Chapters Transcript Video POTS: New Horizons, New Frontiers Blair Grubb, M.D., F.A.C.C., presents at the Johns Hopkins POTS Grand Rounds on August 12, 2021. um I just wanted to go over some newer things that we're doing. Um you know, I think everybody here is pretty well versed in in pots and the physiology and things. Um and so the questions that I'm going to try and answer are could plants have an autoimmune basis? Also could there be what's called an auto inflammatory component? And also um could there be an overlap between neuro cardiogenic syncope B. And um and part to revise vagal syncope P. And so we've been publishing a series of things I wanted to share with you. Um yep so what is an autoimmune disorder just sort of going over and I didn't know who my audience exactly was going to be. Um anybody's are these protein complexes that identify areas that are foreign and then sort of become targets for that for T. Cells and B cells to destroy. They bind areas called antigens. And again having had a background mainly in electrophysiology, this was sort of a new uh field for me. And so the anybody's themselves, I think you've seen these pictures. They have several um parts of them that bind and again they normally bind to foreign objects such as bacteria or viruses. And then our markers for immune cells or killer cells to come in and destroy that area. And unfortunately what can happen particularly increasingly in the modern world is that these antibodies combined two parts of us that are that are self instead of other and then your own immune system can come and attack them. So why did we think that there was an autoimmune basis for pots well. And it's 70% of the cases that we've seen. People will describe onset after some kind of federal illness that's been presumed to be viral. There's a higher frequency of of pots with known autoimmune disorders. We see many people who have thyroid itis who have shogun syndrome, who have rheumatoid arthritis, who have a number of other autoimmune processes. Um And also we've also seen that a group of POTS patients will later develop our immune processes, especially multiple sclerosis. So um the we we felt that there was some kind of link there and um again the group again, I wasn't sure who would be talking to, but just to review what happens in many people is there is an inability of the peripheral vascular should vasculature to maintain sufficient degrees of constriction during Ortho static stress which allows excessive amounts of vascular pooling with a compensatory tachycardia and increase in myocardial contract ill itty. Um This is from the work of Julian Stewart who was a pilot, has been a pioneer in the in the field and this just shows you a control subject. Um And in a patient with pots showing a much higher heart rate and somewhat lower blood pressures. And also you can see the cooling effect with the development of acro cyanosis and also some degree of swelling of the tissue is measured by politico's mammography. Mhm. And then they have a whole range of symptoms which as I've learned, are not unique so much two pots but rather are seen in many autoimmune disorders where there's a generalized sense of malaise and feeling unwell that seem to occur in many, many patients. And this is from work done at the Mayo Clinic. Um one of the, one of the amazing things to me is how interconnected this is with other illnesses and other things. Um and I came across this quote from da Vinci which I think is applicable to um uh these matters. So um the idea that there are, we could isolate anybody's to give credit where credit is due. Steve Marino did Land Mark pioneering research while at the Mayo clinic and was the first one to identify autoantibodies to acetylcholine receptors that were in in a somewhat different group of disorders. But autoimmune disorder know MiA's and um This is from a paper he published in the New England Journal in 2000, looking at thermo regulatory sweat testing and individuals and comparing it to the antibody titles that were that were seen there and he demonstrated extremely convincing evidence that there could be an autoimmune pathology to some of these disorders. Um later in 2014, Dr. Kim who unfortunately passed away due to COVID and his group at the University of Oklahoma did again, landmark research demonstrating the presence of of auto antibodies principally to alpha one receptors in in vascular tissue And did this in about 14 patients that were published in 2004. I mean 10 patients were published in 2014 and again, this was this was a truly landmark study that I think he doesn't get the credit for he deserves. Um So just to go over where these are um the there are Adan ergic receptors throughout the body. Um the alpha one receptors are in the blood vessels oftentimes in the skin. They also are heavily within the gastrointestinal track. Um and alpha two receptors are in the brain, they also are in uh paris synaptic nerve areas and things. So these are extremely diffuse lee found throughout the body, not just in one particular place. And based on Dr. Kim's research, we suspected that there was a high density of Alpha one receptors that could be that could be part of the ideology of these. There's been a series of people who have been looking at the presence of autoantibodies and a variety of autonomic problems. And these include not only just pots but also idiopathic Ortho static hypertension and also in diabetic patients as well. And so there's been a huge amount of research that has been coming out lately. One of the great contributors in the field is dr arthur Federov Ski in Sweden and this is somewhat of an overview um of these studies that have that have come out to date. Um and sort of recap them here. Um and everybody's been using various technologies to be able to look at this but we all have the same idea that there's some kind of autoimmune pathology going on. Um So there's been a progressive building of research and a number of different studies looking at could we find these antibodies and different individuals. Now there's also a feeling that there could be um uh screening component especially dr Marino's research at Dallas Southwestern has has been showing that he feels that there is a must clinic um anybody that's present that also could play a role. So we decided to look at these and uh we looked at uh 55 patients originally and then we we showed that 89% are close to 90% had extremely high levels of auto antibodies to alpha one receptors. Um and there were other ones too, but they were a much smaller frequency. So the number was high enough that we were extremely um uh Intrigued by this as a potential pathology. We also incidentally found that in 50% of the people who were positive for alpha one auto antibodies that they also had must clinic and four receptor anybody levels at very high levels. Um and we feel that this has a role in the path of physiology although it's unclear exactly what it is. The M four receptors have not been well characterized in humans. Um So their their role is somewhat of a mystery. However uh M four receptors are very densely found within the basal ganglia of the brain and help govern dopamine release. Now interestingly, we also identified seven patients where the levels of everything was elevated. Um and these tended to be very sick individuals. And it really sort of I think brings home the fact that we're dealing not just what with one um uh entity, but rather a number of different subgroups that could be present with different people having different levels of antibodies present, not dissimilar to what some of the rooms neurologic disorders have. So to summarize in this study we showed that 89% of patients had high levels of circulating, alpha one an urgent receptor antibodies. And then um 50% of patients out of that group had elevations in the most clinic and for receptor antibodies. Now we also thought that there could be a another component. Uh My my research partner dr gunning is a internationally known expert in platelet function and there is a growing body of research that is demonstrating that the platelet may play a important role in the immune system. Um Indeed, platelets may be part of the first line of defense um uh in the immune system. Uh Dr Gunny is an expert and and co discoverer of a condition called delta granule storage disease of platelets. Uh it is a type of clotting disorder which was originally thought to be relatively uncommon. However, as we began to look at our patients, many of them would complain of bleeding problems, extremely heavy menses, um nose bleeds, easy bruising and as part of our evaluation of these individuals, because it's one of the tests that are done at this institution, we would we would not only get the standard coagulation panels on them, but also would look for delta granule storage disease. And to our amazement, many, many, many of these patients would come back positive. So we wondered if there was some kind of association here. Um And when you look back through, you know, these pots patients, a number of the patients we saw would complain of of of um symptoms that were suggestive of platelet dysfunction And indeed, um many of these people, as they said, had all kind of bleeding disorders. What we found is that almost 80% of patients had evidence of delta granule storage disease as opposed to an expected incidents. When this was a case control study of only about 5-10%. These are examples of normal platelet morphology with normal amounts of dense Granules that you can see in these areas. Um So when we compared our our patients um with pots who had a history of bleeding to match control subjects, we found this huge difference in in the frequency of this disorder, suggesting that it was acquired rather than a congenital thing and suggesting it had some role in the pathogenesis of it. Um Now again, I am sort of getting out of my level of expertise. I am fortunate enough to have an immuno pathologist to work with? Um But the platelets have um all the known 10 toll like receptors on it appears to be an integral part of the innate immune system. We'll talk a little bit more on that in a moment and it's thought to be one of the first lines of defense. Um I didn't know this but it creates a number of the inflammatory cytokines that are released during the innate immune response to infections. Now. Um the most, most of us have kind of forgotten since medical school that there are two aspects of the immune system. There's one part called the innate immune system you were born with. The other is the adaptive immune system that you acquire over time. The innate immune system will use mass cells, macrophages, neutrophils and a series of compounds that are called inner Lukens to be able to identify and be chemical signals. Um uh that there's some kind of invader present and the adaptive immune system is one you're more used to thinking about because of T cells and B cells with anybody's that mediate the response. We suspected that there was a innate immune component that could be present in individuals and that could play a role in the path of physiology. Oftentimes the innate immune system is very non specific in nature, whereas the adaptive immune system is very specific in what it attacks. So we decided to ask the question, Could is there evidence of an innate immune involvement. Um So we took plasma from patients that were known to have pots we did this mainly, and this was during the height of the pandemic. And we could not draw any new samples, but we had a number of samples stored in the freezer from our initial study. So we said, well let's look at these and see what the levels of different cytokines are. Um And we found we also re ran the levels of auto antibody of alpha one L two antibodies as well as most chronic anybody's. And we found the exact same things as we did in our initial study, but we also found a number of of markers of interleukin and cytokine levels that were that were markedly elevated um compared to normal ranges to the established normal ranges that have been that have been published. And again, suggesting that there is a innate immune response system going on in an auto inflammatory response as well as an autoimmune response. Um Now we took this further and we again, we had a number of samples frozen in the freezer. And because of the fact that we we because of the pandemic, we couldn't go out and get new samples, we had 35 samples left from one of the studies that dr gunning had done Uh that were control subjects for for a platelets study and we decided to use these to compare to 35 pots patients that we had samples stored for. And we looked at it at 16 citations uh that we're done. This is was assayed by a company in Georgia that we've been working with Ray biotech. And again, what we found is a market elevation in inflammatory cytokines compared to matched control subjects um indicating some kind of auto inflammatory response that's that has been very, very prominent. Now, this is we're sending for publication in the next week or so. Um but but again, it shows there is a heavy inflammatory component going on suggesting some kind of auto inflammatory autoimmune process is going on in large numbers of these patients. Um Now again, this has to be worked out in much larger scales. We're actually, now the university has allowed us to resume research and we've gone back, we're initiating a study looking not only at POTS patients but also at matched controls. Um So these are the conclusions we've come to so far. Um These are going to have to be confirmed by larger studies which we have initiated uh and hopefully um now that we're able to uh draw samples again, we'll be able to get back to being able to demonstrate this. Um We've also been seeing as you've no doubt seen in the news. And Hopkins has a center for these individuals, a number of patients who have developed um pots like symptoms or autonomic symptoms after suffering a covid 19 infection. These are the long haul patients. There have been a number of reports about these. We have published one of them. And another arm of the study that we are doing is looking at post covid pots patients to determine whether or not they possess the same auto antibodies and inflammatory markers as our regular post viral pots patients. And again we've just enrolled our first several patients. Um so I I can't give you much in the way of progress thus far except that we're working on it. Now. Another aspect of things which we've been looking at is um whether or not there could be crossovers between these different autonomic conditions. So we got interested in this because some of the POTS patients would describe frequent episodes of of um Cinco B. And near syncope. E even though in the office they would demonstrate all the classical to Kartik responses. And during tilt table testing you would see people who would suddenly um become hypertensive and go into a sisterly much the same as the neuro cardiogenic syncope applications would. And we began to ask the question, are they doing this on the outside? And so to test this hypothesis, We wanted to monitor them long times. Uh the idea of monitoring people by the way on the outside was is credited to Dr. Norman Halter, you may not know that was a person, you just call it a halter monitor. This was the original found that when I was doing some research for a paper, this was the original halter monitor built in 1947 and it weighed £85. Um And uh that's a motorcycle battery up here to power it. Um But by he was he was a genius and got it down to about 62 and by 1964 to £2.8 what we've used our implantable monitors and these are injected under the skin. Uh These were the original ones, we were one of we were fortunately one of the first centers in the US to implant these in the mid nineties. Um Every major pacing company now makes one of these and they can provide long term monitoring with the newer devices lasting up to five years. Um They're injected under the skin here and women we put them a little bit higher um to be out of breast tissue. And this is what it looks like on an X ray. And this is a example of what we've seen. So we we had a group of pots patients that had recurrent episodes of sync api and near syncope? E even though in the office, they did not, they displayed all the classical features of pots and things like that. So we asked the question, could they be having periods of bradycardia asystole. In our previous studies, we identified three factors that were predictive of individuals having periods of a sisterly or at least extreme bradycardia and they were single, be without warning uh convulsive activity witnessed by by bystanders associated with it or prolonged loss of consciousness. That we defined is greater than five minutes. Recently we've added 1/4 which is injury bodily injury suffered during a sinkerball event. So this is a young woman who had post viral pots had classical symptoms, had classical symptoms and human dynamic findings in the office, but again, was experiencing episodes of sudden loss of consciousness that were associated with convulsive activity and at the same time, uh that were, that lasted longer than five minutes. So this is her during an episode that she's just going along a little bit higher rate than normal. And suddenly you can see that during her episode she slows down Um to fairly braided chronic levels and then just goes into complete a sisterly lasting 25 seconds or more on this episode alone. Um, So based on this, we published the first paper, we looked at 39 patients that were clinically found a postural tachycardia syndrome. And again, in these individuals, we demonstrated prolonged a sisterly or bradycardia and we defined bradycardia is less than 30 beats a minute for this. In these individuals who have proven refractory to any other therapy, they underwent implantation. We used a pacer that has the capability of quality of closely of closely, closely single episodes were eliminated. Not there other pots symptoms. So it this this approach is only applied when you, when we've documented without any doubt that they're having recurrent episodes of a sisterly associated with their CinCO B. And again when we put the pacers in, its eliminated the sinkerball events, not the other symptoms. Um Just a word on on CLS pacing. Um this system attempts to have an almost surrogate marker for blood pressure by creating an electrical field between the tip and the can. When the when the heart is full of blood, there's less resistance to current flow than when it's empty. So it's an indirect measure of how full the ventricle is and when the blood pressure drops rapidly, the impedance will raise and then the device knows to pace faster. And this has been shown in neuro cardiogenic syncope, be in double blind randomized placebo controlled trials to work seven times more effectively uh in preventing sync api than standard pacing. There was a published study called the spain trial published in the journal of the American College of Cardiology that demonstrated that um we just recently published a series of papers, this is another paper where we looked at again, a larger group of patients that we've uncovered utilizing implantable loop recorders and again gotten the exact same results that if you uh if you have people with refractory sync aPI and they are demonstrated by implantable loop recorder to have recurrent a sisterly that's associated with their loss of consciousness utilizing CLS pacing can virtually eliminate these events. Now at the same time. We one of the things that that I that I think needs to be emphasized is we found that patients will be telling us things and and no one else has listened. So we've seen groups of patients who say you know I have taco cardio and they get really fast but you know some of them just come on like really rapidly and then end really rapidly. And sometimes I can even get them when I'm lying down or when I'm seated and um utilizing the loop recorders. What we owe this is put through this in the today this is um a young person who's in their middle twenties who again is a classic pasta patient was having recurrent episodes of of cinco B. With convulsive activity and incontinence. Um And we just put this loop recorder in a couple of months ago and this came across um yesterday evening. Um and um and this was not a bad episode but it shows you you know what's going on out there. So what we've seen using these is some of these people actually have true S. V. T. S. With rates of 220 beats a minute. And um looking at that we've said well maybe we can fix the part of this and taking them to the E. P. Lab identify the fact that they've had a V. Node reentry accessory pathway reentry, atrial flutter you know a whole variety of things which we then have been able to successfully of late and again these do not this does not eliminate their all their symptoms. It just takes away one aspect of their symptoms. But at the same time it's one that you can eliminate. We've also seen more and more that individuals can display a kind of a tacky brady syndrome. Um They can alternate between extremely high rates in in in pots and then spontaneously have extremely low rates as well. Um And again we just published this again a case series that we just published uh demonstrating again utilizing implantable monitors that that there can be tremendous swings in heart rate. And these are individuals who were not being treated with agents that lowered the rate. So this was not uh being produced by pharmaceuticals but rather these are just normally what they what they were. And then treating these individuals becomes very challenging just the same way it does in classical sick sinus syndrome. When you go to treat the tachycardia as you can make, the bradycardia is even worse. So but the point is that that oftentimes you have to listen very carefully. People can have coexisting pathologies that are going on and if you need to be able to filter out, you know what what's happening. We have found the loop recorders very very useful in distinguishing whether or not other rhythm problems are going on because of the fact that they they're they're they're monitoring constantly. Um and they're transmitting wireless wirelessly to us. They can't be manipulated by the patient. Uh and they give good objective data. Um So it's also made me made me question, even though I've been part of the committees that have established guidelines and all that, but sometimes you have to remember that, that while we do things for research purposes, reality may be very, very different. Stephen Hawking's once said that um the the universe's analog, not digital. This is I I enjoy reading stuff on quantum mechanics and things because I find it fascinating about how the universe works differently than our day to day perceptions are. And Heisenberg said since the measuring device has been constructed by the observer, we have to remember that what we observe is not nature itself but nature exposed to our method of questioning. So I think one of the things that we've been seeing is there can be a group of individuals that live in this realm here. And I borrowed this Venn diagram from the pulmonologist who used to show the relationship between asthma bronchitis and emphysema and I think that the same inner relationship occurs here that while there are people, there are many people who are purely one thing are purely the other, there are individuals that coexist in this overlap zone that have aspects of both disorders. Um the currently there is a again, I wasn't totally sure who my audience was going to be. Um there is a very well done double blind trial done by dr steven Marino at the Dallas Southwestern utilizing intravenous gamma globulin in, in patients. Um we have begun to to utilize the the same therapy. Uh this is an example um just wanted to show as an ending .32 year old woman who was um spent um several months in a in a hospital in another city near us, um had um uh developed pots and also was just totally incapacitated uh when she would get up when she would be laying flat. Her heart rates were in the fifties and sixties when she would stand up, her heart rate would literally go up to the 1 72 1 eighties. Um she began to experience sinkerball events, I guess you could say that's partially not classical pots, but for all intents and purposes. Um She was worked up, this was a major center. Um She was transferred, she was trying on a number of therapies transferred to us and then we tried other therapies to, and just nothing would make her better and she was ended up being in the hospital months at a time. Um and so she was completely bed bound, completely disabled, had been running her own business, had two Children and all this began after a viral infection. Um so we administered I. V. I. G. Again, this is just a case study. Um and very quickly, it's often said that that it takes several doses to really see an effect. But let me tell you very quickly she began to respond. Um And uh we she was so de conditioned. We had we had to admit her to our rehab hospital. However last time I saw her she walked in the clinic. Um and so she's been a example of an amazing uh success to I. V. I. G. We've written case reports looking at the effects of people who get drugs like Humira um who have coexisting conditions. So we haven't given anybody but purely pots but there have been people who suffer from Potts who also have enclosing spondylitis who also have rheumatoid arthritis. And they've received these immunosuppressive and their human dynamics have amazingly improved almost to the point of complete resolution. Um One of my patients was multiple sclerosis, received um their immunosuppressive therapy for M. S. And her heart rate and blood pressure completely stabilized. So you know I think that we're onto something. I think there's a lot of work to do to be able to look at this further. But I think it opens up a whole new possibility of understanding of the path of physiology and at the same time not only understanding the path of physiology but also providing therapeutic modalities for people who are unresponsive to um um normal normal treatments. So but at the same time I can tell you that my my wife receives Humira therapy was put on Humira therapy for um Rheumatoid arthritis and within one year had five major infections. Um So it you know and and so it can be you can trade one set of problems for another. There was a part of my life years ago when I was heavily involved in heart transplantation. And one of the major problems that we ran into was not so much people rejecting their heart but the complications they would um have due to the rejection, any rejection drugs. So I think while this is a very um exciting kind of phase we have to approach it with extreme caution that we don't cause as many problems as we're solving. So um thank you for the opportunity to be able to present this to you. Um I will I will qualify my statements by saying I'm a real novice to the world of immunology but I'm trying to learn and I have the great good fortune to be able to work with a partner who it is very easy to work with and understands all the things that I don't. Uh dr gunning has been a valuable research partner and and and you know I'm extremely thankful that we've been able to work together to look at this. So this is just the beginning of a whole new era and I think this will extend not only to autonomic disorders but a number of other disorders as well. Um So it's been an exciting time having been in this field for a long time. This is probably the most exciting time of all because we're finally beginning to understand how these disorders work and have the capability of putting them into remission. I think your would be a bad word about putting them in remission. Um I'd also like to thank the people who don't get thanked much. My first wife Barbara, who died of brain cancer, is a Hopkins alumna. She went through the Hopkins pediatrics program and uh was an attending physician at in pediatrics at the johns Hopkins Hospital and was the co director of the East Baltimore Health Plan, the pediatric part of the East Baltimore health Plan for years while we were still in Baltimore and she was, I don't think I would have made it through medical school without her. And uh I after she passed away every married doctor ever who's a PhD and uh direct and now the associate dean at Bowling Green State University. And um I have to say, I don't think I could have gotten anything done in life without their help. So, um I'd like to express my gratitude to both these women and thank you for letting me share this with you and I'd be happy to answer anything. I can thank you so much dr the accident Created by
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