# New insights into CFS and ME

## Метаданные

- **Канал:** York Cardiology
- **YouTube:** https://www.youtube.com/watch?v=nMx38g1OguE
- **Источник:** https://ekstraktznaniy.ru/video/43166

## Транскрипт

### Segment 1 (00:00 - 05:00) []

So, thank you so much for inviting me and thank you for being so willing to share your findings. I guess I better tell you a little bit about myself. Um, just so that you know my background and my background is basically that I'm a cardiologist, a practicing cardiologist. So, I'm not an academic. I just, you know, practice full-time in the NHS. But over the course of about 12 or 13 years, I've acred a large number of patients uh who have a disordinomia, postviral disordinomia, otherwise termed POTS. uh and what becomes very apparent is that many of them also carry labels of chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, functional neurological disorder and I became very interested in this because I started realizing that perhaps this is all one big condition rather than being different conditions. Um so inherently when whenever I'm dealing with a patient with parts or disordinomia fatigue is a huge part of their symptomatology it is perhaps the most debilitating part of their illness. — [clears throat] — And I think this is why you're be so valuable to me and all the people who follow me online and watch some of the content I create about this condition because fatigue is one of the biggest problems in this and it is perhaps one of the hardest things that for me to address with whatever I do. So know a lot of people will say my heart rate goes fast. Well that's easy. I can address that. You know we have medications to slow the heart down. People say that I don't digest well. Well, we have gastric motility agents etc. But fatigue is very difficult for me and that is why I think it is so valuable to me to listen to you. So I would love to hear your insights. — So uh I'm a also medical doctor by background but I have 40 years of uh expertise in drug research. uh there is I think no organ I haven't worked on in 40 years which helps me a lot to understand this multi-organ uh multi-system disease and most of the time maybe 50 20 years I worked in cardiovascular pharmacology and there's a lot of cardiovascular disturbances and also worked a lot on the heart and skeletal muscle and heart muscle are not so different there are differences of course but uh but concerning for instance the ionic regulation transporters and so it's it's almost the same. So I think I have an understanding of uh of the organs that are affected the target organs in ME in ME/CFS and uh 7 years ago 7 and a half years ago by chance only by chance I saw a report on TV on a young man that became betridden very sportive before and suddenly betridden with ME/CFS. Then I looked up in Google and I saw yeah there must be mental and muscle fatigue and then next day I went into PubMed and saw the second abstract. So I saw was a paper by K shbong who reported about better twoic receptors and other antibodies other antibodies. I worked a lot in a stroke project on on vas active drugs and uh I investigate many in a model a pig model where measured cereal blood flow and in parallel I measured skeletal muscle blood flow for comparison and there I found how important better two receptors are for the perfusion of the brain and muscle and for the heart. So this is the yeah let's say the exercise receptor more than perhaps at least as much as beta one you know in the pona it's dilating is better too so you can call it really uh the exercise receptor and without a bundes you would have of course less brain and less muscle perusion this is where I started of course it became much more complex but it's still right in part but this is where I started then I I went into the literature and I found this hypervol IA with low renin the rein paradox — and I tried to found I tried to find out what it is and finally I had an explanation. I worked a lot on compounds like procycling bradikinine and so things like that and uh and these raise renal perfusion and they inhibit uh tupular sodium uh reuptake. So sodium is excreted and this two effects they would anhilate the signals for rein. So reenin would be low and hypoalmia would stay. So uh there was a clear track to skeletal muscle. Skeletal muscle could release these mediators.

### Segment 2 (05:00 - 10:00) [5:00]

These are also the mediators of eskemia. Adenosin bradikinine protocyclinosia. These are the mediators and of and China pain to together with acidosis and they are all released. They are even released in the normally working skeletal muscle assessed via micro diialysis. So these are not only media mediators of eskemia but also mediators of hypermia. And if you have a skeletal muscle that is severely disturbed energetically, these med mediators will be produced. And if excessively produced, they spill over into the circulation. And these mediators are voactive, ales, hyperalesic, basmogenic. They uh raise micro they cause microvascular leakage. And of course, if you have them in organs where you don't need them, they would disturb the physiological blood regulation. So this is where I started and then the next step was then to postulate mitochondrial function which was not original because it has been shown postulate before but uh what has been postulated that it's disturbed in the whole body also in lucasytes so uh there are some reports about minor disturbance in lucasytes but I said it's not a general mitochondrial problem it's a mitochondrial problem in scal muscle And of course we don't know what's in the brain but in skeletal muscle I know these disturbances from eskeemia perfusion injury we worked a lot on this and also on on sodium transport and calcium transport in the heart uh with the sodium proton exchanger and sodium calcium exchanger. I spent at least 10 years with both uh transporters. So and these play also a role in uh in ME/CFS. So if you have a hyperparusion, you have a sodium overload, sodium loading, sodium overload and then sodium overload can cause calcium overload. This is the damaging mechanism in the eskeemia reperusion injury. It is not eskemia. It's a sudden reperusion that causes calcium overload via sodium overload. and I saw this disturbance could also be uh [clears throat] the main mechanism of mito damage which has now been proven when the electron microscopy uh init has been shown now Rob in Amsterdam also confirms uh cases of the electron the damage electron uh in the electron microscopy and we see all these change metabolic changes when the patient is on a sep you seeh lactate [clears throat] or even addressed and I have also an explanation for lactate addressed. You see the rise in lactate. You see the grounded opic incompetence and of course the much lower oxygen uptake. some performed invasive CPAT and you see that the Venus uh the Venus oxygen content rises is increased not decreased with a hyper perusion alone it would be decreased but if uh if it's increased this just means a diffusion problem or mitochondrial problem that oxygen is not taken up so they take up much less oxygen diffusion problem or mitochondrial problem probably both and these are really objective finding with this level of energy you can survive but you cannot live a normal life. The better at disturbance uh and later on I also realized that the sodium pump the sodium calcium sodium potassium must be activated by beta 2 receptors and also by small by uh by neuropeptides that are released from small nerve fibers which are also damaged. So this is mech mechanistically this is how it started. — Yeah. And if I may also come in there. So, just to introduce myself, um, my name is Patrick Usher and I'm the non-medical professional here. I'm an ME/CFS patient. Um, and I've been ill now for seven and a half years. And for me, the first few years of living with this condition, I was very much in the dark. Uh, I knew very little about how it worked. I was aware of a fair bit of the research, but I couldn't see how it all played together. And uh I first came in contact with Professor Vit's work around four years ago and I was really excited by it um because what he did is he wrote a unifying hypothesis of ME/CFS and for anyone who has ME/CFS who's watching us now um and they follow the research it often seems quite random all the different findings you know X is happening over here Y is happening over there there's something going on in the gut something in the brain something in the cells but what I was really excited about in seeing professor Vit's work was along with professor Carmen Shyenbogen they were tying it all together and showing how X could lead to Y could lead to zed and then could feed

### Segment 3 (10:00 - 15:00) [10:00]

back into X painted all out as an illness of interlinking vicious cycles that self- sustain each other and this just set off lots of light bulbs for me and you know some people you know I find professor Ver's research fascinating but it's it's not so easy to get your head around as a patient initially but I really tried I read all the papers. I studied them as best I could. And something that I do now is I have a YouTube channel uh understanding ME/CFS where I particularly talk about uh Klaus's work in an accessible way so that people can also hopefully not feel in the dark and my uh recent book understanding ME/CFS and strategies for healing is in the first part of it also focused on explaining Klaus's uh work. And so for me that unifying model is so important because other conditions like rheumatoid arthritis or multiple scerosis, you know, they have models of their of the disease. Um, and they have certain patterns that you would expect to see actually occurring. But we've not had that for ME/CFS yet. It's always been this kind of thing that's kind of random. Um, but I'm excited about Klaus's work because it sort of I think could lead us to a situation where doctors in the future and medical students in the future will look at it and say and it will be alongside the other conditions because everything will have been mapped out. Um, so there's more I could say about uh what Claus picked up on there in terms of the low blood volume or the muscle sodium uh content or the calcium content of the muscles, but I just wanted to introduce myself and say that for me um I find Klaus's work really exciting because it's this big picture model that actually can demystify a lot of the seemingly random findings from before. — So it's very interesting. I mean this is incredibly interesting because I've also you know so as cardiologists we've always seen things in purely hemodynamic terms you know particularly with disordinia pots etc we always see it as oh it's a condition of standing up people are worse than standing so there's a hemodynamic compromise made when people stand and they don't compensate very well and that's why they feel worse but then when you talk to them they say well we feel rubbish even when we're lying down. — Yeah. And so for a while we always used to think, oh, it's maybe that the blood isn't getting there. But there's no doubt that the blood gets there. It's just that the nutrients that the blood brings are not being utilized in the way they should. Right. That's what you're saying. — Yeah. The neurovvascular coupling, I mean, uh, the skeletal muscle can raise perfusion 30fold. Heart, it's four-fold. And the brain, we don't know. It's no neurovvascular coupling. It's also probably a lot that it can uh it can it can increase on demand and this doesn't work. I think this ondemand uh rays arise in in uh in perfusion you know in now I mentioned uh Rob he found basement membrane thickening and we know it from diabetes basement at the expense of the capillary lumen now in MECFs you have oversized blood uh cells white blood cells less deformable artoyes you have micro clots and imagine if they get stuck in a narrow capillary and preload is low. So the pre-capillary pressure can't be high. How long such a blood cell or micro blood will remain in this capillary and then other capillaries if there's enough blocked temporarily others are hypoparused. So uh this normal blood regulation doesn't take place. — Absolutely. this the term that um I know Veran Shiden Boen us is this hypoprofusion this underp proferusion of blood um into the muscles and Klaus is talking about Rob Woo's findings but these are basically the capillaries in the muscles um have become very thick and because they've become thicker the blood and the oxygen from the blood is not able to get out into the muscles and then as Claus said you add in microclots for example which I used to have very badly uh I actually went to Germany a couple of years ago to have help apheresis treatment, a blood washing procedure to take out the microclots and my blood was so full of them that it had actually turned black. So it was actually so viscous and so condensed that it had become extremely dark in color. So yes, all of these things are creating this under profusion um uh from the blood into the muscles which makes them very hard for them to cope with taking activity. — Yeah. And the consequence is then this ionic disturbance consequence of this hyperfusion which then causes this mitochondrial dysfunction this sodium and calcium overload. U hyperusion always causes uh sodium loading because the proton that are generated from the anorobic metabolism cannot freely diffuse cell membrane. They are transported by uh sodium proton exchanger and it graces

### Segment 4 (15:00 - 20:00) [15:00]

sodium. As long as soon as sodium reaches a certain level, the calcium transporter uh reverses its mode and it starts to import calcium instead of exporting it. And this is the mechanism of calcium overload. So we must explain the damage when you put them on alometer. uh the patient of course he had a lower performance but if you would put a patient with heart failure anemia or pod on theometer they would also have a limited exercise capacity but they wouldn't have this cost exertional malas and drop we find out that one day after exercise he saw muscle necrosis muscle necross cell muscle necrosis even before exercise there are signs of damage and regeneration I have reviewed a Brazilian uh paper just a few days ago and they also show this they show uh muscle signs of muscle damage and regeneration in parallel. So this takes time all the damage and regeneration take time all yeah all the time and probably at the latest with an effort that yeah that makes pam that causes pain. So that there is damage and in this Brazilian work they also showed that the that the uh connective tissue of the muscle is much weaker and that some muscles tear and they tear because hyper contraction calcium and because of the weakened uh weakened fibrodic tissue connective tissue. So there there's a real damage and there's a new thing I don't I think I sent it to you this YouTube video of a PET CT where you can visualize the sick muscles. So uh investigator Stanford uh she tried to [clears throat] prove neuro inflammation with a an out with a tracer for TSPO. This is a usual tracer for yeah also for showing inflammation in the brain and it's a mitochondrial protein. But when she applied the method she didn't see a rise in in the activity in the brain but in the adjacent muscles in the neck muscles. So yeah, the muscles were lightning and then she made a systemic systematic examation examination over the whole body and he found he saw he could visualize the muscles and particular the muscles that are most effective vasus lateralis and head and neck uh and shoulder they showed the stronger signal. So we may even have a biioarker now at least a scientific biomarker. So this really proves and it's a mitochondrial protein tsp mitochondrial protein and you don't see these muscles in the healthy situation but you see them uh in in the patients. So we may even have a biomarker and it's clear proof it's the muscle and it's mitochondria. So I think our what we already see with these data with numeric data lower oxygen uptake and electron microscopy damage we can now visualize it with a radiological technique. I mean here we are just at the beginning but we can see the muscle disturbance. Could I so could I ask you the way it presumably the pathophysiology as far as you understand it is because a lot of it is postviral isn't it happens so we think that the virus attacks the body creates auto antibodies to beta 2 receptors — and are there many other there are many — there are many others but beta2 receptors are to do with blood flow to your sipal muscle your cardiac muscle because of that the blood flow gets disturbed so the blood flow becomes sluggish and what affects what causes the swelling of the blood vessels that you describe. I get the fact that do you think that the same antibodies attack the renan system and also cause the muscle the vessel walls to thicken? Yeah, it's probably uh in the beginning it's a cytoine problem over activation and that doesn't heal properly inflammation and auto antibodies. So I think the vessels are independ are also disturbed independent of other antibodies and these auto may have are further risk factors. It's not like you have myostenia gravis where you have for one single antibody that makes it they're numerous and they're not always the same in patients. Some patients have also auto antibodies against alpha 1 receptors. So autoatic uh autoatic dysfunction against the alpha 2 receptor again it's important in veins and many have also these mus cells problem also present on veins the H2 receptor and the alpha 2 receptor in the brain uh is a modulatory receptor which inhibits the release of adrenaline. So there is more uh

### Segment 5 (20:00 - 25:00) [20:00]

release of adrenaline and northern also in the periphery. So we have an overshooting sympathetic response. You have an overshooting response but at the same time it's present on veins to weaken the contractility of the veins to cause autoatic stress and then more adrenal is released because the alpha 2 receptor is also present on the nerve endings. So we get an overexaggerated sympatic response which can cause cereal vaso constriction. I mean there is there are three manifestations of autoatic dysfunction. It's not only pots. It's not only hypotension. It's always uh the tricardia doesn't make the problems uh per se. It's the decrease in cable blood flow always. All these three mana manifestation show a decrease in cable blood flow. And you can have it without tricartia. hypertension and then it's simply overshooting cereal vaso constriction. — Absolutely. I agree with you completely because we find that patients so I come purely from a clinical background you know I come purely listening to people and the first thing I would said if you do tilt tests on them you get a different result. One day you get one result another day you get a completely different result on the same patient — which is very interesting. The second thing I say is that actually in POTS for example if you just go by the current model it doesn't explain the patient's symptoms because the heart rate is going up to compensate for the drop in blood pressure or whatever and despite that the patient is still incredibly symptomatic. So I completely agree with that. There's a couple of things I was very interested in finding out. Number one, I seem to think that virtually all my patients, all my patients I would say have a genetic vulnerability which is generally joint hypermobility. — Yeah. Yeah. Of course. This then you have this of course weak veins. Exactly. as it is with a stanlo syn syndrome mafan syndrome and I think uh after the corona infection patients develop uh but starting very soon and it's a microvascular disturbance a severe microvascular disturbance and uh u I mean the veins the medium-sized veins they have a lot of vasavasaurum for arterial supply because work to perform by contraction so there are signs in the literature of that these are damaged and I have written a paper on that it could be that this oratic dysfunction comes from a microvascular disturbance of the vasavasaurum in uh in the veins. They cannot perform work with venus blood. They need arterial blood. And the structure of these micro vessels is relatively similar to that in the small nerve fibers which are also damaged. I think in both the microvascular disturbance plays a strong role in degeneration and instatic dysfunction. So I don't think that autoatic dysfunction is a primary has a primary cause. I mean there is little hypodnamic autoatic exists but often it's a response hyperdamic as a response. So I think it's often the capacity vessels that are damaged either by connective tissue diseases or by the corona infection that these are more I mean vessels are disturbed and damaged by the infection in particular the small ones. So if you have in the veins that the veins would be themselves disturbed and additional their vasavasaurum you would have autoostatic dysfunction. You're quite right because the orthostatic hypotension is a consequence rather than a cause. The simple reason that people have brain fog all the time they're tired all the time. They don't wake up feeling refreshed. All things have nothing to do being with being upright. You see? So that's very interesting. The other thing is so do you think it's just the corona virus and glandular fever which is historically the one that used to affect most patients or is it any virus in the vulnerable? So the there's a vulnerability the patient has a genetic vulnerability but why is it mainly glandular fever and corona virus we don't see it with other viruses my experience — I think the Epstein bar virus has a particular particularity and very uh arginine rich regions uh on and the outer bound the other the outer antibodies one finds are direct against body structures receptors and that show arginine rich regions. So in in in the herpes virus and the

### Segment 6 (25:00 - 30:00) [25:00]

EBV virus it's the similarity between uh the viral uh antigens where there are arginine rich regions and there is human receptors that affected are arginine rich so it's a crossover uh and this explanation for EB EBV uh for autoimmunity in corona virus it's probably the more the vascular damage And of course it's always a reactivation of the other virus. This has been shown if you have severe viral infection you get this other virus re reinfection uh of the other virus and endochenis from uh — yeah and also I think um — during yeah during a covid-19 you can produce then also again uh high titles of EBV during uh corona infection or after because you get a re reactivation of your pre-existing uh viruses that remain in the body. — And I think also um you know Klaus is explaining these viral triggers but one of the things I also appreciate about his and Carmen Schidenogen's work is how they have the model that of ME/CFS that can perpetuate itself ultimately irrespective of whatever the initial trigger was. — Um and there can be so many triggers and actually of course in my case it wasn't viral. It was stress and trauma related from complications due to a car accident. Um, and yet I've ended up with a very similar ME/CFS to someone who had it from a virus. And I think sometimes, I'm not saying it can't help people, but I think sometimes patients get very uh tunnel visioned on what triggered it all and think that must the answer must lie there. Uh, but actually the important question is what does ME/CFS become independent of whatever tipped it all off in the first place. — Could I ask you Patrick, are you do you have a genetic vulnerability? I mean, do you are you hyper mobile? — Um, that's interesting because I I don't get dislocations and things like that, but I do think I am hyper mobile to some extent, and that even was picked up at least a decade ago by a physiootherapist. I do have quite stretchy skin — as well. — Um, now the stretchy skin actually developed very obviously when I became sick. It wasn't there before I became — Um, so yeah, I'm not sure. I mean I don't know if I recover would that go back or is that a genetic triggering and even if I recover from ME/CFS I'll always have the stretchy skin and bit of hypermobility. I don't know the answer to that but um I would say that I have some of that predisposition. Yeah. — So the way to work that out is then to look at your family members and see if they have gone through a similar journey to you. not necessarily with the same trigger but if you find that in your family members there is a over representation of IBS disordinia fibromyalgia all that kind of thing then that I think is a clue for you and I don't know whether you have but I get so many patients and they'll come in with a family member and this happens all the time where they'll bring their daughter in who's 18 and they'll say her life is miserable. She got this. She got COVID four years ago and she's been wheelchair bound and it's awful. And you talk to them and I in my own simplistic way try and explain the model I understood until I met you guys. Um and then I just show I let them go home and then next week they come back and I'm always like, "Oh my god, they're probably unhappy or whatever I did didn't work or whatever. " And often it happens that they come back and they say, "No, now I've come for me. " when I heard you talk to my daughter, I realized that was also me and I've been living like this, but I just thought that was me. And now it's starting to make sense. So, it'd be very interesting to look in your family and see if other people in the family have similar symptoms. Perhaps not. It's a spectrum, obviously. — Yeah. Well, my dad uh who's now in his early 80s has had fibromyalgia since he was about six years old. And these are all conditions that hang around together you know it's — yeah of course and there are also vascular and mitochondrial genes abnormalities I mean this may be mild but there are number of risk factors and triggers that come together and then they they cause um this u disturbance which is self-maintaining uh sodium calcium alloy once the mitochondria is disturbed and this u has initi initiated uh and you have these uh disturbances small fiber neuropathy or uh these beta 2 receptors or the stress then you have this desensitization of the better receptors. You know from heart failure beta receptors are typically desensitized and they are the most sensitive receptors or

### Segment 7 (30:00 - 35:00) [30:00]

desensitization and we know this also from experiment from our experiments that these receptors desensitize and you have autoatic autostatic stress even when you're sitting the patients even in this the sitting position there is uh brain perfusion is decreased and in the most severe cases uh in a 20 angle degree tilt it's also decreased. So when you try a reading position from a recumbent position then your ter blood flow go already goes down. So this is all they are under autoatic stress mostly all the time and then you have a high level of stress then in heart failure and your better receptors they sensitize then you have small nerve fiber degeneration and the sodium pump is stimulated by patu receptors and calcetonate peptide from the small nerve fibers and uh the sodium pump is very sensitive to reactive oxygen species to ross which are produced once you have mitochondrial dysfunction and then um probably this pump is relatively inactive and then you easily get calcium overload and sodium overload calcium cannot get out of this vicious circle. — Sorry, go on Patrick. Sorry. — Uh thanks Dr. Gupta. So just for people watching to make that really um uh kind of clear visually um this image here is from the work Klaus was talking about by Rob Worst and — this is actually a biopsy of the muscles during postexertional malaise and the kind of way the muscle has gone sort of gooey here that's actual tissue necrosis so the muscle tissue has actually died during post-exertional malaise um which for patients is why feels so terrible. But what Klaus is talking about is this sodium and calcium overload. Just to make that so people can understand that there's a little you know pump on the cell wall which is responsible for keeping sodium potassium concentrations and [gasps] all right in the muscle cell and there's also another pump that controls the calcium concentration. But in Claus's work this the sodium pump is not working well. So there's sodium overload in the muscles which creates weakness. Then post exertional malaise comes along which is actually when uh calcium overload occurs in the muscles and it's calcium overload which can one would argue can actually create this tissue death because calcium overload is toxic to the cell. So this is one of the reasons I'm so excited about Klaus's work is because only his to my knowledge can explain this phenomenon during PM — which makes it more likely that the overall model is correct because PEM is so important to get a grip on. So I just wanted to show that um to you Dr. Gupta and to everyone watching that this is actually what can happen during PEM. I mean it can be that serious physiologically. Yeah, you have to explain the damage not only exercise limitation for instance heart failure or anemia and pod would also have limited but it really does a damage and uh there's no other explanation for this damage than ours. It's all the others uh with other antibodies simply or yeah they do not explain the damage. We but one question I have is we don't see muscle wasting in these patients. We see deconditioning but we don't see muscle wasting. So in heart failure you actually see cardiac cexia. Whereas the fundamental challenge that patients with CFSME parts face is that they look well and they're not believed. — Yeah. [clears throat] — It doesn't occur. uh Rob Vist has investigated made a study with six p with healthy volunteers six weeks bait rest and he compared it with MCFS patient he saw differences it's not the same and atrophy doesn't take place and the simple explanation is that calcium I'm talking about calcium overload calcium is the signal for hypertrophy so of course if you are betridden you have a tendency for atrophy but you have also a tendency for hypertrophy because the calcium is behind and damages. So you have atrophy and uh and hypertrophy. So there's no change. This is probably my explanation for the lack of sarcopenia and atrophy that you have high calcium which is a signal for muscle hypertrophy. — So would you say that the muscle stays the same but it is actually weaker? — No, it's simply it has it its mass but it's uh it's weak. Yes, it can be very weak electrphysiologically because for uh because it's probably deolarized once you have these fibrillation fast circulation and dre which yeah the severe patients severely ill patients have uh you have

### Segment 8 (35:00 - 40:00) [35:00]

yeah uh muscle deolarization and this causes the weakness. For in the sodium pump, sodium potassium uh ATPAS generates the action potential and the resting membrane potential. So if it doesn't work, you don't have - 80 m volt, you have maybe - 60 and minus 50 is the threshold, the firing threshold. So uh if the sodium pump doesn't work, you are close to minus 50 and then you have hyper excitability. you have uh muscle tone is raised anyhow because of the stress and uh there are other antibodies against GAPA and things like that. So you have a higher level of central muscle tone and in the presence of a dipolized muscle the muscle becomes hyperexitable and you get grams you get dremor fastulation and probably also fibrillation but then the muscle becomes also weak only for electrofphysological reasons because when the the action resting membrane potential gets more positive and closer to -50 or -60 uh a number of sodium channel that you need for excitation — [clears throat] — uh gets into an inactivated state, a permanent inactivated state as long as the potential is more positive and then these sodium pump the sodium channels are not available for exitations and so uh the action potential is not propagated. Less uh muscle fibers are rec recruited at the same time. So this causes muscle weakness. It's very similar to uh the effect of deoxxin in the heart. It also inhibits a sodium pump and if you have an intoxication the resting membrane potential gets closer to the firing threshold and then you have these arhythmias a lot of arythmias also not only because of this but also because of calcium and things like that. But the main cause is that the membrane potential gets closer to the firing threshold more positive and then you have hyperexitability a lot of arhythmias and then suddenly you have cardiac arrest because all the sodium channels are in the inactivated state. So this is why you can from deoxxin you get from one moment to the other you have arythmias and then nothing because all the channels are then in the inactivated state then you have no more exitation and the situation is very similar in the muscle because the sodium pump doesn't work the deoxin inhibits the sodium pump without but of course much less and if you have the same in you also this fasticulation are uh yeah they are is analogy to uh deoxxin induced arhythmias in the heart. — What I find interesting uh is and the question I guess I have is so a lot of my patients the first thing I'd say is that they all feel a bit better when they're moving around rather than standing still. And I'm sure that's because they're using mechanically trying to push blood around because of the you know so they're better driving rather than being passengers. They feel worse if they're passengers and they're better if they drive because they're using their legs, — which is interesting. But you know, we when these patients come to see me, they've gone through a battery of cardiac tests and many of them are sent for exercise testing and they do okay. You know, they don't they're not horrendously limited on during the exercise test. They seem to do okay. semi layers. — Yeah, you can't there's a new uh invasive CPAT study and they showed there is no change at rest. There's no change. You only see you see during exercise. In this example, they had a cardiac output of I think 19 liter per minute the healthy controls and the ME/CFS patient had 12 and concerning oxygen uptake the healthy control had 2 L and the patients 1. 1 and their Venus oxygen was much higher than uh in the healthy control. So you only you see the disturbance during exercise and many patients can still the moderate the mildly uh the patients with mild degree they can exercise but they pay then for it later on with PEM. — Yes they definitely pay for it. I get that. But my question then is so as someone who has to deal with a large number of patients who have this based on your research what test should I be doing for them given current availability. So a lot of the testing is in the very much in the research domain. But in a on a practical way, what can I to demonstrate to them that what they're experiencing has a true physiological explanation rather than relying on perhaps cruder tests which then come back as normal and these patients then get gas lit by doctors

### Segment 9 (40:00 - 45:00) [40:00]

because everything comes back normal. So I'm just trying to work out based on your research what kind of test should I do for these patients to show them that actually there is an issue here. Yeah perhaps cable blood flow over a large uh artery SD the Dutch group does they published many papers and measure it uh Doppler on a large I don't know which one it was. So they found in all these uh almost in all patients they found a decreased several blood flow also in these patients with no pots with no hypotension but the autoatic problem is the decrease in several blood flow I don't know uh I mean we don't know the normal values before the patients came sick that's always the problem and uh of course uh hand grip strength is in MCF is hand grip strength it reduced but again you don't Oh, this is so individually variable that you don't know the patients had before. But when you do it the first time and you follow hand grip strength, it decreases with a severity symptom severity in the prognosis. So it not really a biioarker because the diagnostic because you don't know the value before. — Yes. when they are sick as soon as they would be do it you can see whether they improve or worsens uh um yeah with the hand grip strength — in terms of therapy given the hypothesis that you've developed which certainly seems very plausible to me from everything you've said you know we're these are observations I've made without having a research background and you're answering them and so clearly there's a lot of synergy there what I'm trying to work out is so where do you see the therapeutic targets? I mean let's say if it's a beta 2 receptor problem one it's an important other antibody but not the only one there are many others that — but are there like their beta 2 receptor agonists then presumably that would that should then help. — This is the problem the receptor is already desensitized. Uh yeah the question is this desensitized and auto antibodies and whether card tapicard is really good with hypoalmia I don't know I'm not sure but the question is whether one could reensitize the receptor with a beta 2 blocker like propranolol which also includes the beta one and beta 2. This is what we are thinking about and we're talking with others. Uh whether it would make sense to give proper for a few days to reensitize and then you have reensitized beta receptors or with a low dose of proponol you may protect from adrenaline and then the receptor can reensitize and of course you still have a degree of blockage but when you make exercise you get much more adrenaline and then can the effect of adrenaline can be higher than without. So during heart failure the beta receptors are also s reensitized. So you need them for exercise you block them at rest but during exercise the effect on the bet the receptors is higher than without because they're sensitized also block to a certain extent. So the question is whether one could try at this strategy. I mean — I um I have used we use beta blockers very regularly. — Yeah. Yes. And the response is very mixed. It doesn't seem to work for a lot of the patients. — Yeah. Because you need a better one. one receptor. Of course, it's also it raises blood flow and you need it for anotropy and — yeah, — is harmful. Of course, Eva may sometimes better because it doesn't have these negative effects. — Eva braden is by far the most effective medication I've come across. So I say 70% of my patients well there's one thing which is more effective I'll tell you that I've seen practically beta blockers I would say maybe 40% 50% evad in 70% patients say I feel a bit better um the thing that it makes a dramatic difference I have noticed at least is introvenous saline if you give these patients — yeah of course — saline they seem to — you much better for a couple of days and obviously they can't hold on to water because of the luren etc and therefore it wears off but there is something about saline that seems to work very well for them for a couple of days — except that they come in a wheelchair and they walk out — yeah absolutely I mean Dr. Gupta I haven't done the introvenous saline but one change that massively helped me was going from drinking plain water to 90% of my fluids now are in the form of oral rehydration solution. Yeah. So for me doing that was like a big change and I

### Segment 10 (45:00 - 50:00) [45:00]

can be in a very bad crash and if I drink a liter of OS — I can actually you know it's almost biblical. I can get up and walk you know. Um so that constant blood volume boosting is a very important strategy for me. So the uh the thing about this re rehydration solution is that absorption rate is very way very very fast. Uh and uh excretion is also fast. This is the problem. You can give 10 liters they excrete it. So uh you must have a higher speed of absorption than of excretion and you can reach this with IV or with a re rehydration. Of course this is only for a moment. I don't know how Patrick how long this last this effect. uh but I think it's only limit because you excrete it also quickly but at least for a moment for I don't know for how long uh you have a higher volume when you have a fast uh absorption rate faster — yeah I drink like a half liter over an hour you know I will have a nice effect for a couple of hours but yeah it goes down and you have to keep going throughout the [clears throat] day to get the same effect — and concerning the bit the the ticardia I mean yeah if you have hypervalmia The filling uh cardiac filling is a problem with taric cardia because the time for filling is much is shortened and I think many patients have for instance women have mild diastolic dysfunction. I mean you know diastolic dysfunction, heart failure in women this is the most frequent cause of heart failure and uh the question is whether many have a mild or hidden diastolic dysfunction that becomes manifest not when you make this examination addressed but maybe in upright position or when you work or things like that. So you have taricardia hypoalmia and a mild diastolic dysfunction. Many patients seem to man some pat seem to have all also smaller hearts. The question is whether this a consequence of chronic hypoalmia as to if you have hypoalmia chronically you have larger hearts. So the question is whether you have some adaptation and perhaps mild beginning diastolic dysfunction and then the interactions is so fatal if you have hyperolmia taricardia um which means shortened filling time hyperolmia [clears throat] tricardia and diastolic dysfunction. So I I will I don't know whether you probably look always whether these have normal diastolic dysfunction. I think this is probably then in the in a normal position but not in upright position or — I mean I think the other thing I'd say is I've used desmopressin as a means of stopping them urinating the and very mixed results. For some people it makes a tremendous difference but for the majority they don't notice a huge difference — which is again very interesting because at the end of the day the question really is how do we use your insight to try and work out of course there may well be that at some point there is drug development and drugs are made particularly to target those auto antibodies etc. But at this point in time, I'm just very interested in knowing I mean I there is a medication that I came across called neimodipene which is a calcium blocker which preferentially causes vasoddilation in the brain I think as opposed to you know — normally not I invest it doesn't and the healthy dua doesn't do it but uh maybe if the if there's I investigated these calcium channel blockers against I've investigated 100 compounds on server blood flow And calcium channel blockers don't do it in in in the healthy situation. But once you have a a contractility contracted vessels, the situation can change. But the advantage of the calcium blockers could be that they do not dilate the capacity vessels that the veins. They do not they spare the veins. — So they only they dilate more the smaller vessels and arterial vessels. So they won't disturb they can make vasod dilation particular where the tone vascular tone is high probably not so much under normal circumstances but they could become more effective once the tone is high and they do not dilate the larger vessel kimbong tests very the ST activator and this would make sense for let's say yeah vasilation it's uh it uh replaces uh N the N deficiency And uh it will also probably be beneficial structurally on these structural changes, paint membrane thickening all these things. But this takes time. But of course you always have the problem of dilating the capacity vessels. Then you can worsens — yeahic function. — Absolutely. I mean practically most of my patients don't seem to benefit from calcium blockers. uh uh — they do not I do not see really effects of calcium blockers on

### Segment 11 (50:00 - 55:00) [50:00]

skeletal muscle blood flow. I don't didn't see effects on cereal blood flow. You see the blood pressure goes down some. Of course, there has to be vasid dilation but it's not you can't see a rise in blood pressure because also blood pressure falls or there's also not much change in resistance. If I measure resistance collateral muscle not really better per fused brain is not better for a fused things may change once you have a high tone and vessels are contracted but I was very disappointed about the calcium channel blockers and their effects in on skeletal muscle blood flow and on cable blood flow. There I saw much better effects with varicquat or with PD5 inhibitors. But of course these also lower blood pressure and dilate the capacity vessels which then would worsen of course the uh oratic or static function. — It's very interesting. The question I guess is how does one collaborate or how do people who are suffering from this who are seeking answers contact you in case you're running a bigger study to not necessarily even to assess therapy but actually to develop an understanding of what may be going on in their bodies. — Yeah. I [clears throat] mean I have no u clinics and I'm not in a hospital so I have cannot make research with patients at all. Yeah. We are a virtual company. I worked for Sanori 37 years and now we are a virtual company. We have selected a compound from previous activities in the pharmaceutical industry. There have been so many things that have been dropped for a strategic reason. And we take one we take up one of these comp one of one a compound which I showed has beneficial effect on serial blood flow muscle blood flow and later on we found that it also activates the sodium pump and uh we have selected one compound. I made a few ex tests in research of my own at the University of Frankfurt in isolated muscle to show the efficacy. But apart from this the the work we have now is simply the which we call development work. You would have to do it for every and any compound. So this is always the same. You need to show uh to perform toxicological kill study in the two species and perform all the work before uh in vitro work uh safety pharmacology and the effect on receptors transporter transporters on panels of receptors and trans and so on. So you have a safety package, you have the safety pharmacology, toxicology, uh things like absorption, bioavailability and things like that. And then you have to go for to talk study 4 weeks study which could be [clears throat] perhaps next year, end of next year. And then with these studies, if the compound is well tolerated, go into phase one and phase one studies in healthy wallet here will take one and a half year. you cannot shorten it and only then you can go into patients and perform a study. But this will then be a single center study for organizational reasons and also uh because this is what we can afford. So normally the phase 2 a study is a single center or in one country or let's say multi-enter with very few with few centers and then if works there then there will be much international multi-enter studies but it will so it will take years until we are at a point where we can say we can get do it in the UK or so this is years away — and this is fundamentally the problem that people like Patrick you know whilst because everything is so slow you know another 10 15 years may pass by and — it's faster with us much faster but if you're not financed it will it will take really uh could take 15 years or so really if the industry now takes it takes will probably a few take a few years that the industry takes it up then they had to find a compound takes a few years then development takes 8 to 10 years so it's 18 years it's not yeah the question is in imology ology there are a lot of activity there are hundreds of companies worldwide that are involved in in inological drug research. So uh if uh yeah in these patients with an imological background and auto antibodies there can be uh a treatment much earlier. For instance, the Norwegian group now and also Kamcha Bong, they will start a study with the anti CD uh 30 38 theatunum map uh which also uh removes the long living uh plasma cells and not only the B cells as does the antiCD 19 form. So it seems that the

### Segment 12 (55:00 - 60:00) [55:00]

small pilot study show that this can is more much more effective than the vitoxim. So there is hope that we get a relief from from uh emological principles earlier because there are so many on the market and in development. So if imology plays a strong role I think we can have drugs uh let's say perhaps in the next year or in a few years only. Yeah. always a few — that would be great from the patient perspective but um with Klaus's pill that he's trying to create the which is called my toddure which he was describing um you know that might whatever take seven or eight years and I personally hope to be well before then um but I'm very excited about it because it is based on his unifying model and I think it's very rare I'm not sure if it's really happened before that someone is trying to develop a pill based on a unifying model of ME/CFS and so it's not just like lowd dose deltraxone, you know, another pill around the edges, it would actually be targeting the disease in a very concrete way. And so it could have a much greater effect. And my understanding of the m the action of mitoic cure is that the aim is essentially to be curative in principle that actually it will prevent the sodium overload therefore prevents the calcium overload preventing post-exertional malaise. PEM is what creates the mitochondrial damage and then the mitochondrial pool can replenish and the cellular muscular situation can be restored and then hopefully at that stage the patient could taper off and actually be well. So that's my understanding and I think that that's a very exciting possibility. Yeah, I think there's a potential of a cure and uh it's probably it could be from autic point it's it would be effective in all patients whether it's imological background or non because they have all the same uh final common pathophysiological pathway which is this sodium and calcium overlap mitochondrial damage and perusion damage that also evolves then secondarily uh all is maintained by the mitochondrial dysfunction via Ross and and all these disturbances you have in in in the muscle. So uh despite the heterogenity of triggers and risk factors, there's a commonality and this is exercise intolerance with PM and we think there's uh there's a mechanism behind the same in all patients. This is this mitochondrial damage via sodium calcium overload where also vascular damage is involved. So there's a vicious cycle which is the same uh in all the patients. — Patrick, you've obviously written a book about all this. So how do um do you tell us how people can access this and people can access you your content and information that you very kindly share with people who are in a similar boat to you? — Yeah, sure. So, if anyone's been a bit foggy today and they've been struggling to follow some of the ins and outs of all the science, uh my book which I wrote earlier this year is called understanding ME/CFS and strategies for healing. And it has a forward written by Klaus and the first three chapters of the book are trying to explain the unifying model put forward by him and professor Shyenburg in a way that is accessible for patients uh including brain fog friendly summaries. Um and the rest of the book is also about other research much of which fits into the model that Klaus is proposing. Um but it also includes my own treatments that I have tried like the help apheresis which is a conventional blood washing procedure or various um complimentary approaches that I've also found useful in improving my own quality of life because I once was pretty severe and I actually was in life-threatening situations from ME/CFS. Um, so this is a book of everything I've learned about the research and about treatments. — Um, and in terms of where else people can find me, I have a YouTube channel, Understanding ME/CFS, that's ME-CFS, where I'm also doing lots of videos breaking down the research, talking about my own experience, talking about the lived experience as well. Um, and I also have a a Patreon and Discord community, which is a treatment and research support community where a group of us patients are helping each other out, pulling our collective wisdom. So, people can find out more about me if they go to my personal website, which is patrick usher. com. — Yeah. And I think I really can recommend it. It's really excellent. It really reflects the uh Yeah. the concept, our concept, and the patient can understand it. It's written in the languages that the patient can understand and it fully reflects the yeah our concept. — I have to confess I found this very completely fascinating. I mean it's incredible that you know um you sort of

### Segment 13 (60:00 - 62:00) [1:00:00]

live as a doctor who deals with this. I sort of live in my own bubble thinking oh I know what there is to know about this. and then to meet you. I'm truly humbled both by Patrick your resilience, your willingness to work and bring attention to this and to take complex research and make it user friendly is incredible and professor wor I am you know blown away by your knowledge and the way you express it. So it's been a wonderful experience for me. Time has flown by and I did not feel foggyrained at all. — I must say if I had 10 years less of these 40 years I have I wouldn't I couldn't understand it really. It's incredible. I if I'm thinking about it if I hadn't made this or that I wouldn't understand it. — It's really a chance it's — and what is remarkable is that it offers us or people who are working with this condition an opportunity to become pioneers. you know virtually everything else you you already know so much about but here is a condition which is this very silent invisible condition which is an epidemic really I [snorts] think particularly after co so many people in the best times of their lives young otherwise healthy doing everything and suddenly you know their quality of life is just snatched away from them and it's years and years of trying to just, you know, one step forward, one step to the side, one step forward, then two steps back. And it's always like this kind of stuttering progress that patients make because any infection, anything just pushes them right back. It's incredible really. — I'm contacted by many people and many are really they are extremely sportive, triathletes, [clears throat] they are marathon runners, they are bicycle and they got it. They some are bitritten some really after they try to recover and to restore their capacity and after one run they were bit ridden. — So never do this long co or to try uh yeah to get your force again and your sportive capacity. This can be very uh detrimental and — thank you so much. I really enjoyed talking to you. — I thank you for your time and attention. — Yeah. Thank you. Thank you for the opportunity, Dr. Gupta. We'll be in touch. — Yeah. Okay. — Take care. — Byebye. — Bye-bye.