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...