Thread by @nerdymedzebra

#Paper time! 🧵

annualreviews.org/doi/10.1146/an…

"Thus far, the literature has identified three different pathophysiologic mechanisms that are capable of manifesting the POTS phenotype:

(a) partial autonomic neuropathy,
(b) persistent predilection for hypovolemia,
(c) central hyperadrenergic state. "

"While many conditions, such as mast cell activation disorders, Ehlers-Danlos Syndrome, deconditioning, and genetic mutations of norepinephrine transporters coexist with POTS, their downstream effects also funnel into these three principal pathophysiologic mechanisms."

--> offshoot of this, I went to look into "genetic mutations of norepinephrine transporters" and !? Why is this the first time I've heard of this connection?

Quotes:

"NET is a monoamine transporter and is responsible for the sodium-chloride (Na+/Cl−)-dependent reuptake of extracellular norepinephrine (NE), which is also known as noradrenaline.

NET can also reuptake extracellular dopamine (DA)." /

"NETs, along with the other monoamine transporters, are the targets of many antidepressants and recreational drugs.

In addition, an overabundance of NET is associated with ADHD."

?!!?

I don't know enough about all this yet, but could this possibly be connected to the higher rates of ADHD found in EDSers? (I am adhd to a debilitating degree, fwiw)

(I haven't seen papers on adhd & mcas or dysautonomia i don't think, but i have for EDS at least)

Now I'm trying to figure out how my own daily antidepressant, venlafaxine, a Serotonin-norepinephrine reuptake inhibitor plays into this, if at all.

Wiki says SNRIs are used for depression PLUS anxiety, neuropathic pain (!), ADHD (!), fibromyalgia problems, etc.

wiki: "There is evidence [for relationships between]... [norepinephrine transporter mutations] and various disorders such as ADHD, psychiatric disorders, postural tachycardia, and orthostatic intolerance."

"The SNPs rs3785143 and rs11568324 have been related to [ADHD].

Thus far, however, the only confirmed direct association between a SNP and a clinical condition is that of.. Ala457Pro, and orthostatic intolerance.

Thirteen NET missense mutations have been discovered so far."

HEY LOOK AT ADHD & ORTHOSTATIC INTOLERANCE SHARING POSSIBLE ETIOLOGIES??

::maximumly relevant to me personally::

okay back to the paper proper, now reading the Neuropathic POTS section:

"There is much evidence.. suggesting preferential autonomic neuropathy in certain vascular beds promoting blood stasis in the pelvic, splanchnic, and lower extremities."

(I think i understand the gist?😅)

"Amounts of norepinephrine released at sympathetic nervous system synapses in the __lower extremities__ in response to a cold pressor test, a nitroprusside infusion, and tyramine infusion were markedly lower in POTS patients than in healthy controls."/

"In contrast, the amounts of norepinephrine released in the upper extremities in response to the same stimuli were no different between POTS patients and healthy controls."

"POTS[ies] demonstrate an exaggerated vasoconstrictive response to locally administered norepinephrine in the lower extremities, suggestive of a functionally denervated or depleted postganglionic state at baseline."/

"The extent of partial autonomic neuropathy extends.. into the pelvic & splanchnic circulation.

Both Doppler ultrasound & plethysmography.. have demonstrated abnormally increased blood flow & pooling in the splanchnic & pelvic circulation of POTS[ies] both at rest &.. upright"

EDSers prone to autonomic dysfunction & orthostatic intolerance:

"This [orthostatic] intolerance primarily manifests as excessive orthostatic tachycardia and reduced QSART (cholinergic sympathetic nerve sweat testing) responses when compared to those of healthy controls. "

[MCADs].. frequently coexists w/POTS. Mast cell degranulation causes a variety of vasoactive substances (histamine, prostaglandins, platelet-activating factor) to be released into circulation, potentially causing excessive vasodilation & blood pooling in the lower extremities."

"This may also be associated with an inflammatory neuropathy. These patients commonly complain of excessive flushing, abdominal cramping, and diarrhea in addition to the more traditional presyncopal symptoms experienced by POTS patients."

"Evidence of autoantibodies that act as partial alpha-1 antagonists have also been found in POTS patients.

These could have an effect similar to a partial autonomic neuropathy due to inadequate vasoconstriction in response to alpha-adrenergic stimulation"

Now on to the section on Hypovolemic POTS! It mentins the thing I just RT'd right away:

"Studies have shown that some POTS[ies] have 13–22% less plasma or blood volume than do healthy controls. Despite.. low blood & plasma volumes, plasma renin activity & aldosterone levels are also inappropriately low.. This..has been referred to as the “renin-aldosterone paradox”"

"Despite these low blood and plasma volumes, plasma renin activity and aldosterone levels are also inappropriately low in POTS patients. [the “renin-aldosterone paradox”]

Additionally, the aldosterone:renin ratio was found to be lower in POTS patients than in healthy control[s]"

"plasma angiotensin II.. levels in some POTS[ies] are [2-3x higher than].. controls.

Ang-II is the major effector of the RAAS axis, [leading to]
- systemic vasoconstriction,
- raising blood pressure,
- fluid retention,
- fluid balance homeostasis thru aldosterone secretion."

"Despite high Ang-II levels, POTS[ies] are paradoxically prone to hypovolemia.

One explanation would be that POTS[ies] respond differently to Ang-II.. POTS[ies] have an attenuated hypertensive response to Ang-II [vs controls] after infusion of a standardized dose of Ang-II"

"Deconditioning is an important comorbidity [in hypovolemic POTS] due to the prevalence of hypovolemia in deconditioned patients.

"..in six previously healthy male astronauts, just 16 days of spaceflight resulted in a decrease in blood volume of nearly 6%"

"Under normal gravitational conditions, two weeks of strict bedrest resulted in a 17% reduction in plasma volume and a near 10% reduction in stroke volume. The decrease in stroke volume.. was out of proportion to the degree of plasma volume reduction."

"[after] several months on a space station.. previously healthy individuals can.. almost meet some POTS criteria (avg orthostatic HR increase by 26 bpm in the absence of orthostatic hypotension), with one.. [+31bpm].. despite.. regular cardiovascular exercise during spaceflight"

"Regardless, the renin-aldosterone paradox and dysregulation of renin-angiotensin aldosterone system play a central role in the pathogenesis of this POTS endo-phenotype, and clearly would be worsened in the setting of any deconditioning, either voluntary or imposed."