Norepinephrine transporter variant A457P knock-in mice display key features of human postural orthostatic tachycardia syndrome.Shirey-Rice JK, Klar R, Fentress HM, Redmon SN, Sabb TR, Krueger JJ, Wallace NM, Appalsamy M, Finney C, Lonce S, Diedrich A, Hahn MK.Dis Model Mech. 2013 Jul-Aug; 6(4):1001-11. doi: 10.1242/dmm.012203. Epub 2013
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
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.
Excellent article, thanks Cort. I am hopeful that Vanderbilt will keep up the good work they are doing. We desperately need better treatments for this condition.
Thanks Emily, Vanderbilt is, I believe, one of the top, if not the top, autonomic nervous system center in the US. I just heard from somebody that the Mayo clinic has reduced it ANS staff and is now only seeing patient under 50….
I called Mayo in AZ this morning and asked if they see new POTS patients over the age of 50. They said that they do. I then asked about why MN is not accepting patients over the age of 50 (I’ve heard of two people that this was told to.) He said he didn’t know and had me hold while he talked to someone else. He said they had not heard this and had no notice of this as being the case. So, not sure why this is being told to people. He suggested asking further of someone else at Mayo in MN and see if maybe the person that said that –just didn’t know. I know that a lot of the studies that are done with many of the POTS doctors limit the ages of those they allow to participate in the studies. They want the majority range of those that would represent a more accurate picture of the patients they are trying to get the information for. For most of those studies it is age 50. For those of us over the age of 50 – most of us are women and post-menopausal. This would not represent the majority of the POTS patients. Since there are limited studies – it would make sense that they limit the age. But, as for seeing patients that are searching for help —not sure why they would say they would not take a patient over the age of 50. Knowing how Mayo works and how you are referred to other doctors as you go through their process – my beat was that if you needed to see a POTS doc. they would get you in – if they could. There are so few POTS docs and they can only see so many in a week. So, maybe they are swamped and that is the problem. Otherwise, Mayo in AZ will see you if you’re over 50. Dr. Goodman is the POTS doc here and is my doctor. He is swamped and booked up for a ways out. But, he is really trying to help others and trying to make us as comfortable as he can. It’s a trial and error type treatment with no clear solutions. Lot’s of bandaids applied. 🙂
Issie
OHHHHHH, I could just cry. I was working on a post in response to this all day and just lost the whole thing.
WOW, Cort – you put lots of research into that and did a good post. Thanks for putting the info out there. We need all the exposure we can get. I’m one of those hard to treat HyperPOTS people whose NE levels are way above the required 600 mark for NE on standing. They have to rule out a pheochromocytoma (adrenal tumor) when the NE levels get so high. There are so many different subset types of POTS and even amongst those with HyperPOTS. It is a very complex problem with lots of theories and not a lot of things that are concrete. Some POTS people have low NE levels. It is thought that maybe this NE release is a compensatory thing. The bodies way of trying to get very important and needed blood back up to the heart and the brain. Tachycardia occurs as an attempt to get blood where it desperately needs to be. There has only been one family of twins known to have the NET genetic problem. But, it is suspected that there may be more problems with NET than this gene variation with these two twins.
Also, another study shows that possibly NE is not recycled properly by the NET protein and leaks out into the plasma.
http://atvb.ahajournals.org/content/early/2012/06/21/ATVBAHA.111.244343.abstract
There is also a bit of a paradox that happens with me in regards to NE. Even though I have high NE levels, Tramadol calms me down. If NET were a problem then this would be a paradox because Tramadol is an NET inhibitor.
http://www.ncbi.nlm.nih.gov/pubmed/11916794
Many of us with HyperPOTS also have Ehlers Danlos (EDS) and Mast Cell Activation Syndrome (MCAS). A trilogy that seems to go together. There is still so many unanswered questions.
What is causing the problem with blood flow going upwards back to the heart and to the brain above heart level? Is it a problem with valves or a blockage of some sort causing issues with blood flow (plaque, biofilms)?
My doctor has recently done an interview as to what he feels could be the problem with a lot of the neurological issues that we have along with CFS/ME, FMS, POTS, OI, MS etc. Here is the interview. I was tested positive for this organism and am working on my immune system to try to tame it.
http://protomyxzoa.org/wp-content/uploads/2013/04/Protozoal-Infection-Dr-Frye-Interview.pdf
Well, I guess that’s it for now. Good job, Cort. Keep the information coming. We all need answers.
Issie
Ouch…..that is so painful; I’ve done that more times than I like to remember…
But lots of interesting stuff. What a complex disorder POTS is! Interesting about Tramadol; ME/CFS patients seem to specialize in paradoxes…I’m looking forward to getting into MAST Cell Activation Syndrome and EDS…and reading that interview. Thanks for all the info..
Thanks! I was not happy about losing all the research material that I’d re-read and noted. But, hopefully this will give people some info that will be of interest.
There are so many possibly reasons why people have POTS and it appears that so many of our disorders appear to be connected and related. I keep saying if they find a “cure” for one thing —the other won’t be too far behind.
I know you’re interested in MCAS and EDS – more info coming your way, I went through my saved files. So, you have lots of info for blogs on these.
Thanks for opening the doors for us POTS people and allowing us to use your forum to try to connect more of the dots and get information out to others. Since I honestly believe there is a connection —the more information we can get and tell others about, the better. We all need to have as much exposure as possible when we are dealing with complex issues that are considered rare. Not only might someone read the information we put out and find a piece of their puzzle and answers that they so desperately search for —but, maybe the doctors that we need to help us – will notice a pattern or something that may help them connect the dots and come up with more and better solutions for us. I keep saying that I’m looking for my purple bandaid. Why purple? —it’s a pretty color and it’s also supposed to help one heal faster. If I have to have something to mask the problem and cover it over (a purple bandaid) and it will bring me more quality of life —even if I might not can “fix” it – that’s what I’m searching for. More quality of life —for whatever quantity of life I have left —that’s the goal! There is an idea that a friend of mine came up with showing it’s really all in how we look at life. Is the glass half full or is it half empty? The glass is always full and is overflowing —what you see may be half of something but the other half is air and it is overflowing even to the outside of the glass. So, life can be full and overflowing – even if appearances may say otherwise. It’s all in how we look at life and our determination to LIVE our life despite what we may be dealing with and not let these “illnesses” define us and take our purpose and meaning away. Our illness is not who we are. We can make our lives mean something by giving of ourselves to others and our lives will have great value and purpose. There is another saying by Anais Nin that I LOVE, I have it on my desk.
“We Don’t See Things as THEY are, We See Things as WE are.
That is so true. Everything is seen with our perception of how WE perceive it to be. Not necessarily how IT truly is.
Okay, so where’s my purple bandaid? 🙂
Issie
It really is all about quality of life….
“We Don’t See Things as THEY are, We See Things as WE are.
That is so true. Everything is seen with our perception of how WE perceive it to be. Not necessarily how IT truly is.
There is so much to this…so much freedom…..
In a seminar I’m taking this is our homework for this week
*Notice how much you are “on it” – stuck in a position or with a point of view – practice “getting of it.”
*Some tips on getting off it:
-give up being “right” and try on another’s view
-give up arguing for your way being the only way
-let go of being attached to how you see it, and get interested in finding a new solution
-see the “payoff” and “cost” of being stuck in your position
Loved that, we all should make a mental note and not be so “full of ourselves”. There are other players in the world – we just have to open up our own personal world – to let them in. We decide who we admit to “our world” – it’s a choice. Allowing others to enter may enrich our lives and make it more complete.
Issie
Cort, You are a unique talent. So you think that the development of animal models is a stride forward?
thx
Here is a video put out by the DINET association of a few people with POTS and what POTS looks like. There are different types of POTS and not all of us faint. It affects both men and women – but more women than men. One of the persons interviewed on this video is a Doctor from Florida – Dr. Randy Thompson who himself has POTS and that’s what he treats (when he’s able to work). There is a lot of technical information here and it is explained by these doctors but anyone should be able to understand this. It makes you aware of what POTS is and how debilitating it is. It is suspected that more people have POTS but get DX’d with another illness when in fact this may be what they may have. We are trying to get awareness out there. We feel there are more people that need to know about POTS and when it is not considered a rare disease – then maybe we will have more research and answers.
http://www.youtube.com/watch?v=8UPMYNkm6Bc&feature=player_embedded
Issie
For purely monetary considerations, one discipline in medicine does not encroach on another. In other words, if one has a heart malfunction, ONLY a cardiologist gets to address that. If there is a gut problem, it’s strictly the territory of the endocrinologist! So what? IF like me, your heart malfunctions are due to dysbiosis in the gut because that’s where the autonomic nervous system resides, and has a profound effect on how the heart responds or functions, the Cardiologist isn’t permitted to go there!! And he does not!
The Endocrinologist doesn’t dare mention that your heart malfunction could be due to your gut issues and risk making your Cardiologist look incompetent. That is an unwritten rule that must never be broken. HOW DO I KNOW THAT? AS YOU MAY KNOW, I’VE BEEN THERE.
Remember, I was sent home to die in a few weeks with Afib and tachycardia. Fortunately, some supplements and certain food avoidance got it well under control about a decade ago.
If the different disciplines were permitted and ENCOURAGED to address a problem in conjunction, the outcomes would be much, much, better.
Makes the case for the Alternative practitioner. They don’t like that.
Cort -Some of the best posts yet. Cannot thank you enough for opening up more doors for us.It is exactly as
Rich Perillo said. Most of the Dr. will not cross that line. That to me is the most frustrating. Is that some unwritten code? Please put more on about how we see things in relationship to ourselves. That sounds simple -but very thought provoking. THEN WE HAVE THE CFIDS DR. THAT SAYS HE KNOW EVERYTHING-AND SOMETIMES DOES MORE HARM THAN GOOD.
I have definitely found the alternative doctors more open to listening to other opinions. I had the same experience
as Rich-only in a different dialogue- GO HOME AND DON’T DO ANYTHING. AVOID STRESS AT ALL COST.WAIT AROUND- AS YOU CAN’T DO ANYTHING ABOUT IT.
NOTHING WEARS ME OUT MORE THAN GOING TO A NEW DR. GETTING ALL MY PAPERS TOGETHER FROM CFIDS AND THEY WILL NOT EVEN LOOK AT THEM.
THANKS CORT – ANOTHER HIT OUT OF THE BALLPARK !!!!!
SAN DIEGO #1
It is so hard when we allow certain people into our “world” and they don’t realize how important they are to us. Doctors for example, we choose our doctor and open up our lives – trying to find answers from them. We invite them into “our world”. Most doctors are just completely overworked or so wrapped up in their own “worlds” that they don’t have time for us. One time after repeat visits to a doctor and each time him saying he would look up something that I’d asked him about and him never doing it. For the last time, he told me —-“I didn’t have time”. This doc had become a friend to me and he and I learned a lot by trying to figure out what was wrong with me. This time, after my having seen him three different times —he again had not looked up what I had asked him about. I told him —do you know what it means when someone says —“I haven’t had time?”. He looked at me and said —what? I explained —when a person says they haven’t had time –what that means is that person did not consider what you wanted them to do as important enough for you to spend your time on it. It’s not that the person hasn’t had time —it’s that they basically didn’t want to do whatever you have requested of them. More things were of more importance. Just be honest with me and say that you will probably not look it up or that you keep forgetting to look it up – just be honest with me. I’ve invited you into my world. It is important to me to have you in my world and it is important to me for me to have the answer to this question.
(Don’t forget, we’re friends and about the same age). He didn’t say a word for a good long time. And then he said —you are right. You are soooo right. If I would just be honest with myself and my patients, I’d feel better about myself. I don’t think he EVER told another patient he didn’t have time. That was a life lesson learned and he never made promises that he wouldn’t keep – at least not to me, again. 🙂
It is so hard when we are so complex and it requires more than a 15 minute conversation and a lab draw – to find our answers. This doctor became and is a very good doctor that looked at the whole body and tried to figure out what was going on. I have many times thought of him over the years and even though he didn’t find my answers for me —he tried. I have expressed my appreciation to him many times and because of him so many of the pieces got sorted for me, just putting it all together —has been the biggest problem.
Issie
Since this blog is about POTS and I’m trying to get as much information out as possible so that others will get more of an understanding of what we deal with. I had a friend read what is here, so far to help me to determine if there is something that either I or Cort hasn’t said or that the two videos didn’t cover.
There are two things that he felt needed to be commented about. One is the fact that many people have issues with their sleep and have apnea. I’ve talked about apnea on some other blogs – so won’t go into the technical reasons for why this is an issue. But, because in POTS the autonomic (automatic) nervous system is messed up – this affects every organ and every function in our bodies that is not under conscious control. That also includes our brains telling us to breathe. When we are trying to sleep – many people’s brains don’t send the signal to tell you to breathe. We may wake up gasping for breath or feeling like we never slept. This is usually also connected to severe drops in blood pressure, creating tachycardia trying to get the blood pressure up and blood flowing. Feeling more tired than when we went to bed. This problem could be Central Sleep Apnea and is controlled by the central nervous system. (There is also obstructive sleep apnea. And a person can have both kinds.) It’s important to know if this is a problem – because not only might a person not have enough oxygen at night – but, it interferes with sleep and therefore restorative healing that should be taking place during sleep.
The other thing that he felt important to bring out was about ankylosing spondylitis and some of the other autoimmune things that have been found amongst people with POTS. It seems that there are many of us that have issues with autoimmune connected problems. Some are finding antibodies to things connected to myasthenia gravis with acetylcholine receptor problems. Some are finding problems with mitochondrial issues. There are those that are finding real issues with neuropathy. There is also an inability to regulate temperature and some don’t sweat properly and therefore could over heat in warm places. Like some MS patients – many wear a cooling vest in the summer and/or just stay inside in an air conditioner. But, being too cold is not good either – as we don’t have the ability to warm ourselves up properly. Some have Raynaulds syndrome. Lot’s of autoimmune type problems.
There are many people that are wheelchair bound and many that are bed bound. For us that are more functional – standing in a line is not something we look forward to. We have to keep our legs tensed or squat down – as being upright brings on severe dizziness, nausea, headaches (many have migraines), brain fog etc. We tend to fidget a lot – that’s to try to keep our blood moving and prevent the above symptoms from happening. Not all of us are fainters —but more are than not. Along with tachycardia (extremely high heart rate) that occurs with standing comes what we refer to as surges. It’s a very uncomfortable feeling – sort of like anxiety. But, it’s our bodies release of NE trying to get the blood to our heart and heads. That brings on those type feelings. Many people get DX’d wrongly with anxiety disorders when in fact it is POTS causing these feelings. It’s not an emotional reason – but physical. I call it “having the heebie jeebies”. My husband knows when I’m having the “heebie jeebies” – as I also have tremors with mine. There are many that do have what is referred to as Orthostatic Tremors. But, the internal feelings that go along with it – is what is so uncomfortable. Some feel that the dizziness is their worst symptom. We must be some pretty strong people for this to happen to us daily, and we deal with it, try to have lives, and desperately continue to look for answers.
Thanks Cort, for helping me get more awareness out.
And I like talking philosophy too and enjoy exploring the meaning of “Life” and why people do what they do. It’s fun talking about those things. I’ve still got more that I’ll share later.
Issie
New video by Dr. Rowe, on CFS, EDS and POTS.
http://vimeo.com/71903707#at=0
Issie
Hi Cort,
Just re-read this post and wanted to add that people with pots have trouble with histamine and other amine reactions, from food, pollen, heat, stress etc. I’ve read that NET is also affected by amines – Reuptake of NE is competitive with a variety of naturally occurring amines and drugs. See http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1518795/ . I guess this is why antihistamines help some with POTS. So now how do we fix the NET?