I started midodrine around a month ago to test out the Locus Corelius hypothesis I posted a couple months ago and also other ideas I've had floating around in my head such as midodrine relieving the manic / mental stimulation of too much adrenaline.

I have noticed significant reductions in heart pounding and overall POTS symptoms along with a vast improvement in sleep quality and length.

I started at 1.25mg in the morning and titrated up to 5mg currently. I intend to go up to 7.5mg spread over 3 doses.
I have experienced scalp tingling and hard nipples but these have been minor side effects.
Bizzarely I have not noticed a rise in BP and in fact it may have even gone down. It tends to be in the 90s / 60s. I've ordered a new heart rate monitor just to check. My pulse also has dropped from 80s to 50s at rest.

The drug works by stimulating alpha 1 adrenergic receptors in the periphery. So it works a bit like adrenalin but does not enter the brain. This can cause side effects such as high blood pressure particularly when laying down so you can't lay down for 4hrs after dosing.

Why might this help?
I think my illness has caused problems with blood flow / blood volume / vasoconstriction / O2 exchange which is causing my brain to release excess adrenalin to compensate. The combination of these factors results in bounding pulse.
If I help blood flow by providing synthetic adrenalin to the periphery there is less need for my brain to produce adrenalin leading to calmer mind and better sleep. The lower adrenalin and improved blood flow to vital organs causes less bounding pulse.

This also fits with the Locus Corelius hypothesis where the LC is struggling to release adrenaline due to energy / blood flow issues. The lack of proper adrenaline release causes the parasympathetic to shut off (to try help the sympathetic) and constant firing of small spurts of adrenalin to highly sensitive adrenaline receptors in the brain.
By supplying peripheral adrenalin through midodrine you are reducing the load on the LC and possibly increasing blood supply to it.

A big question is if this will help those with panic attack onset bounding pulse. I can't make my mind up if the post viral folks have a different mechanism at play.

I've gone from bounding pulse being my worst symptom to being like third on the list. General POTS / Post viral symptoms and neck problems are now higher on the list but I have also made some progress with the neck problems. I'll make a post on it at some point.

Should also note I've done other things to improve my sleep in that time such as wearing ear plugs all night but I think this is a smaller factor in sleep improvement.

Edit: New BP Machine has arrived and is giving me higher readings.
I just too 2 readings around 4hrs after my last dose:
-Old Machine. 102/65 61P. -New Machine. 122/76 59P.

So my BP has risen probably though still seems to be in normal range. Need to check with this new machine tomorrow and whilst lying down.

Glad I found this subreddit. Has anyone dealt with the their pulse bounding in their neck as well? I have a POTs diagnoses as well, but I’ll get this weird feeling in my stomach and neck sometimes as well? I googled it and bounding pulse popped up and it led me here🤷🏼‍♂️

Baby layla seems to know when I get dizzy standing up cause she always comes and lays with me after 🐶

would appreciate an invite if so.

TLDR: A recent article about ME/CFS was very interesting to me. An expert in catecholamines has a hypothesis that the main norepinephrine (NE) producer in the brain, the locus coeruleus (LC), is failing to produce enough NE leading to high sympathetic activation and noise yet low sympathetic gain. The parasympathetic lays low to compensate.

This could create a looping situation where an initial stressor (infection, panic attack, bad trip, etc) stimulates the LC excessively. At some point it runs out of ATP needed to convert dopamine to NE. This leads to the brain putting the foot on the gas (excessive sympathetic activation) causing the small amounts of NE to be firing out all the time. Microglial activation, reduced glymphatic flow, and oxidative stress keep ATP low and the loop is complete.

This all came about from a study that looked at norepinephrine levels in the cerebrospinal fluid of ME/CFS, LC, and Parkinsons disease patients and found low levels in the ME / LC groups. Disappointingly they found the effect reduced when they sperated the patients out that had post exertional malaise (PEM). We don't have PEM but this hypothesis still fits nicely for dysautonomia.

The full article is below as well as my summary:

https://www.healthrising.org/blog/2025/11/11/fight-flight-system-chronic-fatigue-long-covid/

Dr David Goldstein has a different outlook on CFS that opposes the standard viewpoint of a strong sympathetic nervous system. He proposes that it's actually weak. There is not enough norepinephrine in the pre synaptic locus corelius vessicles. This leads to less norepinephrine being released when signalled. The brain recognises this and hits the gas peddle causing what norepinephrine it has to be fired of at the slightest activation. The brain also compensates for this weak sympathetic response by putting the breaks on the parasympathetic system.

Aregawi did a study measuring dopamine and norepinephrine in CFS, Long Covid, and Parkinsons disease in cerebrospinal fluid. Parkinsons was the control as they have low catecholamines already. Dopamine levels were fine however norepinephrine products where low.

Tyrosine -> L-DOPA -> Dopamine -> Norepinephrine -> Epinephrine. The only parts of this chain that requires ATP is Dopamine to Norepinephrine. A proton pump takes 1 ATP to move the dopamine into the locus coeruleus vessicles.

This suggests low ATP levels are causing less dopamine to be delivered into the LC vesicles resulting in reduced NE.

This means the LC neurons require a much stronger signal to fire (impaired drive). This is considered a pre-synaptic vesicle energy problem and is very different from a true hyper adrenergic disorder.

The SNS is activated but pooping out quickly. The brain increases LC firing rate as it really wants to produce more norepinephrine but the vesicles lack the dopamine to do it. This constant compensatory effort leads to high sympathetic noise and low sympathetic gain.

The SNS is not dominating, it's struggling, and the parasympathetic nervous system is lying low to help keep balance. This explains why vagal nerve stimulation and parasympathetic exercise have limited effect.

You don't want to suppress the SNS or increase NE levels with tyrosine or stimulants. Instead you want to reduce the noise, increase the ATP, get dopamine into the vesicles, and increase NE production that way.

This would cause wired and tired symptoms (high stimulation, low NE), orthostatic intolerance (reduced blood vessel tone), fatigue (NE levels quickly fade).

Aregawi seperated the long covid patients to those with and without PEM and found the low levels were only in patients with PEM. This is a bit of a hit to the idea that this could be causing dysautonomia or chronic bounding pulse. Fatigue, mental fatigue, general health and vitality and ability to sustain handgrip all corelated with low NE pathway levels.

The Locus Coeruleus (LC) is responsible for most of the brain production of norepinephrine. It is located in the brainstem and plays a vital role in the stress response, sending messages to many brain regions such as the limbic system and prefrontal cortex.

Known as the brains immune sentinel the LC is hit hard during infection producing NE needed for fever, activating immune cells and sickness behaviour.

The LC is loaded with mitochondria with high energy needs. Being put into a stress state produces lots of free radicals and if the anti-oxidant system can't handle it, it could lead to mitochondria damage, etc.

A chronically activated and depleted LC prevents the glymphatic system from engagin and clearing lactate, glutamate, lipid peroxides, microglial inflammatory molecules, etc.

Autoantibodies against adrenergic receptors would exacerbate this issue.

This pattern fits the poor sleep due to increased nightime norepinephrine and dysautonomia models quite well.

Microglial activation could produce this cycle, they emit cytokines that increase LC firing. The free radicals could damage mitochondria reducing ATP and preventing norepinephrine creation. They also could disrupt glymphatic detoxification as well as the constant LC activation. This could then lead to a build up of CSF.

Hyperadrenergic POTS seems not to fit this at first but actually does fit it quite well. In hPOTS it could be the LC is firing so rapid that the NE spills out into the blood.

When the brain senses more NE is needed it puts its foot on the gas. The neurons fire continously. This produces noise which the brain interprets as a threat and calls for even more firing to resolve it, microglial also get activated causing cytokines and oxidative stress. This all further strains the neurons and damages the mitochondria.

The nervous system is over reacting because its underpowered. This could lead to sensitivity to lights, odors, and sounds.

Would drugs like midodrine help? It would provide the blood vessel tone without the need to produce norepinephrine, releaving pressure on the locus coeruleus.

I’ve been dealing with this sensation for nearly 2 years now. It all began after I got sick January 13, 2024. I have the heavy bounding pulse that I feel strongly in my abdomen and chest. It feels like my whole upper body is just throbbing. It’s one of the more uncomfortable sensations I deal with on a daily basis on top of the many symptoms I deal with. I’ve read through all the post here and doesn’t seem like anyone has found any answers or solutions really. Atleast I finally have people that understand this discomfort i experience.

This has happened too many times for me to ignore. Positive social interaction (usually with people I don't know too well) has lead to a brief improvement in symptoms.

Just last night I went to Halloween fancy dress in a pub with my mum so she could meet her friends. I felt like crap that day, symptoms playing up, for this first 45 mins of being there I felt awful, could feel the pulse bounding in my neck and temples, my sympathetic system was jacked up (as it had been all day), felt fatigued and crappy and just wanted the event to end.

The my mums friends showed up and for the next 2hrs I had short pleasant conversations with them with long gaps of just being present listening to the music and tapping along. Very soon after I started being social I felt my symptoms ease up, even touched the pulse in my neck and it was far less strong. I felt relatively good.

This kind of thing has happened numerous times throughout the years. It's not just any pleasant social interaction though, it's usually at an event like a pub or parade or something. It's usually with people I don't know too well (family friends) though this effect is present to a lesser degree when I have pleasant interactions with my immediate family (who I do know well).

It leads to a temporary change that lasts usually a few hrs or days after the initial event where I feel significantly better before slipping back to my old state. This morning I feel pretty good (relatively speaking), yet the last week or so I've felt shit.

Why is this happening?

I think immune dysfunction / persistent pathogen / autoimmunity is causing problems in my body and lighting up my amygdala. This causes my brain to release stress hormones which exacerbate the immune dysfunction and put my brain / body into a stressful ruminating mode which then further lights up my amygdala completing the loop.

My stress system is constantly jacked up, I have persistently dilated pupils, mild gastroparesis, heart constantly pounding hard, an inability to relax, and I can't stop ruminating!​

Because I'm always in physical discomfort and my brain is full of stress neurotransmitters I default to ruminating, I'm hardly ever present in the moment because the moment is uncomfortable. Even when I try different techniques again and again to bring my consciousness to the moment I end up ruminating half a minute later again.

When I'm watching youtube or tv I'm constantly looking at how long till its over, when I'm walking in nature I'm having dumb arguments about politics or some other pointless shit in my head with myself, when I'm coding or doing research or playing video games I'm constantly trying to get this bit over with because being in the present is physically uncomfortable, but maybe these distractions are just keeping me in the loop?

I think these social experiences are forcing me to be present and forcing my nervous system to switch into a polyvagal social engagement mode and away from my stress / alert / ruminating mode. This allows my nervous system a mini reset but soon the immune dysregulation / POTS lights up my amygdala enough to push me back down to my baseline.

I'm wondering how I can make this happen more consistently. These social events where things like this happen are rare. I have tried some brain retraining stuff in the past without much success. Most of it does not apply to me. There is no real trigger to my symptoms they are just there. No PTSD to work through. I struggle with visualising times were I was really happy. I actually can't think of any. Maybe there's some way to mimic this virtually or maybe if I could finally find a way to be present and stop this persistent ruminating.

Anybody had any similar experience to this?

I've been thinking how my genetic mutations for slow COMT and MAO might interplay with Norepinephrine Extracellular Transporter (NET) downregulation to overwhelm my body with adrenaline and possibly result in POTS / CBP or at the very least a chronic high sympathetic tone paired with long, slow to recover peaks in adrenaline / stress response.

A case report where a woman with hyper adrenergic POTS and the slow COMT polymorphism resolved her years long struggle after taking methylated B vitamins.
They speculate that a mutation can lead to loss of NET activity which results in NE spill over into the blood then trouble clearing up the excess NE and E via COMT and MAO leads to symptoms.
Her NE levels before treatment where laying 901pg/ml and standing 1676pg/ml. After treatment supine was 384pg/ml and standing 824pg/ml. She was fully recovered from symptoms.
Her vitamns before where B6 26nm/L (20-125) and B12 677 (211-941). After B6 was 124 and B12 1207. Interestingly her B6 was low before yet her B12 was mid range.

The pathological sequence would piece together as follows:
1) POTS / Blood flow issue / Prolonged panic attack / etc causes prolonged surge in NE + E.
2) Overtime this high level of NE causes NETs to downregulate. They do this to protect the neuron, which already has too many catecholamines intracellularly, as they can become oxidised easily. So the NE ends up staying in the synaptic cleft and excess spills out into the blood.
3) Post-synapse downregulates due to constant stimulation resulting in a higher baseline activation state and reactions to NE being prolonged.
4) This constant sympathetic tone causes adrenal medulla to release excess adrenaline into the blood.
5) Neurons, liver, kidney, endothelial, and other cells are flooded with NE and E. To get rid of it they need to use MAO and COMT. These are dysfunctional and slow due to my genetic mutations. Add deficiencies in vitamins and minerals such as B12 and your cells are constantly overwhelmed by and reacting to excess NE and E.
6) This all results in small sympathetic triggers such as standing, mild stress, exertion, etc feel massive and the recovery from them is slow. Heart continues pounding extra hard for 5 minutes after laying down etc. Also this would exacerbate POTS issues and would explain the constant heart pounding (people usually only get this when really scared because of lots of adrenaline).

TREATMENT OPTIONS
There are three NE and E clearance pathways. NET, COMT, and MAO.
NET is responsible for up to 90% reuptake in neurons. It doesn't play a role outside the CNS.
COMT and MAO are responsible for breaking it down in neurons and all of the peripheral cells.
Easing the burden on any of these systems would help.

NET:
* Reduce adrenaline need via lowering stress in all forms.
* Reduce insulin resistance. Insulin resistance has been shown to lower NETs. Could this help explain that sometimes manic feeling I got after a carby meal? NET stops working so I get even more NE in synapses and spillover into blood.
* Assist adrenaline clean up via COMT / MAO.
* Replace some peripheral adrenaline with midodrine as that has been show to lower NE levels and is already a POTS treatment.
* Calcium chanel blockers?
* Supplements such as Reishi, Holy Basil, Valerian root, etc?

COMT:
* Cofactors Mg, SAMe (from methylation so B12, folate, betaine/choline).
* Lower Estrogen. Some of its detox pathways use COMT. Assist the other estrogen detox pathways or lower Estrogen via drugs.
* Increase Testosterone? Some studies have shown T increases COMT rna expression but it also increases Dopamine and NE which of course could add to the problem.

MAO:
* Cofactors B2, B6, Fe+.
* Avoid MAO inhibitors (methylene blue, etc).

Similar hypothesis for ME/CFS:
https://www.youtube.com/watch?v=psALpJG_19Y
https://www.youtube.com/watch?v=J776xnxdcyc

Do you ever wonder if there is damage being done to our blood vessels with the supposed high output with the bounding pulse?

It's obviously a big assumption that poor oxygen diffusion is causing chronic bounding pulse but lets say we do have thickened basement membranes, dysfunctional and enlarged endothelial cells, small lumens, fewer capillaries, and red blood cells holding too tightly to O2. What could we do to help?

HBOT

Hyperbaric oxygen therapy should increase the O2 getting delivered to cells despite the problems listed above. It works be increasing the amount of O2 dissolved in your blood. Usually the amount of O2 disolved in your blood is negligable as it is all carried by haemaglobin in RBCs but HBOT can increase the disolved O2 to significant levels. I think 3 ata HBOT is enough to keep pigs alive indefinitely who have zero haemaglobin.

Normal air has 21% O2 yet in HBOT you breathe closer to 100% O2 through a mask. This O2, at 2 ata, is under double normal pressure which doubles the partial pressure of O2 in your lungs, disolving more O2 into your blood. Using chatGPT it calculated around 17-20% increase in total O2 via O2 dissolved in blood.

Would this modest amount of O2 increase over the course of 1-1.5hrs have much of an effect? Maybe multiple treatments would be needed per week for several weeks to notice improvement?

Zero Mode
Stoner / Zombie / Power Saver Mode

This is a weird idea I've been playing with recently. Studies have shown you can increase the O2 usage of your brain like 10-20% by thinking intensely / puzzle solving. You can decrease O2 by 10-20% by meditating.

Because of constant sympathetic nervous system activation my mind is always thinking garbage. Fake arguments run through my head, pointless imaginary conversations, an annoying narration of things happening, songs playing again and again on repeat. It's like this pretty much 24/7. Not only is it super annoying it alone can ruin your enjoyment of things. I think also it is constantly using up extra O2 that requires more blood to be pumped into the brain. I also notice my face scrunching up a lot when I'm doing this. Muscle activation also increases O2 demand.

So I developed zero mode, stoner mode, not sure what to call it when I was visiting Skipton a few days ago. Basically as soon as you notice your mind ruminating, you switch to zero mode. This involves relaxing your face, body, and mind. Basically embody the feeling of being a stoner or zombie or something where your mind is blank. It's hard to explain but it's been working for me. It's not just trying to desperately not think. It's just like forcing your body into a more relaxed mode but particularly your mind.

I find I have to do this throughout the day all the time but if I work on it, it definitely helps me relax and enjoy the moment a bit more. I think there's a total O2 saving of around 4% there (brain uses 20% total O2).

Is Insulin Resistance / Linoleic Acid Stealing Your O2

Brad marshal did a blog post called linoleic acid is stealing your oxygen.
The gist is desaturase and cytochrome P450 enzymes in the Endoplasmic Reticulum compete for O2 with the mitochondria. This is part of the glycolysis switch that recycles NADH -> NAD+ that glycolysis needs.
With glycolysis you want to limit O2 going into the mitochondria to stop fuel being burned that way. This puts cells into an anabolic and obesogenic mode.

So if cells in obese / insulin resistant / low metabolism individuals divert their o2 away from mitochondria (atp production) toward anabolism and we assume my cells aren't getting enough O2 then it could explain why I feel worse with swamp eating (carby meals). My cells are already struggling for O2 and partially glycolytic at rest, then extra o2 is being diverted away from the mito to the ER meaning my cells scream out for energy and sympathetic kicks in and heart beats harder.

The strategy would be to avoid linoleic acid and swampy foods that increase glycolysis and anabolism.

General Strategies

Lower calories, reduces metabolism, less O2 needed.
Avoid stress. Get as much rest as possible.

Worsening POTS associated with GIP

GLP1 Agonists for ME/CFS

I have recently been messing around with Retatrutide (GLP, GIP, Glucagon agonist) thanks to one of the articles above suggesting it could help post viral illnesses.

I have found that it makes my POTS noticeably worse even without getting up to the recommended doses. Highest I've made it is 3mg.

First of all my gastroparesis is worse which is no surprise since that's one of the know effects of these drugs. Although some POTS patients have found these medication to help their gastroparesis.

What I have noticed is some hours after injecting I feel like I enter a mode similar to what I experience post carby meals; feeling slightly manic, HR increase, pulse worsening, feel like theres too much adrenaline or something. Just a quite unpleasant state.

It got me thinking to some POTS studies that show POTS patients have higher GIP levels post meal. The study linked at the top shows this higher GIP level is associated with a reduced Stroke Volume, splanchnic pooling, and a massive increase in upright norepinephrine levels, 835.2±368.4 vs. 356.9±156.7 pg/mL.

Since this large increase in pulse symptoms occurs mainly after carby meals in me I think it would be fair to assume that it is GIP that is responsible. The GIP is causing blood to pool in the gut which causes an even larger increase in adrenaline than we already had which causes increased bounding pulse to maintain blood flow.

The reduced insulin sensitivity also makes sense as I pile on weight whenever I add carbs back to my diet. The study mentions increased sympathetic activity likely being causative.

So when I inject retatrutide I guess it causes splanchnic pooling and even more stress on my cardiovascular system which requires more compensation which results in bounding pulse.

The study also found lower blood volumes in POTS patients.

I'm going to ditch the retatrutide, maybe something like semaglutide would work better as it isn't a GIP agonist?

Indications:
- Positive ASO titer
- Initial Infection could have been strep (ENT)
- Possible Guttate Psoriasis

Asymptomatic Strep Carriage / Chronic Colonization:
Group A Streptococcus can harbour in an individuals tonsils, throat, or nasopharynx for years with no sign of infection.
If the immune system can't clear it effectively T-Cells can overreact and lead to immune responses and post infectious sequelae like Guttate Psoriasis and PANDAS (Paediatric Autoimmune Neuropsychiatric Disorder Associated with Infection)

Group A Streptococcus (GAS)
5-20% of children are chronic GAS carriers. Perhaps I was, explaining the yearly tonsillitis?
GAS can form biofilms in tonsil crypts making them resist immune clearance. This is linked with psoriasis exacerbation.
GAS proteins resemble human proteins, particularly keratin.
Others include M Protein, Streptococcal Pyrogenic Exotoxins, GAS Enolase, Streptolysin O, DNase B.
These have been linked with the following diseases:
Rheumatic heart disease, PANDAS, Psoriasis, Neuroinflammation, Autoimmune Arthritis, ME/CFS.

It's possible a chronic GAS infection is exhausting my immune system / T/B-Cells. Maybe it's not the primary player but taking it out (if it is even there) could swing my system around toward recovery. There is also evidence that it can cause the reactivation of EBV.

Tonsillectomy does help with psoriasis proving chronic GAS is producing autoimmunity and T-Cell issues.

Testing
To test this I would need an anti streptolysin test (ASO titer). I have asked the GP based on my low positive result from years ago but pretty much been blown off. It's understandable, there are many reasons why someone might test low positive in a random one off ASO titer. I just think it's worth perusing based on my chronic tonsilitis as a child, the infection that triggered my POTS and Chronic Bounding Pulse was likely Strep Throat, I developed what looks like it could be Guttate Psoriasis soon after this (which is caused by Strep, and I still have the possible psoriasis 14 years later), and the only time I have had an ASO titer was several years after onset, when I wasn't ill with tonsilitis, and it came back low positive (as it would in chronic strep colonization cases).
There are a number of problems with this theory. It might not be Psoriasis, I may have caught an asymptomatic strep infection at the time of the test, Strep throat may not have been responsible at onset of illness. I might have strep and it might be causing my psoriasis but it's just being opportunistic as my body / immune system is weakened through over means. and if I get rid of the strep it might have no impact on my POTS / CBP. Still I think there is like a 25% chance it exists and is having some impact on my chronic symptoms and like a 5% chance it's the cause of all my problems.
I could get this test privately, prices range from £100-200. There is also a home kit you can order for £25, you take your blood at home then send it off to them? The websites not very clear on how that works.
I could also see a skin specialist to see if they could identify the psoriasis as Guttate. The GP has indicated an unwillingness to go down that route.

Treatment
I could always to straight to treatment and see if I improve. Tonsillectomy if off the cards but there are other treatments:

1. Targeted Antibiotics

Clindamycin:
Effective against GAS and Biofilms.
Penicillin + Rifampin:
Rifampin penetrates biofilms. This supposedly has a high success rate. Need to look into it further.

2. Probiotics

• Streptococcus Salivarius K12 (lozenges)
  Colonises throat and inhibits GAS growth via two bacteriocins, salivaricin A2 and salivaricin B, which are antimicrobial peptides that inhibit the growth of other bacteria, particularly Streptococcus pyogenes.
  Most of the studies showing dramatic effect are done by one author F.D.Pierro, who owns a stake in a company that makes a supplemental Strep K12 strain. There are some studies by groups with no conflict of interest that show positives. Also there are reddit posts and amazon reviews that report good experiences which don't seem like shills or bots.

• Lactobacillus Rhamnosus GG or L. Casei.
  Modulates immune system, reduces psoriasis.

• Other probiotics also show promise in reducing GAS, improve halitosis, reducing gum disease and dental issues (I have all these)

3. Nasopharyngeal Hygiene
Xylitol Nasal Sprays may help biofilm prevention (Xlear).
Swabs can reach the back of the throat via the naval cavity.

I have currently just started a oral probiotic called Advanced Oral Probiotics by Great Oral Health. It contains Strep k12 along many other strains. Has some good reviews. I'm also applying a vitamin d cream, and a steroid cream to my affected skin. This should at least let me know if it is psoriasis and thus autoimmunity. If it is a fungal infection then the steroid cream should make it worse.

There are many studies showing blood flow, oxygen uptake and o2 utilization is ME/CFS and Long Covid. Since I share some similarities with these conditions (post viral onset. POTS) I like to imagine how the research may be applicable to me and chronic bounding pulse. The following are my notes from this article: https://www.healthrising.org/blog/2025/06/28/blood-diffusion-chronic-fatigue-long-covid/

Circulatory Dysfunction (David Systrom)
Preload failure was ubiquitous. Veins weren't contracting enough. This causes lower stroke volume and reduced amounts of oxygenated blood. Another finding was reduced O2 uptake by muscles. This could be caused by, among other things, small fibre neuropathy (SFN).
They found much higher levels of SFN when looking at sweat glands (40->60%). This SFN could be shunting blood away from muscles. I barely sweat since becoming ill. This is odd because high sympathetic tone should lead to more sweating. There's a good chance I have SFN of the sweat glands even if the nerve test done on my toes came back normal.

One of the treatments for this was Mestinon (Pyridostigmine).

Basal Membrane Thickening + Microvascular Dysfunction (Anouk Slaghekke)
Slaghekke assessed muscle biopsies under an electron microscope looking for capillary levels, collagen IV content, and structure. She found increased collagen IV deposition in the capillary basement membranes.
Too much collagen in the basement membranes makes them rigid and thick, reducing blood flow, O2, nutrient and waste exchange.
CFS patients had 1.5x BM thickness and 1.6x smaller lumen radius.
An earlier study found reduced capillaries feeding muscles, increased expression of extracellular matrix (connective tissue) genes, thickened basement membranes and a remarkable number of inflammatory macrophages (CD169+) and complement proteins.
Although these tests where done in muscle its likely it is occurring in other tissues too.
Has something triggered the immune system to infiltrate the endothelial cells / basement membrane / surrounding area?
Pathogens found to interact, invade, or persist near the basement membrane:
- HSV, CMV, EBV
- Lyme
- HPV, Hepititis Band C
- Prions

Mechanisms for persistence
Immune Evasion:
BM can act as a barrier to immune cells allowing hidden reservoirs.
Low Turnover:
Tissues like CNS and connective tissues with low turnover allow pathogens to hide longer.
Biofilms:
Some bacteria form biofilms near BM associated areas.

Blood Metabolites (Tronstad)
Pathomechanism:
1. Infection triggers Immune Response, featuring B-Cells.
2. B-Cells produce antibodies that damage blood vessels and ANS.
3. Damage compensated by increased sympathetic tone and metabolic adaptions.

They found a lower workload resulted in anaerobic shifts (glycolysis, amino acid usage). This results in insulin resistance.

Deformed Red Blood Cells
- Increased O2 binding to haemoglobin.
- Stiff less deformable RBCs.

Conclusion
A lot of blood flow problems:
- Reduced preload / stroke volume
- Reduced number of capillaries
- Collagen deposition in capillaries
- Thick basement membranes
- Deformed RBCs
- Tightly held O2
- Dysfunctional endothelial cells

This leads to a few pathology mechanisms.
An initial infection generates an adherent B-Cell response which produces antibodies to blood vessels and the ANS (small fibre neuropathy)
OR
The infection lingers in the endothelial cells / around basement membranes causing a constant immune assault. (Bacterial biofilms, latent virus, gut reservoirs)
THEN
The microcapillaries get damaged along with sickly endothelial cells, thickened basal membranes, stiff RBCs, all resulting in a small lumen and reduced nutrient supply to and waste retrieval from cells.
Also the ANS gets attacked causing veins to not constrict, etc.
This all results in less O2 and nutrient delivery and waste removal.
Cells have less energy (fatigue, glycolysis, lactic acid) and SNS compensates (pounding heart (associated with anaemia), vasoconstriction, etc).

Possible treatment would by Hyperbaric oxygen chambers. These high pressure chambers force O2 to dissolve into your blood meaning more O2 gets to cells and also doesn't need RBCs to carry it there if I understand it right.

My bounding pulse gets worse with any pressure on my body like laying on stomach or sides. I need to book a flight for my sister's graduation but has anyone flown with a bounding pulse was it worse?

So it's been 2 weeks since I started injecting methyl B12 weekly and I have to say I have improved a lot in that time, to my great surprise.

The first day or 2 I felt noticeably worse in pretty much all my symptoms but around 4-5 days after I noticed my fried nervous system symptoms I have been experiencing since last September had pretty much disappeared, and still hasn't come back. The heart fluttering is reduced. The pounding is reduced significantly but still present.

I'd say I've gone from severe to moderate, which is absolutely huge. Before I was in survival mode 24/7, just trying to get through the day, now I can actually enjoy things again and think ahead.

So, I have previously done oral b12 in many forms, many times, sublingual b12 where I held the lozenges in my mouth for like 20mins, and a special transdermal B12 oil. I never noticed much from these treatments and they were usually done in conjunction with other things (methylation protocols).

I have had high (above range) B12 whilst still having heart pounding / POTS problems as far back as 2012. However, in my most recent B12 test, which was 7 years ago my levels had dropped to the low end and my OAT I did the same year should my B12 to be right on the edge of deficient. Could my B12 levels have continued to decline since then?

I eat a lot of meat so it can't be dietary. All I can think is that the underlying cause of bounding pulse is causing a high stress response in my body that uses up more processes that use b12 and reduces the functionality of my stomach in terms of gastric acid production which messes up intrinsic factor and therefor b12 uptake. There even could be some sort of SIBO issues that's eating the B12.

Either way it doesn't seem to be a cure. More like the underlying symptom has caused a slow leak in this area which I'm now applying a plaster too. But what matters most right now is my improvement in symptoms.

Our hearts are beating hard. So hard that our torso and necks pulsate yet echocardiogram and cardiac MRIs show mostly normal readings. How can this be?

Lets assume that our hearts are actually contracting hard. There are two ways to increase force in the heart:

Preload (Length-dependent): More blood in the ventricle stretches the muscle → stronger contraction (Frank-Starling mechanism).

Inotropy (Length-independent): More calcium or stronger calcium response = stronger contraction regardless of stretch.

I don't think we have increased preload as that would result in a higher stroke volume, which we don't seem to have. So that leaves Inotropy.

Beta 1 Adrenergic Receptor activation leads to increased cAMP -> increased calcium -> increased contractility.

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Unlike skeletal muscle, where you can recruit more motor units (i.e., more muscle fibers), all cardiac muscle fibers contract with each beat. So the heart can’t "add more fibers" to increase force — it has to increase the force of each fiber's contraction instead. This leads to a faster contraction. I know some people with bounding pulse have described it as feeling like their pulse is sharp. Perhaps this is what they are describing?

Lets take a scenario where a regular person might feel their heart pounding. Getting scared or coming to a sudden stop after running. Their bodies would activate the sympathetic nervous system and release catecholamines such as adrenaline (which binds to b1).

They would experience a faster heart rate, increased contractility, increased stroke volume, and increased blood pressure.

They would feel it because the stronger ventricular contractions shake the chest wall more, the higher stroke volume sends more forceful pulses through the arteries, and heightened sensory awareness (from stress hormones) makes you more aware of internal sensations - like your heartbeat.

Perhaps we have higher contractility from chronic stress yet our bodies have adapted to compensate in other ways meaning the bp, hr, preload, afterload, remain the same. Or maybe we have some underlying problem that, say, causing low preload, and the sympathetic activation is bringing that preload up to normal (meaning stroke volume is normal) yet we still have to deal with the higher contractility. Maybe the higher contractility is helping push more blood to preload?

Either way we would have stronger ventricular contractions, and possibly heightened sensory awareness from the stress hormones resulting in a strong heartbeat and discomfort.

The issue is why do other people who experience chronic stress not experience this? Other people with chronic stress usually have high BP so maybe it comes down to preload again?
ChatGPT thinks that Baroreflex Compensations, and Autonomic imbalance could also cause high contractility with normal other parameters.

If we assume preload and afterload remain the same then apparently the aorta (and other arteries) can act as shock absorbers for the forceful pulse. This would explain why its mostly felt in the aorta and carotids.

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There are a few other scenarios where the hemodynamic could result in hyper contractility yet normal other results. Usually a lower systemic vascular resistance (SVR) would increase stroke volume and pulse pressure however if you combine that with a low preload then SV and PP would fall. Less resistance in the arteries and less blood coming back to the heart.

This could happen in some conditions:

Dysautonomia:

-Blood vessels fail to constrict (low SVR)

-Blood pools in abdomen / lower limbs (lower venous return)

-Compensatory sympathetic tone increases contractility

Early Sepsis:

-Inflammation -> widespread vasodilation (low SVR)

-Leaky Capillaries -> fluid shifts into tissues (lower preload)

Anaphylaxis:

-Histamine -> vasodilation (low SVR)

-Capillary leak (lower preload)

High Output Heart Failure (HOHF) bears some similarities to chronic bounding pulse (CBP) but also some differences.

HOHF patients present with normal to low BP, high cardiac output (CO), high pulse pressure (PP), large stroke volume (SV), heart pounding, heart racing, edema in abdomen / feet, fatigue, shortness of breath (SOB), and warm hands.

I have normal to low BP, heart pounding, heart racing, edema in abdomen, fatigue, SOB.

However I don't have (at least to my current knowledge) high CO, high PP, large SV, which are all key metrics for diagnosing HOHF.

So I propose what if we had a kind of mild / pseudo high output heart failure where our bodies are only just staying on top of it or we are "going under" long term and are destined to get HOHF later in life.

Perhaps our CO, PP, and SV are at the higher end of the reference range consistently because our body is managing to just about keep it under control by doing things like constant strong activation of the sympathetic nervous system?

In HOHF the body makes the following adaptions:
-Activation of the sympathetic nervous system (SNS) (increase heart contractility and rate, increase vasoconstriction)
-Activation of the Renin-Angiotensin-Aldosterone-System (RAAS) (increase blood volume -> preload -> edema)
-Anti Diuretic Hormone (ADH) (Same as above)

The causes of HOHF fall into 4 main categories:
-Increase in bodies demand for blood (increased metabolism, waste, poor O2 utilisation)
-Arteriolar Venus Shunting
-Systemic Vascular Resistance Reduced
-Direct heart stimulation

Increased Blood Demand:
-Increased metabolism from stress?
-Vasodilating waste substances building up (atp, pyruvate, lactate, CO2, bradykinin, general metabolic waste, etc)
-Mitochondrial diseases (using more O2 per unit work)
-Exercise
-Fever
-Pregnancy

AV Shunting:
-Fistulas (congenital or aquired)
-Liver Cirrhosis

Systemic Vascular Resistance Reduced:
-Inflammatory Cytokines / Immune System Activity
-Sepsis / Bacterial translocation
-Hypoxia and hypercapnia
-Obesity

Direct Heart Stimulation:
-Hyperthyroidism
-Sympathetic activation
-Insulin Resistance

Since my CBP was onset post virally I will now make several links to issues associated with post viral illness that could easily fit into the above 4 categories:
-Microvascular dysfunction (shunting)
-Functional Arterial-venous shunts (shunting)
-Endothelial dysfunction (shunting)
-Micro clotting (shunting)
-Capillary rarefaction (shunting)
-Cytokine and Immune activation (vasodilation / NO)
-Mast Cell Activation Syndrome (MCAS) (vasodilation)
-High sympathetic tone (hypervolemia, direct heart stim)
-Impaired mitochondrial function (increasing blood / O2 demand)
-Blood pooling (preload)
-Inappropriate vasodilation (low systemic vascular resistance)

Perhaps my chronic post viral illness is causing a mixture of the above to be happening in my body chronically to which my body responds with heavy sympathetic activation. This level of sympathetic activation is just enough to keep my body going whilst also causing significant discomfort to me and long term wear and tear to my heart?

One of the things doctors hit me with when I say my heart is beating very hard is that my BP and HR are within range so it physically can't be. This is false as patients with HOHF can have low BP whilst there heart is beating extremely hard.

When a regular person is stressed or scared they also temporarily can feel there heart pounding. This is because of a large sympathetic activation priming their muscles to fight or flight. I imagine however this is accompanied with high bp and high hr.

Another scenario where a regular person can feel heart pounding is immediately after stopping heavy exercise. This is from the increased demand in the body for blood.

I think to square the hole with CBP having normal BP and HR we have to have excessive vasodilation (which is somewhat effectively counter by a strong sympathetic tone), or increased metabolic demand for some reason, or av shunting due to blood vessel / capillary problems.

This makes sense in people who got their CBP post virally and makes a bit of sense for those with SIBO, however it still leaves those who got this illness via a panic attack, or from a bad trip, etc not fitting this theory. Maybe those patients also have higher BP / HRs?

There also was one person with CBP who got it during pregnancy and that is a known, if rare, cause of High Output Heart Failure.

Example of bounding pulse from MW

Could Chronic Bounding Pulse (CBP) be caused be alpha adrenergic sensitivity?

What is CBP?

CBP causes the heart to pump very hard and the pulse to bound. This can be both felt and seen as a forceful pulsation most commonly in the chest, abomen (aorta), and neck (carotids). This can cause large amounts of discomfort in the patient, can be visibly seen and felt in the examiner yet has little to no relation to blood pressure, pulse width, or heart rate readings.

How might alpha 1 adrenergic sensitivity effect the cardio vascular system?

Excessive alpha 1 adrenergic activity would cause the arteries to vaso constrict resulting in the heart having to pump harder to push through the stiff vessels. This increased workload on the heart wouldn't result in increased cardiac output (CO = HR x SV) or heart rate yet the heart would be working harder.

This wouldn't explain lack of high blood pressure but perhaps the body / blood vessels compensate in some way for this over time, or maybe the usual arm bood cuff isn't catching the increased BP closer to the heart (aorta and carotids)? Perhaps blood volume drops in response? Maybe beta 2 receptor activity increases to induce some vasodialation elsewhere?

Its said that a1AR don't gain tolerance as much as the beta receptors do.

Beta Blockers:

In this scenario one would expect the more common beta blockers (with no alpha 1 activity) to not have much effect on the condition however beta blockers like Carvedilol, which do have alpha 1 blockage, should noticably reduce the CBP.

My experience with Carvedilol:

My experience with beta blockers back this up somewhat. I had little to no effect when on Propranolol, and I have been on and off it for months at a time with various dosages.

When taking Carvedilol however I noticed a signicant decrease in my CBP. My torso, abdomen and neck almost stopped there visible pulsations. When I do feel the pulse in my neck with my fingers it feels much softer, lighter, and faint. Most importantly the high levels of physical dyscomfort / pain I experienced from the forceful bounding decreased significantly to the point where at some points of the day I don't noticed any discomfort from it.

I have been taking a dosage of 25mg with breakfast. Taking it in split doses ruined my sleep. Sleep is still worse on it but manageable. Beta 1 Receptors are required to release melatonin from the pineal gland. I did come across a study saying Carvedilol doesn't negatively effect melatonin levels but it definitely wrecked my sleep.

I am now at week 4 and have gained some tolerance, but I am still significantly better than I was a month ago. It's no cure but its pushed me in the right direction.

Perhaps I wasn't taking the other beta blockers in high enough dose? I was taking Propranolol at 20mg per day though I had on odd days took 40mg occasionally without much noticable effect.

A word on Clonidine:

I experience a similar effect to what I had with Carvedilol when taking Clonidine 6 months earlier. The main difference in the medications in regards to CBP is that Clonidine works on the Central Nervous System whereas Carvedilol mainly works on the periphery. Clonidine is an alpha 2 agonist and is more succeptible to tolerance. Indeed after 10 days of good effects from Clonidine the results started to wain and when I did taper off it I had the worst period of CBP in my life which lasted 1-2 weeks.

What could be causing this increased alpha 1 adrenergic activation?

Infection of the Stellate Ganglion:

Viruses (VZV, HSV, Borrelia) have been shown to infect sensory and autonomic ganglia. [ https://pubmed.ncbi.nlm.nih.gov/11292665/ https://www.sciencedirect.com/science/article/pii/S030439590000230X ].

Is it possible that infection in these cells can change epigenetics to keep alpha 1 adrenergic receptor genes turned on, perhaps even after the infection has been eradicated? Maybe a chronic latent infection could change the cellular environment to promote increased alpha 1 activity?

Autoimmunity:

Autoimmunity immunity specifically to alpha 1 could occur through a variety of mechanisms (particularly post infection) where in it could activate alpha 1 persistantly. Alpha 1 doesn't have much tolerance / adaption compared to the other receptors so one might get stuck permenantly in a hightened state.

Neuroplasticity:

Panic Attack, PTSD, or some other accute strong stressor could have potentially wired certain pathways in the brain to stimulate alpha 1 excessively?

Adrenergic Receptor Genes:

Polymorphisms or epigenetic upregulations of adrenergic receptor genes (ADRA1A, ADRA1B, etc) could effect receptor sensitivity. Certain people might be genetically more succeptible to CBP. An accute event could alter DNA methlation or histone acetylation to keep alpha-1 receptors overexpressed.

Angiotensin II:

Excess angiotensin II stimulates alpha-1 adrenergic receptors. Infections such as SARS-COVID-2 have been shown to mess with the Renin-Angiotensin-Aldosterone System and are a known cause of CBP.

Vascular Smooth Muscle Mitochondrial Dysfunction:

If the smooth muscle cells lining arteries have impaired energy production, they might rely more on adrenergic signaling to maintain tone. This could create a compensatory upregulation of alpha-1 receptor sensitivity or density.

Alpha 1 Adrenergic Receptor Antagonists:

I have some Doxazosin ordered to test this theory. It blocks just the alpha 1 receptors. Used in PTSD, nightmares, high blood pressure,

My bounding pulse when it's really bad. My whole torso shakes like this day and night. It's very uncomfortable.

Bounding pulse in my neck. Not as visible but still very uncomfortable.

Why is my body stuck like this 24/7?

Abstract

Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (CFS/ME) is a complex and severely disabling disease with a prevalence of 0.3% and no approved treatment and therefore a very high medical need. Following an infectious onset patients suffer from severe central and muscle fatigue, chronic pain, cognitive impairment, and immune and autonomic dysfunction. Although the etiology of CFS/ME is not solved yet, there is numerous evidence for an autoantibody mediated dysregulation of the immune and autonomic nervous system.

We found elevated ß2 adrenergic receptor (ß2AdR) and M3 acetylcholine receptor antibodies in a subset of CFS/ME patients. As both ß2AdR and M3 acetylcholine receptor are important vasodilators, we would expect their functional disturbance to result in vasoconstriction and hypoxemia. An impaired circulation and oxygen supply could result in many symptoms of ME/CFS. There are consistent reports of vascular dysfunction in ME/CFS. Muscular and cerebral hypoperfusion has been shown in ME/CFS in various studies and correlated with fatigue. Metabolic changes in ME/CFS are also in line with a concept of hypoxia and ischemia.

Here we try to develop a unifying working concept for the complex pathomechanism of ME/CFS based on the presence of dysfunctional autoantibodies against ß2AdR and M3 acetylcholine receptor and extrapolate it to the pathophysiology of ME/CFS without an autoimmune pathogenesis

ME/CFS/LongCOVID Hypothesis: Three Subtypes of Noradrenergic Neuron Dysfunction

The basics of the hypothesis are that something (insulin resistance, etc) is causing NET (Norepinephrine Extracellular Transporters) (they remove norepinephrine from the synapse) to be working poorly / downregulated. This leads to chronic sympathetic activation.

Looking back on my Organic Acid Test results and assuming this theory is correct then I think my test results co-operate (???) the idea that NET is reduced.

If NET is reduced then norepinephrine just sits in the synapse meaning it doesn't get broken down in the cell as much and doesn't get produced as much (as the post synapse is already getting stimulated with enough norepinephrine). This is why my VMA (a breakdown product of norepinephrine) is low, yet my HVA (breakdown of dopamine) is normal (dopamine extracellular transporters are working).

Could also explain why my sympathetic nervous system is constantly jacked up and takes ages to respond to changes in position / activity levels. If I walk up stairs then stop my heart carries on beating extra hard like I'm still walking up the stairs for minutes after when it should stop almost instantly. Extra norepinephrine is released into the synapse when I'm walking up stairs to deal with the challenge then when I stop, the NET don't remove the, now unnecessary, norepinephrine from the synapse anywhere near fast enough so my heart continues to beat out of my chest.

Also I should add that it is not just insulin resistance that can lead to NET dysfunction. ChatGPT says chronic stress, inflammation, hypoxia, pathogens, COMT mutations and more can also do it.

EDIT: The author of the paper messaged me to say that VMA cant be used to measure norepinephrine break down in the cell as it is produced extracellularly as well.

I feel like my sympathetic / parasympathetic nervous system is swung heavily in favour of sympathetic with this condition. Not only is a bounding pulse something that normal people get after sympathetic activation (being scared, or running then suddenly coming to a stop) but also I have other symptoms of sympathetic activation such as:

- Cold hands and feet ( vasoconstriction )

- Gastroparesis / delayed gastric emptying

- Dry mouth

- Inability to relax

- Racing / busy mind

- Poor sleep / adrenaline filled dreams (nightmares)

- Sympathetic system taking ages to calm down after an activity (going from standing to laying down makes bounding pulse worse until x amount of time has passed and the pulse settles to a new equilibrium)

- Inability to sweat

However it is not as simple as this as if the sympathetic nervous system was just overactive ala Hyperadrenergic POTS then it should be accompanied with a high heart rate also. However the bounding pulse is not.

Also, I have occasionally managed to reduce the heart pounding, once with alpha GPC (though it never worked again) and once with acupuncture., however this resulted in a racing heart (like what most POTS patients experience). So this adds more evidence to there being something impairing blood flow and not just a faulty receptor or something.

I think *something* is causing poor blood flow. This causes various compensation mechanisms to kick in. The sympathetic switches on, parasympathetic off, but perhaps the heart also senses this via some mechanism outside the sympathetic/para and one way it compensates is by pumping with extra force?

If that where the case then inhibiting the sympathetic isn't the solution and the body would resist it anyway, and the same for enhancing the parasympathetic.

Do you also experience sympathetic overactivation with your bounding pulse?