ramakentesh

Low Flow angiotensin II pots is the 'renin aldosterone paradox' subgroup. Neuropathic pots may result in sluggish aldosterone responses. Sympathetic activation alone can cause volume loss. In NET deficiency elevated peripheral dopamine may cause duiresis.

1. All the etiologies presented for 'hyperadrenergic POTS' involve low blood volume and reduced vasocobstrictive responses in the splanchnic circulation except the very rare central hyper which is more like baroreflex failure. The postural hypertension is either just an expression of increased peripheral resistance with reduced central, thoratic and stomach constriction or it is the potentiation of NE effects peripherally. This means that none of the dangers of essential and sustained hypertension are present and salt loading and volume expansion ARE essential. 2. Where aldosterone levels are low or suppressed oral salt loading may be useless other than acutely. 3. In low flow pots when patients were given a vasodilator on tilt their symptoms worsened suggesting that the peripheral vasoconstriction is not the primary problem and may even be compensatory. 4. Angiotensin II blockers are given to suppress sympathetic activity not to vasodilate. 5. Midodrine was nit suggested for low flow pots.

They measure the tachycardia not because it provides a meaningful measure of how symptomatic you are, but because it is the easiest objective measurement that indicates dysfunction. I can have massive tachy and feel great and have days where hr and Bp appear normal and I feel like crap. I don't generally bother measuring these vitals as they are not indicative of how well or otherwise I feel. the only doctor that I am aware of that tried to suggest measures of heart rate were indicative of severity of pathology was the one trying to argue that exercise 'may cure' pots.

It appears that all forms of pots could potentially effect blood volume - usually by sodium handling. Dr Stewart found that many with obviously low aldosterone and renin had paradoxical elevations in angiotensin II peptide. Ang II increases transduction responses to norepinephrine, increases brain stem sympathetic outflow and also directly stimulates norepinephrine release. Vanderbilt more recently confirmed the high ang II subset originally labeled 'low flow'. how these abnormalities result in pots and low blood volume is still being determined.

I tend to save it for days when I need to perform.

Yeah I agree with fire watcher and note a reduction in hr when standing as well massive improvements in dizziness/lightheadedness, weakness and fatigue. it works better than midodrine for me by miles.

I can't get that link to work. I have ankylosing spond and this is an area of interest.

Sorry pressor

There are other press or agents that usually pose less side effects like dihydroergotamine and phenylephrine but these really boost blood pressure to help with dizziness and for me also energy. I'm not sure they would help with 'lead legs'. one doc used to treat brain fog with low dose calcium channel blockers but that was experimental. My personal favorite brain fig buster is licorice tea but caution as it combines with florinef.

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

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...

well the information provided here should set you on the right path re diagnosis. Another way to look at it would be - do symptoms of sympathetic activity predominate or does dizziness/weakness?

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.

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

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...

Yes or some say postural hypertension but its probably not that simple.

Its interesting that pharm blockade of net does not result in a hyperadrenergic presentation and in both the Australian net papers as well as work by Jens Jordon show normal NE levels in net deficiency.

Hyperadrenergic pots may have many causes - some if the worst hyper presentations I know have underlying neuropathy. It may be useful in terms of treatment but neuropathic, high ang II low aldosterone 'low flow' crowd and some but not all net deficiency patients can have a hyperadrenergic presentation. evidenced by the fact that the same amount of hyper and non hyper patients have abnormal QSART results. there are also some that mayo find that they call the central hyper crowd with MASSIVE NE levels - some at 5,300. interestingly Ernie in this site had 2,000 NE levels but responded to norepinephrine transporter inhibition meaning that in her case net deficiency was not an issue but I'll responding to that video post with more info on that tonight.

It could be and is often used to suggest wider autonomic involvement as a manifestation of the autoimmune disease as in some small fiber neuropathy with signs of autonomic involvement has been proven to be a sign of wider sympathetic denervation.

There are many. Pots is a syndrome with many suggested causes, none definitively proven and many hotly debated. some suggested etiologies include selective autonomic neuropathy with associated small fiber neuropathy, norepinephrine transporter deficiency which can cause tachycardia and reduced stroke volume, low aldosteron/high angiotensin II, perhaps primary peripheral or central parasympathetic problems and then those with huge norepinephrine release (central hyperasrenergic) which may have an association with mast cell disorders. still others continue to search for other mechanisms such as deconditioning, cerebral auto regulatory failure, spinal presynaptic denervation, abnormal expression of vasodilating molecules or diuretic peptides, etc.

No idea why my phone autocorrects norepinephrine to notepinephrine lol

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.

How is it possible 4 people havent taken either propanalol or florinef?

haha - yeah a healthy dietary choice - could have been just what i was doing when it randomly improved - but its funny how you cling to the belief that what you were doing at the time was the reason...

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