Carrie

New 2-Hour Lecture On Pots And The Autonomic Nervous System

37 posts in this topic

Hi everyone,

Hopefully this won't seem like self-promotion because it's really meant to help!

I'm a biochemistry professor and also have hyper POTS and NMS. Since I'm not teaching over summer vacation, I spent some time this week making a lecture explaining POTS, along with the normal function of the autonomic nervous system. It ended up being two hours long. It's designed for college students and healthcare professionals, but it's meant to be accessible for POTS patients and our families, too.

It is so difficult to find good information, and we all spend so much time searching message boards, research journals, textbooks, etc., that I wanted to help simplify things and offer a comprehensive lecture that includes not just a list of symptoms but a physiologic explanation for why they occur, a detailed look at the autonomic nervous system in "normal" people, an explanation for the possible genetic causes of POTS, and a review of the medicinal treatments and how they work on adrenergic receptors. I don't want to spam here with too many terms, but the lecture includes topics like NET deficiency, COMT, autoimmunity, etc. The video description on the YouTube page has a timeline to subdivide the sections and topics.

Anyway, NO OBLIGATION to watch, and I feel a little awkward posting my work here, but I really hope it can be beneficial. Hopefully it will give a thorough overview for people who are new to POTS, and also offer more advanced detail and insights for those who have been dealing with this for years!

Be well!

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Thank you! I look forward to watching it and adding it to my list of "pass-alongs". :)

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I will watch it this afternoon, but THANKS! That is a great thing to contribute to the POTS community with your background and knowledge. I'm sure it will help many!

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Wow! What a wonderful presentation! Finally something I can truly understand. I really appreciated the way you broke down and explain everything. Thank you so much for sharing this with us. I can't wait to show my family. Again, many thanks to you Carrie. Welcome to the forum.

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Hi Carrie! We spoke through emails a LONG time ago! Wow it seems like another life time ago! haha.... Nice to see you on here. I will check out the video sometime this week. :)

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Excellent! Good resource incorporating symptoms, potential causes and current treatments among other things.

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Thank you, everyone! I really appreciate the kinds words and hope that this offers some help. Over the years I've learned so much from the generous sharing from other people, and I want to be part of contributing and "paying it forward" to provide comfort and understanding to someone else!

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Outstanding! Thank you for sharing this.

While watching I kept thinking 'Cognitive dysfunction didn't affect her!' Bravissimo.

K

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Interesting I'll watch this video tonight. Its interesting in net deficiency that there may either be blunted notepinephrine release in response to orthostatic stress and variations in the action of NE dependent on the size of the synapse - NE getting 'caught' in narrow synapses like in sympathetic synapses in the heart yet leaking out into plasma and lost in wider synapses effectively exhausting the presynaptic vesicles of notepinephrine resulting in blunted orthostatic venous vasocobstriction in the splanchnic region.

in the many patients found in the recent epigenetic study that found epigenetic gene silencing notepinephrine levels were not raised suggesting many with net deficiency are not actually 'hyperadrenergic' - once NE leaks out of the synapse it has little effect other than on distant beta receptors.

also stimulants like pseudoephedrine have no effect on the transporter - rather they stimulate release of NE from presynaptic vesicles that may be blunted in net deficiency.

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No idea why my phone autocorrects norepinephrine to notepinephrine lol

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Hi Carrie

I watched the video and despite my rather usual cynical opinion of these kinds of things I must admit the quality of the information you have provided is well structured and an accurate reflection of current views on the etiologies of POTS. Infact Id recommend it to any patient.

What I really enjoyed was the fact that you noted a point that nearly everyone - even doctors - regularly miss. That much of the NE stored in presynaptic vesicles is indeed from reuptake source via the transporter, thus over time the sympathetic vesicles become depleted of norepinephrine causing blunted NE release in response to orthostatic stress or tyramine infusion and impaired orthostatic tolerance and reduced stroke volume.

Whether it is the norepinephrine that leaks into plasma that is responsible for the classic 'hyperadrenergic' symptoms is equivocal. Remember that there may be variations in the size of synapse allowing NE in some substrates to have more of an activating effect than areas with wider synapse shapes where NE leaks out into plasma more readily. In the recent study on Mice with NET deficiency it was interesting that in the brain and cardiac muscle it appears that NE synethesis was maintained which provided the possibility that perhaps NE synethesis is sustained in the brain and cardiac muscle sustaining sympathetic central activity and tachycardia while perhaps other regions experience a decrease in NE synthesis and may be more reliant on reuptaken norepinephrine before stores are reduced and NE release is blunted.

Another small thing is that while alpha 2 presynaptic receptors offer a negative feedback loop that supresses release of NE where NE levels are increased in the sympathetic cleft, there are also postganglionic alpha 2 receptors in the splanchnic circulation that are involved in venous constriction at these locations.

Another interesting thought is that the original POTS research paper that identified 'neuropathic POTS' specific to the legs identified this through the finding of impaired norepinephrine reuptake at this location. THis is because in heart failure and other conditions impaired NE reuptake is considered a sign of symapthetic denervation.

That is why in conditions like heart failure and also Diabetes type II and CAN the MIBG cardiac uptake scan using the radiotagged norepinephrine analogue to measure cardiac NE reuptake is presumed to represent sympathetic denervation rather than absense of norepinephrine transporter protein.

it is possible and some have considered that the faulty NE reuptake phenotype in POTS might be a consequence of POTS itself or a epiphenonema associated with some forms of autonomic neuropathy.

I guess I would have probably included maybe a little more on the abnormal QSART results and the association between small fiber neuropathy and POTS with the implication that this constitutes more widespread autonomic neuropathy - but again this is murky because Dr Stewart recently found that some 'neuropathic POTS' also have elevated norepinephrine levels.

Lastly I noted that you missed the now reasonably well characterised subset of POTS patients that have elevated angiotensin II, paradoxically low aldosterone levels and possibly a genetic defect in ace 2 activity causing impaired angiotensin II catabolism, potentiation of norepinephrine's effects at the sympathetic synapse (hyperadrenergic presentation), absolute hypovolumia and blunted vasoconstrictive responses to angiotensin II infusion. This cluster of symptoms was identified by Dr Stewart and Marvin Medow and then by Vanderbilt.

I wasnt aware that published work had connected POTS with genetic mutations in COMT, Tyrosine or the other locations you mentioned in your talk. Do you have any links to published research on any of those genetic defects?

As for orthostatic hypertension - as you may be aware it may just represent an increase in peripheral NE transduction with blunted NE mediated vasoconstriction in the splanchnic circulation causing reduced stroke volume which is what I believe Dr Jens Jordon suggests.

In relation to the use of stimulants in POTS - even NET deficiency - I tend to disagree respectfully with your view that its 'adding fuel to the fire' in terms of the wired/tired scenario. if there is blunted splanchnic NE synthesis or release due to faulty reuptake then many of the symptoms of wired/tired may actually constitute the result of reduced stroke volume - reduced cerebral hypoperfusion. And remember that when hypertensive patients are given too many antihypertensive medications they experience 'adrenalin surges' similar to those experienced by POTS. it is possible and in my opinion (and I have bounced this off various researchers) that the wired/tired feeling is mainly this blunted NE mediated splanchnic vaso/veno constriction, impaired venous return, reduced brain perfusion and importantly - compensatory release of epinephrine in a poor attempt to improve upright hemodynamics - but ofcourse with the stimulation of beta 2 receptors it is a failed attempt. But anyway - what i tend to believe is that those with NET deficiency where symptoms of sympathetic excess predominate should use medications that suppress NE activity whereas there may be some with NET deficiency that do not have elevated NE levels (as per three of the research papers I have published below) and in these cases if NET is effectively bleeding presynpatic vesicles dry of NE then medications that promote its release might be helpful (pseudoephedrine being something that a number of Hyper patients are reporting recent benefit from for dizziness and orthostatic intolerance).

You can find a number of hyperadrenergic POTS patients on this forum and on facebook pages with outrageous NE levels. Interestingly many of these patients also exhibit small fiber neuropathy and perhaps have denervation hypersensitivity. Some here report responds to IVIG, etc.

This is an important point - vanderbilt and others now suggest that the 'hyperadrenergic' subgroup constitute not only NET deficiency, but also some neuropathic POTS and low flow/ang II POTS. There is also the reported association between extreme NE levels and MCAD disorder. Infact nearly all of the POTS patients I know personally with very high NE levels seem to have or suspect neuropathy. Mayo believe florid hyper POTS is a central problem as they would believe that presynaptic alpha 2 receptors should supress the NE release peripherally.

Lastly a patient here with very elevated NE levels responded to norepinephrine transporter inhibition! Work that out...

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Ill post some links that im sure you are aware of in the off chance that you arent :)

* Firstly - the challenging of the relevance of Hyperadrenergic POTS as having etiological significance:

http://www.ncbi.nlm.nih.gov/pubmed/20035362

RESULTS:

Of 30 women (ages 20-58), 17 patients (56%) had an abnormal QSART which was typically patchy and involved the lower extremity, while 13 patients had normal QSART results. Other autonomic tests, catecholamines or spectral indices did not correlate with QSART results. No differences in autonomic tests or spectral indices were observed between hyperadrenergic and non-hyperadrenergic POTS.

* Here we see that Norepinephrine transporter inhibition resulted in blunted sympathetic responses to orthostatic stress - without increases in plasma NE levels:

http://www.ncbi.nlm.nih.gov/pubmed/18187607

* Here we see more widespread reductions in the expression of norepinephrine transporter expression in POTS patients - with a mismatch between MSNA responses to orthostatic stress and NE levels in plasma (which were again within normal ranges and not hyperadrenergic):

http://www.ncbi.nlm.nih.gov/pubmed/19808400

CONCLUSIONS:

Patients with POTS exhibit a decrease in NET protein in their peripheral sympathetic nerves. Paradoxically, whole-body NE spillover to plasma during rest in the supine position and in response to head-up tilt is not altered despite excessive nerve firing rate in response to the head-up tilt.

* The game changing study - more widespread supression of NET in POTS patients via an acquired epigenetic mechanism - again NE plasma levels were normal in these patients:

http://www.ncbi.nlm.nih.gov/pubmed/22723437

OBJECTIVE:

The postural tachycardia syndrome (POTS) has multiple symptoms, chief among which are tachycardia, weakness, and recurrent blackouts while standing. Previous research has implicated dysfunction of the norepinephrine transporter. A coding mutation in the norepinephrine transporter gene (SLC6A2) sequence has been reported in 1 family kindred only. The goal of the present study was to further characterize the role and regulation of the SLC6A2 gene in POTS.

METHODS AND RESULTS:

Sympathetic nervous system responses to head-up tilt were examined by combining norepinephrine plasma kinetics measurements and muscle sympathetic nerve activity recordings in patients with POTS compared with that in controls. The SLC6A2 gene sequence was investigated in leukocytes from POTS patients and healthy controls using single nucleotide polymorphisms genotyping, bisulphite sequencing, and chromatin immunoprecipitation assays for histone modifications and binding of the transcriptional regulatory complex, methyl-CpG binding protein 2. The expression of norepinephrine transporter was lower in POTS patients compared with healthy volunteers. In the absence of altered SLC6A2 gene sequence or promoter methylation, this reduced expression was directly correlated with chromatin modifications.

CONCLUSIONS:

We propose that chromatin-modifying events associated with SLC6A2 gene suppression may constitute a mechanism of POTS

* And an interesting study that suggests pro inflammatory cytokines might supress NET expression in sympathetic nerves:

http://www.ncbi.nlm.nih.gov/pubmed/21241805

* abnormal MIBG cardiac uptake in POTS - presumed here to present selective sympathetic cardiac denervation but could also (and is now presumed) to represent NET deficiency in some POTS patients:

http://www.ncbi.nlm.nih.gov/pubmed/19687022

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I also forgot to mention the theory that NET deficiency may cause supressed sympathetic outflow in some by stimulation of brain stem alpha 2 receptors although the increased MSNA in many argues against this.

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But please dont allow my rambling to distract from your lecture. Which I think is fantastic and probably exceeds the knowledge of the majority of doctors currently treating POTS...

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Carrie, I want to thank you for this and appreciate the work you did. This will help others to learn a lot about what is going on with POTS. I learned a lot from it!

Rama, thanks to you too for clarifying some things. You amaze me with your knowledge!

You guys keep up the good work and keep us informed of the studies and the meanings of those. THANKS!!!!

Issie

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Thank you for all of the comments!

Kitt, "fortunately" my main problems have been with temperature regulation, fibromyalgia, fatigue, and anxiety. Things feel manageable right now, and I've been lucky not to have headache, GI problems, or brain fog.

Ramakentesh, what a treasure chest of information! Thanks! QSART is not something I've read much about, so you're right that it is missing from the presentation. You've given excellent info. to get me started learning about it. I also didn't know much about the angiotensin II / aldosterone differences. All of this points to the idea that no-one's POTS is really the same thing. We all present with a similar end result, but figuring out the cause is going to be unique for each person. For example, I've always had low blood counts (RBC, WBC, electrolytes, minerals, hormones), pointing to HYPERvolemia causing a dilution of everything else. At the same time, most POTSies have HYPOvolemia. It's hard to explain both sides! You're also right that lots of work has to be done for hyperadrenergic POTS. Many people present with the hyper symptoms but have normal catecholamines. I also have the "hyper" form but low blood pressure. :-/

I really appreciate all of your suggestions. You know many things I do not yet!

With regards to the TH and COMT-- no, I've not seen studies relating SNP differences to POTS in particular. I was mostly referring to Amy Yasko's work and extensions of that in the CFS community-- more with the mood and mental symptoms rather than with tachycardia.

Thanks again. :-)

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Fascinating stuff and refreshing to hear someone actually understand net deficiency correctly. Keep the informative posts coming!!

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Thank you for all of the comments!

Kitt, "fortunately" my main problems have been with temperature regulation, fibromyalgia, fatigue, and anxiety. Things feel manageable right now, and I've been lucky not to have headache, GI problems, or brain fog.

Ramakentesh, what a treasure chest of information! Thanks! QSART is not something I've read much about, so you're right that it is missing from the presentation. You've given excellent info. to get me started learning about it. I also didn't know much about the angiotensin II / aldosterone differences. All of this points to the idea that no-one's POTS is really the same thing. We all present with a similar end result, but figuring out the cause is going to be unique for each person. For example, I've always had low blood counts (RBC, WBC, electrolytes, minerals, hormones), pointing to HYPERvolemia causing a dilution of everything else. At the same time, most POTSies have HYPOvolemia. It's hard to explain both sides! You're also right that lots of work has to be done for hyperadrenergic POTS. Many people present with the hyper symptoms but have normal catecholamines. I also have the "hyper" form but low blood pressure. :-/

I really appreciate all of your suggestions. You know many things I do not yet!

With regards to the TH and COMT-- no, I've not seen studies relating SNP differences to POTS in particular. I was mostly referring to Amy Yasko's work and extensions of that in the CFS community-- more with the mood and mental symptoms rather than with tachycardia.

Thanks again. :-)

Carrie, can you share what kind of problems you've had with temperature regulation? Have you managed to resolve this? Any tips on how you did that?

Inability to regulate my body temperature is my second worst symptom with hyper pots, (First being the inability to sleep). I go from hot to cold to hot, and am sometimes hot and cold at the same time, (fire and ice sensations). I also have extreme 'sweats' particularly during the night.

Like you I'm hyper but have low blood pressure. Are you basing your hyperadrenergic status on catecholamine testing or something else?

Thanks again for sharing,

K

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*******One thing to note about the following post is that a lot of the results of this is based on individual patient response. It's important to check for individual methylation mutations. This has to do with genetics. There are also labs that can be done to check for deficiencies or excess.*****

One of the things that Dr. Yasko and Dr. Mullan are doing is connected with methylation pathway mutations --there could be a problem in BHMT pathways and issues with CBS mutations that could mimic COMT dysfunctions. I don't have a COMT mutation but have mutations on three of the different BHMT pathways and several CBS mutations. (There could be a SUOX problem with sulfite/sulfate - but 23&me doesn't test for that). I do think there may be a connection with POTS. But, not sure there has been any formal research on this. There is also the problem with balance between glutamate and GABA and that goes along with mutations in CBS. Since glutamate is an excitatory neurotransmitter and if the conversion doesn't happen into GABA - that might play a role in the higher levels of anxiety type symptoms some experience. The ideas presented here with this protocol is get the pathways to functioning properly and get things to convert as they are supposed to (at least what is known - because there are many more than just what is presented with this protocol) and the body should start to work better. The main things connected with this are diet which is number one. Then supplements like B-12, Lithium to help with uptake of B-12 and helps reduce excess calcium, (http://www.dramyyasko.com/resources/autism-pathways-to-recovery/chapter-4/ --this talks about excess glutamate vs. GABA balance), Same', folic acid, molybdenum, yucca, phosphatidylserine and choline ---and that all depends on what your mutations are. (There are other mutations - but these are the ones that could possibly be connected to POTS.)

Here's the info from Dr. Yasko in relation to CBS mutation and possible Taurine issues that was referred to in the video by Carrie - http://www.dramyyasko.com/resources/autism-pathways-to-recovery/chapter-6/.

http://www.heartfixer.com/AMRI-Nutrigenomics.htm - This link is to Heartfixer and they have a lot of information on all the mutations and what to do to try to get them to working efficiently. (Very comprehensive.)

(Don't ask me questions on this --because, I'm just learning about it myself. I won't be able to help you - cause, I'm still trying to help myself. LOL! There are however, a few others on this site that are more knowledgeable than me on this and maybe they can answer questions you may have.)

Issie

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One thing I question is your saying that HyperPOTS is determined with catecholamines levels of greater then 600 supine and over 1000 standing. I have read many studies indicating that the levels are over 600 standing. Here is one by Dr. Grubb. This also indicates that there should be an increase of 10 mm Hg in blood pressure.

http://www.ncbi.nlm.nih.gov/pubmed/21947988

I was DX'd at Mayo as being HyperPOTS and my standing levels are slightly below 900.

There however is a study indicating that those with lower bp's can have high catecholamine levels and this is many times connected to Mast Cell Activation Disorder (MCAS).

http://hyper.ahajournals.org/content/45/3/385.full

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Issie, the catecholamines reference ranges issue is strange...

Here is a link from the Mayo Clinic where their "normal" references for NE are up to 750 supine, 1700 upright. It seems they'd have to see higher values to consider a disease state. http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/8532

Quest Diagnostics says their normal range is 658 supine, 1109 upright.

http://www.questdiagnostics.com/hcp/intguide/EndoMetab/EndoManual_AtoZ_PDFs/Catecholamines_Plasma.pdf

Not really sure why the labs use different ranges, but it sure does make a standard diagnosis difficult!

Kitt, the temperature problems still persist and are my main problem right now. Dr. Bev. Karabin at U. Toledo said this is the hardest symptom to treat and they don't have any good treatments for it right now, aside from adjusting how you dress.

My body temperature always ran low. It seemed to like 97.1, and when I was really sick 96.8, and after being outside a short time in winter, 95.5. I've tried lots of experiments over the past few years, including Steve Richfield's CMCS theory and thyroid approaches, but nothing worked. The only thing that has brought me up into the high 97s is eating more (especially quick carbohydrates) and resting more (cutting back on endurance running), similar to the Matt Stone / 180 Degree Health approach.

The problem with having a low temperature is that I always felt cold and achy, even when the indoor temperature was normal and comfortable for other people. My hands and feet still feel frozen to the touch, and layers upon layers of clothes don't help. It's like my body can't generate heat, and this causes deep, internal pain everywhere. Being cold also reduces blood cell formation. There was a study with cats showing that any bone marrow has the ability to produce blood cells if the bone is warm enough. (They taped cats' tails to their abdomens, at which point the tail bones started producing blood.) I have had very low red and white blood cell counts, and my suspicion is that it is temperature-related, at least partly.

The other temperature problem is that when it's above about 74 degrees, I am in pre-syncope all day. The blood vessels in my hands and feet pop out, the blood pressure gets even lower, and I am dizzy and exhausted all day. It's not unusual to completely black out while walking around at a summer craft show or something. So far I don't know what to do about this, except when I'm home to stick my hands in the freezer throughout the day. :-( Until last week when it got really hot here in Michigan, I'd forgotten how tiring it is to feel hot.

So unfortunately I don't have any better ideas about temperature right now, and would love to hear suggestions!

The "hyper" is based on symptoms and catecholamines. What about you? I don't have an explanation for hyper with low BP, though. Probably we'll find out that there are subtypes even within hyper.

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Issie, the catecholamines reference ranges issue is strange...

Here is a link from the Mayo Clinic where their "normal" references for NE are up to 750 supine, 1700 upright. It seems they'd have to see higher values to consider a disease state. http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/8532

Quest Diagnostics says their normal range is 658 supine, 1109 upright.

http://www.questdiagnostics.com/hcp/intguide/EndoMetab/EndoManual_AtoZ_PDFs/Catecholamines_Plasma.pdf

Not really sure why the labs use different ranges, but it sure does make a standard diagnosis difficult!

I think when you look at the ranges, you have to look at the information in regards to POTS and HyperPOTS testing to figure out the ranges that are considered the criteria for the specific illness you are checking for. I've found more papers saying that anything above 650 upon standing. I have seen some that are higher then that - but more seem to indicate that as the starting number. Unless, there is a new POTS paper that I haven't seen with an update on the criteria. :)

Issie

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Heat vasodilates - cold constricts. Could that also be a compensatory thing? It could just be a connection to the faulty autoimmune system. I too have low body temps and tried the thyroid approach to rising body temp. It made no difference. It was thought that I had a conversion issue with T4 to T3 and RT3. That idea, didn't work. Treatment with T3 makes tachy even worse.

There are also connections to autoimmune issues and Raynaud's with cold hands and feet. So many of us are finding autoimmune issues.

Issie

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Thanks so much for sharing your lecture - it was very informative! I was also going to ask about Hyperadrenergic POTS and where those numbers came from. The number given by POTS researchers to diagnose HyperPOTS is quite lower than lab reference range for abnormal standing norepinephrine levels. I never understood looking at my lab work why the numbers would be considered normal by the lab, but not the POTS Doctors. I think work needs to be done in this area to clarify. It's interesting about HyperPOTS possibly causing the sensory symptoms, sensitivities, MCS, the pounding heart all day - that could explain a lot for me. This is the kind of lecture that needs to happen in medical schools so that soon-to-be Doctors have knowledge of POTS. I wonder if it's taught?

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