Norepinephrine transporter variant A457P knock-in mice display key features of human postural orthostatic tachycardia syndrome.Shirey-Rice JKKlar RFentress HMRedmon SNSabb TRKrueger JJWallace NMAppalsamy MFinney CLonce SDiedrich AHahn MK.Dis Model Mech. 2013 Jul-Aug; 6(4):1001-11. doi: 10.1242/dmm.012203. Epub 2013

EKG Chart

POTS is characterized by furious heart racing upon standing.

Postural tachycardia syndrome (POTS) occurs when the heart goes into tachycardia (rapid heart beats) upon standing, causing dizziness, fatigue, cognitive problems, anxiety  and other symptoms. The most common type of orthostatic intolerance found  in chronic fatigue syndrome (ME/CFS), POTS appears in various forms, can be quite disabling,  and is often  difficult to treat.  Quality of life scores for people with POTS, for instance,  are similar to people with congestive heart failure.

Vanderbilt researchers, however,  may be on their way to cracking a core issue in the most common type of POTS that  could allow for the development of new therapies. Their road to insight in this case is through the development of an animal model  that will allow them to dig deeper and more quickly into one of the more complex disorders around.

This is good news for a condition that  commonly occurs  in ME/CFS and many could mistake for it. It’s also a nice preview to a later  examination of an animal model that Dr. Klimas (who is now employing an animal modeler) wants to develop specifically for  ME/CFS.

Family Ties

This story  begins with the identification of  a family with POTS  and the subsequent discovery of  a gene mutation that  knocked out  a norepinephrine (noradrenaline) transporter (NET). The transporter (NET) moves norepinephrine out of the  nerve synapses into ‘holding cells’ where it is rendered inactive.


A gene mutation that knocked out the norepinephrine transporter in a family laid the foundation for this POTS study

Norepinephrine, an ‘excitatory’ neurotransmitter, is produced in response to stress. (Since it activates the fight or flight system (sympathetic nervous system), one could say it causes stress, as well).  As soon as the stressor is gone it’s important  that NE be removed to a place where it can no longer turn on the SNS.

That wasn’t happening in that family; in fact, with almost no NE being removed from the nerve synapses,  the stress response in that  family was engaged all the time.

A similar, if not so extreme pattern can be seen in both ME/CFS and POTS where studies show the SNS is turned on most of the time.  Various reasons ranging from low blood volume, to blood pooling in the legs, to infection of the vagus nerve, etc. have been put forward but in POTS (and perhaps in ME/CFS) an inhibited norepinephrine transporter could be a big deal.

Norepinephrine – Stress Responder and Stress Induce

With its  neurons extending throughout the brain and much of the peripheral nervous system, norepinephrine has a far reach indeed.

The major transmitter in the fight/flight response, NE increases your heart rate, makes glucose available for immediate energy usage, reduces digestion, increases blood flows to the muscles, etc.

Norepinephrine activation is associated with several cardiovascular disorders including heart disease, diabetes and others. Increased norepinephrine production, may, in fact, be the tie the binds the increasingly strong relationship found between depression, inflammation and heart disease. Perhaps not surprisingly,  given its role in the ‘stress’ response, norepinephrine  appears to be able  increase anxiety and depression and has been implicated in cognitive problems.

Chronic overproduction of this  neurotransmitter may be able to make you ‘wired and tired’, anxious and cognitively impaired, at the same time it messes up your ability to respond to stress.

Hyper-adrenergic POTS

Most people with ME/CFS do not have raised blood plasma NE levels – which is something of a mystery given indications of increased SNS activity – but one group of POTS patients do. With their unusually high plasma NE levels, the hyper-adrenergic  POTS patients  clearly need to get their NE levels under control.

Episodes of tachycardia in ‘hyper-adrenergic’ POTS  can be triggered, not just by standing but by emotional ‘stimuli’ (not just stress!) and physical activity.

Vanderbilt Builds  A POTS Mouse

lab mice

Mouse models can move a field of medical research forward quickly. Dr. Klimas has one for GWS, and is looking for one for ME/CFS

The Vanderbilt  research group introduced the gene  mutation they found into laboratory mice and tested them in this study.  Presenting the same pattern as the family, the laboratory mice  had reduced brain NE transport and symptoms associated with increased anxiety. The  most intriguing behavior  was a pattern of freezing up during stress; something, I at least, am acquainted with.

Two studies have confirmed decreased NET activity is present in  many  POTS patients. Now with this animal model confirming that reduced NET activity affects both the cardiovascular and central nervous systems,  Vanderbilt researchers  will  be able to move much more quickly.

Difficult to Treat Patients

That is a good thing because a recent overview stated that POTS, in particular, hyper-adrenergic POTS, is difficult to treat.  One section in another study was titled “Why Are Some Patients with POTS So Difficult to Treat?”  Several factors contribute to that.

The subsets –often not recognized – can cause physicians considerable distress (:)) when their patients fall apart when they give them what turns out to be just the wrong medication. POTS patients, for instance, often do not respond well to drugs used for orthostatic intolerance.  Drugs commonly used to treat symptoms associated with POTS (but not caused by it) such as psychostimulants and antidepressants can make POTS worse. (In fact, most drugs developed for the brain (e.g.|; antidepressants – ‘reuptake inhibitors’)  attempt to increase  not reduce neurotransmitter levels in the nerve synapses. )

Physical deconditioning is a reality that requires careful consideration; too much exercise will hammer POTS patients, but too little will aggravate their condition. Finally, according to one review, the somatic hypervigilance can present complications as well.

While the study refers to drugs that may further bollix up NET functioning (such as antidepressants) it does not refer to any drugs that actually improve NET functioning. (If there is one I was not able to find it.)

Much To Learn


There’s still much to learn in POTS

There’s still so much to learn in POTS. That genetic mutation, for instance, that put a spotlight on NET, thus far, has not been found in other POTS patients.   Those increased NE levels in the nerve synapses should, at times, at least, spillover into the blood, raising NE levels there, but that doesn’t always happen and no one is clear why.  There’s clearly  much more to POTS  and excessive norepinephrine production than NET.

Mast cell activation disorder,  tricyclic antidepressants, amphetamine-like drugs such as methylphenidate,  hyperthyroidism, autoimmune states,  and NET inhibitors can all whack the  norepinephrine transporter and put the SNS on overdrive.  A recent discovery that epigenetic silencing (e.g. methylation turning off a gene) rather than a gene mutation may be turning off the NET transporter in many POTS patients, points the way to a possible treatment.

With their mouse model Vanderbilt researchers can begin to tease out ways to get the NE transporter back on track and POTS under control…at least for some patients.



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