune problem and treating it will help. The moment those studies come out confirming that it does that, I am fully in favor of treating that underlying problem. The problem is that we do not know that information. At least I do not, and I do not think anyone does at this point. I do not think there are good data on that. In the POTS world, which has existed for a lot longer than the post-COVID world, in many cases, we still do not know that.

I think we do patients a disservice if we say to wait until we figure out what the underlying problem is and that we will get back to them. In the meantime, we tell them not to do anything—just hang on. The reality is that patients are suffering now. In the approach we are taking, we are focused on the signs and symptoms. We see the tachycardia and it is clearly abnormal, and lots of patients have low blood volume. We can formally assess that in some places more easily than others. But ignoring that to say that we need to focus on finding an underlying cause and then we will deal with it is a problem.

In POTS, there are only a few people in the world where we know the cause of their POTS. For example, there is a pair of twin sisters with a mutation in their norepinephrine-transporter gene; the case series was published in the New England Journal of Medicine in 2000.5 The proband who was studied at Vanderbilt is a remarkable woman who ended up starting a patient group in the late 1990s or early 2000s. I remember her telling me at one point that other POTS patients would tell her how lucky she was that she knew the cause of her POTS, because they found this mutation while they could not find a specific cause in most other people. She said that while this was true—she knew that there was this gene mutation—she still had all these other symptoms that they had, so saying that she had this mutation that now had a name did not make any of those symptoms any better. So I think there is a bit of a fallacy in the general public that if only we found the cause, the treatment would magically appear. Right now, it is absolutely true that sometimes finding a genetic cause can lead to developing targeted treatments, but that is the exception—it is not the rule.

Fedorowski: You are absolutely right. We may continue talking about different theories, hypotheses, and the underlying problem, but the thing is patients do not care about our theories, hypotheses, and explanations. What they are looking for is the cure for the ailments. They want help. But the reason we are looking for underlying issues is that if we can treat the underlying problem, the issues will probably disappear. This is our hope. But as you mentioned, there is a mixture of different etiologies involved in POTS. If you look at diabetes, you may have autoimmune diabetes or a lack of insulin and a depletion or exhaustion of the insulin system, resulting in type 2 diabetes. So in the end, both groups will have increased hyperglycemia and suffer from diabetic complications. The reason for this disorder may be different in various people, but the treatment is insulin and antidiabetic drugs. We are probably approaching the same stage in POTS, where we are trying to determine what the patient is suffering from and the underlying problem, so the treatment might be the same in the end.

Raj: It may or may not. I want to be clear—I think there are things that we have to do to try and treat the patients as best we can now, and hopefully some will improve. Not everyone will—we know that—but that is what we have. That does not mean at the same time that we should not be thinking about trying to better understand mechanisms and see what is going on. There may well be targeted treatments. We know that there are studies right now, for example, out of Dallas, looking at immune modulation with intravenous immunoglobulin in some patients with POTS, but these all need to be studied. We cannot, based on a one-off result, determine that we should do this or that. There is new literature on micro clots in long COVID and whether this plays a role or not. I think that is a fascinating hypothesis. But I am intrigued by people that have jumped on this as the cause or problem, when this is still preliminary. I do not understand what I am supposed to do about it if I do send a patient to a specialized lab to get this, how is that going to help me to help that patient, besides the knowledge that they have that? So I think we have to look at understanding physiology and research as the first step in the journey to figure out if that may be causative or lead to novel treatments vs something that is actionable in the near future.

Fedorowski: I am going to be a little provocative. Do you think that this virus has created a great opportunity for us to study the syndrome? I have such thoughts from time to time. What has happened is a tragedy, but maybe we will get some new opportunities to study this issue.

Raj: I do not think a lot of the issues around long COVID or the challenges that the patients are suffering from are new. Challenges include sudden disability. In many cases, I think most health systems are not designed or equipped to deal with it. There are problems with disjointed and uncoordinated care, certainly in our jurisdictions in Alberta and I think more broadly in Canada, but I do not think it is a uniquely Canadian problem. I think patients in the United States and Europe have complained about this as well. Our systems are not designed to deal with complex multisystem illness.

A long-time scientist and preeminent autonomic investigator at NIH, as well as a huge baseball fan, has often compared his team at NIH with the positions played on the baseball diamond. To extend that analogy, I think the challenges with a lot of these autonomic disorders are what we would call a bloop single in baseball. It is not that it is a hard-hit ball, but that ball happens to fall between 4 different fielders and those fielders represent different specialties. So the challenge is that the manifestations cross over multiple specialties, and we are all products of how we were trained and the experiences we have. It is not a criticism, that is the way it is. But none of these issues—POTS, long COVID POTS, or orthostatic hypotension—are core to any one specialty. We talked about the issues with orthostatic hypotension in patients with Parkinson’s disease. Does that belong to neurologists, some subtype of neurologist, cardiologists, or endocrinologists? The truth is, it depends on who knows how to treat these patients, because it is not core to cardiology training. It is certainly not an integral part of cardiac arrhythmia training, but it is not necessarily core to what the neurologist thinks is in their area. However, patients have this and need to be treated. The broader challenge is that these patients are falling in gaps, and there are opportunities for health systems to see if we can address care issues for long COVID patients or COVID long haulers. I think that will help other patients who have suffered from similar issues with chronic multisystem disease that is fully understood but where they have had trouble getting that coordinated care.

Although I am not sure it will happen, I think it has the potential to focus more interest from research-funding agencies. Certainly, NIH has explicitly talked about long COVID and tried to create some consortium and evaluation, the RECOVER Initiative, etc. Whether this will translate into more research funding based on investigator-initiated ideas, I do not know. One of the challenges is that, as you said, these are poorly understood disorders.

There is a bit of a chicken and egg element to applying for research grants. We both put in grants and spend time reviewing grants, and it is a much cleaner process when there is a lot known about the pathophysiology and you are trying to make the next step than when you are trying to understand it and group people to figure out those initial steps in pathophysiology. It is a lot harder to get funding at that level. Those projects tend to be less competitive. Could that change? Possibly. If this is deemed to be enough of a public health issue, perhaps funding organizations can make these priority items and indicate that this is something that they want looked at more seriously where the reviewer will take that into account. So there is potential and I am hopeful, but I am not certain that it is going to happen.

Fedorowski: I would argue with you here. From time to time in the cardiology department, I see a lot of patients needing transcatheter aortic valve implantation, which costs a lot of money. We are talking, on average, patients aged 80-85 years. So these are older individuals that we spend a lot of money on and put new valves in to ameliorate their remaining life.

But now we are talking about young people aged 30-40 years and they are incapacitated. They are very hard-hit by the virus and by the sequelae of this viral infection. They are not capable of working as they did before. So I think that people should understand that for us, this is an opportunity to study the virus and the consequences with autonomic disorders. On the other hand, I think we are dealing with a huge social issue as well. At least in Sweden, people in charge of grants have realized it, and there is a separate category for post-COVID complications. So I think it is going to come.

Raj: I hope you are right. There is no question that these patients have been severely impacted. In many cases, this has financial impacts on the individual and their families, but I think it has the potential to impact society as well. We had significant shutdowns with COVID-19 where businesses were not able to function in most parts of the world. While that has eased, the interesting thing is that in many parts of the world—Canada, United States, and parts of Europe—there is now an inability to get enough labor. I think there are lots of reasons for that, but one of the reasons is that I believe the workforce has shrunk. Maybe in some cases, I think it is because people are sick. People are not able to do what they were doing before. If it is 1 or 2 people, that is an individual tragedy, but when it is hundreds of thousands of people, this now becomes a societal problem that will affect societal economies.

Fedorowski: What about brain fog?

Raj: That might be a whole podcast on its own!

Fedorowski: How do cardiologists become experts in brain fog? Please tell me!

Raj: That is one of the challenges—these patients come with a litany of symptomatic complaints and maybe they all have one underlying cause, maybe they do not, but it is unlikely that they are going to come to a practitioner who understands all of those issues. I certainly do not, and I do not think that you do. I think the challenge or the risk is that there is almost a sense that I cannot manage everything, so I am not going to manage anything. I guess if I was to leave our listeners with a key message, it is that you do not have to do everything. Do what you can.

Most of us in cardiology are probably pretty good at managing heart rate and blood pressure issues. We are probably less good at managing cognitive issues, and maybe somewhere in the middle at managing breathing or gut issues. I can personally take an excellent syncope history, but I cannot take a great headache history. It is not the way I was trained. So I think it is important to do what we can, and hopefully, in every community there will be at least virtual teams or someone who is a headache specialist or gastroenterologist who can help with those patients.

I do not think people have to be that clear they can do everything, but they can be on a team and do their part and get their teammates to do their parts as well to help patients in a collective way, as opposed to getting discouraged. This patient has too many things wrong—I cannot fix all of it, so I will not try to fix any of it.

Fedorowski: When I start talking about post-COVID dysautonomia and post-COVID POTS, I used to start with quoting Alexander Fleming, who invented penicillin. He used to say, “An unprepared mind cannot see the outstretched hand of opportunity.” I think we should be prepared to use this opportunity to learn more and find good treatment for all these patients in the whole health care system.

Raj: Artur, thanks for spending the time with me to chat. I suspect that there is a lot more to cover. I do not think this problem is going away anytime soon. I look forward to doing this again with you sometime.

Fedorowski: Thank you for your company and for the discussion. As always, I have been listening to you with great curiosity and have learned a lot of new things as well. 

Editor’s Note: The transcripts have been edited for clarity and length.

References

1. Nalbandian A, Sehgal K, Gupta A, et al. Post-acute COVID-19 syndrome. Nat Med. 2021;27(4):601-615. doi:10.1038/s41591-021-01283-z

2. Raman B, Bluemke DA, Lüscher TF, Neubauer S. Long COVID: post-acute sequelae of COVID-19 with a cardiovascular focus. Eur Heart J. 2022;43(11):1157-1172. doi:10.1093/eurheartj/ehac031

3. Sneller MC, Liang CJ, Marques AR, et al. A longitudinal study of COVID-19 sequelae and immunity: baseline findings. Ann Intern Med. 2022;175(7):969-979. doi:10.7326/M21-4905

4. Raj SR, Guzman JC, Harvey P, et al. Canadian Cardiovascular Society Position Statement on postural orthostatic tachycardia syndrome (POTS) and related disorders of chronic orthostatic intolerance. Can J Cardiol. 2020;36(3):357-372. doi:10.1016/j.cjca.2019.12.024

5. Shannon JR, Flattem NL, Jordan J, et al. Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency. N Engl J Med. 2000;342(8):541-9. doi:10.1056/NEJM200002243420803

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Any views and opinions expressed are those of the author(s) and/or participants and do not necessarily reflect the views, policy, or position of EP Lab Digest or HMP Global, their employees, and affiliates. 

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