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ramakentesh

Very Good Pots Article By Dr.j.stewart

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I just found this article on POTS that I find fascinating - infact I find all of Dr.J Stewarts recent work on POTS (low flow, etc) and the role of nitrous oxide and Angiotenson II to be very interesting.

http://emedicine.medscape.com/article/902155-overview

He breaks up POTS into five apparent catagories - auto immune, Mast Cell mediated, muscle pump defects, hyperadrenergic and NET protein deficient:

Muscle pump defects

Physical forces comprise a primary defense against the pooling of blood in the dependent lower extremities in human beings. This occurs through the activity of the skeletal muscle pump, in which contractions of leg and gluteal muscles increase interstitial pressure and propel sequestered venous blood back to the heart. The efficacy of this pumping is augmented by the presence of one-way venous valves. Patients with incompetent venous valves or those in whom venous valves are congenitally absent suffer from severe orthostatic intolerance. Skeletal muscle may also be involved in neurogenic compensation through chemoreceptors and through local control mechanisms.

Data indicate that although the muscle pump is normal in most patients with POTS, the muscle pump is defective in patients with low-flow POTS who also have decreased resting peripheral blood flow unrelated to exercise capability but exacerbated by bed rest. Therefore, ambulation is essential for the reduction of POTS symptoms. Lower body exercise may be very helpful, but its use has not yet been examined in a systematic way.

Autonomic autoimmune neuropathy

The largest proportion of patients with POTS are said to have a mild form of peripheral autonomic autoimmune neuropathy manifested by a dysfunctional peripheral vasculature. They demonstrate increased adrenergic tone at rest and enhanced postganglionic sympathetic response to upright posture. However, serum catecholamine levels are normal or only slightly elevated when upright. This is currently attributed to an immune-mediated process because autoantibodies to the peripheral nervous system have been identified. The theory that this mechanism is the cause of POTS is further supported by the frequent reports of antecedent illnesses preceding the onset of symptoms.

Histamine-related postural tachycardia syndrome

Other patients with POTS have episodic flushing and increased urinary levels of methylhistamine, a primary urinary metabolite of histamine. These patients are thought to have a coexisting mast cell activation disorder that is associated with shortness of breath, headache, lightheadedness, diarrhea, nausea, and vomiting. Patients can have a hyperadrenergic response that results in orthostatic tachycardia and hypertension. Whether mast cell activation?associated release of vasoactive mediators is the primary event or if sympathetic activation results in mast cell activation is unclear. In these patients, although beta-adrenergic antagonists may exacerbate symptoms, treatment with antihistamines (H1 and H2 antagonists) in combination with nonsteroidal anti-inflammatory drugs may be beneficial.

Hyperadrenergic neuropathy

Measurements of plasma norepinephrine in patients with POTS show that supine levels are often ?high-normal,? whereas values obtained when patients with POTS are upright can be elevated above 600 ng/mL. Accordingly, they show intact or exaggerated autonomic reflex responses. This is manifested in vigorous pressor response to the Valsalva maneuver with preservation of vagal function. These patients often complain about extreme anxiety when upright and having cold, sweaty extremities. Most patients also have true migraine headaches that include prodromes of photophobia and nausea.

Several reports have detailed patients with POTS who have a form of partial autonomic neuropathy with regional denervation of sympathetic nerves that may be autonomic autoimmune neuropathy. This appears to be somewhat paradoxical in lieu of the description of patients with POTS who had elevated plasma norepinephrine levels. Jacob et al reported patients with neuropathic POTS with normal sympathetic neuronal norepinephrine release in their arms but impaired release in their lower body.2

Norepinephrine transporter protein deficiency

Another recent autonomic condition producing a complex form of POTS is norepinephrine transporter (NET) protein deficiency. This has been reported in only a single family.17 Investigators have identified a single point mutation in the NET protein with both central and peripheral effects on vascular regulation. Despite its rarity, the illness has furnished an ideal monogenetic model for autonomic illness, and appropriate animal knock-out models have been constructed and investigated. An NET-deficient mouse was recently shown to have near-normal resting arterial pressure and heart rate, likely due to increased sympathoinhibition.18 However, when engaged in awake activities, these mice exhibited excessive tachycardia and elevated blood pressure.

The importance of active venoconstriction to the orthostatic response is uncertain. Venous capacitance properties in POTS could be abnormal because of altered vascular structure, altered muscle tone, or both. An example may occur in the Ehlers-Danlos syndrome (EDS). Perhaps paradoxically, excess lower extremity pooling seems uncommon in common variants of EDS (eg, type 3). Preliminary data also indicate no change or even a decrease in venous distensibility compared with reference ranges.

The chronic elaboration of cytokines with potent vasoactive consequences, such as interleukin (IL)-1, IL-6, and tumor necrosis factor alpha (TNF-alpha), is a potential link between altered vasoreactivity and antecedent inflammatory disease. Such a link seems established in the type of CFS in which POTS and orthostatic intolerance frequently occur.

And here his honesty impresses me with the last line:

Treatment

Medical and nonmedical treatments for POTS are available, but they are rarely curative and are often incompletely palliative. Agents that expand blood volume, such as fludrocortisone and erythropoietin, sometimes are useful by reducing the degree of thoracic hypovolemia. Vasoconstrictive agents, such as midodrine or phenylpropanolamine (recalled from US market), are sometimes useful.

Selective serotonin reuptake inhibitors have met with some success in treating CFS and orthostatic intolerance. Rapid ingestion of water has been advocated as a benign and temporarily effective means to raise BP. Support hose and physical maneuvers can reduce pooling. Exercises to add bulk to the leg muscles have a similar effect. Raising the foot of the bed at night can increase blood volume. Treatment success is sporadic because these treatments do not directly address the pathophysiology. As always, further research is needed to clarify these issues.

Summary

Orthostatic intolerance is common but often misunderstood. Investigation of the condition is an evolving field of integrative physiologic study. Acute orthostatic intolerance is characterized by simple faint. Despite its ubiquity, scientists do not yet understand why particular people faint. Chronic orthostatic intolerance, characterized by postural tachycardia syndrome (POTS), has been demonstrated in adolescents. POTS, however, remains a heterogeneous entity, likely of varied etiologies. Until better understanding is achieved, treatment remains more guesswork than science.

From my understanding where nitrous oxide is implicated in low flow pots, there could be a possible treatment protocol already in existence that could help this situation.

For me the other very interesting point was in relation to the TNF Necrosis factor mentioned under the NET deficiency section. I have deficient levels of NET although my gene itself was normally functioning. I also have Ankylosing Spondalitis (a very mild form thank god) which always acts up when my POTS goes into remission and vice versa. The TNF necrosis factor is implicated in AS!! so I wonder if there is a common cause for both??

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here is a summary of the three forms of 'FLOW' POTS as catagorised by Dr.J.Stewart which are currently under investigation:

The author's laboratory has described 3 groups of patients with POTS distinguished by differences in peripheral blood flow and peripheral arterial resistance. These groups are as follows:

A low blood flow, high-arterial resistance, high-Pv group, which is denoted as ?low-flow? POTS and is characterized by pallor and generally decreased blood flow, most notably in the dependent parts of the body. This low-flow condition is related to defects in local blood flow regulation and mild absolute hypovolemia. The authors have recently shown that this defect in local blood flow regulation is due to a reduction in neuronal nitric oxide (nNOS).13

A normal blood flow, normal arterial resistance group with normal Pv, which is denoted as ?normal flow? POTS and is characterized by a normal supine phenotype, with normal peripheral resistance when supine but enhanced peripheral resistance when upright. Specific venous pooling within the splanchnic vascular bed is observed, making this a redistributive form of hypovolemia.

A high blood flow, low arterial resistance group with normal-to-decreased Pv, which is denoted as ?high-flow? POTS. It is related to a long tract neuropathy and is characterized by high cardiac output caused by inadequate peripheral vasoconstriction when supine and upright. Patients are typically acyanotic and warm to the touch with extensive filtration, resulting in dependent edema.

The changes in regional blood flow with upright tilt, comparing control subjects with those with low, normal, and high-flow POTS are shown in Media file 3. This illustrates the differences in regional blood flow exhibited by each of these subgroups of POTS and, in aggregate, may explain the wide variation of symptoms exhibited by these patients.

This 3 group classification scheme incorporates various physiological parameters, such as blood flow, blood distribution, and venous compliance, to construct a dynamic model of human vascular dysfunction in POTS. It provides a framework to test hypotheses used to explain the findings of POTS and will likely evolve as more information is accumulated. Although this physiologic classification scheme has the potential to refine treatment approaches, this classification is not easily made in most clinical laboratories. Therefore, further research is needed to translate these research findings into clinical practice.

In the case of POTS depicted in Media file 2, the patient immediately became symptomatic following initiation of HUT, necessitating cessation of the test within a few minutes. Although the patient was not hypotensive, hypotension may follow or occur with tachycardia if protracted. If hypotension does occur, it is often delayed until after the onset of the symptoms and the tachycardia, manifesting only during the artificially sustained orthostasis enforced during HUT.

The form of hypotension may be vasovagal fainting; however, in the author's experience, fainting has mainly been confined to the contrived circumstances of tilt testing. Media file 2 shows how symptoms during testing temporally relate to a decrease in cerebral blood flow, an increase in cerebrovascular resistance, and an as-yet-unexplained hyperventilation with attendant hypocapnia, which may partly account for cerebral vasoconstriction. Cerebral malperfusion correlates well with neurocognitive defects in POTS.

Although onset of POTS symptoms often follows an infectious disease and may relate to inflammatory mediators, genetic and molecular causes have been found in rare instances, suggesting that long-standing deficits may be congenital. A defect in nitric oxide bioavailability is currently suspected

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I want to get tested for "Other patients with POTS have episodic flushing and increased urinary levels of methylhistamine, a primary urinary metabolite of histamine. These patients are thought to have a coexisting mast cell activation disorder that is associated with shortness of breath, headache, lightheadedness, diarrhea, nausea, and vomiting." before I go on a Beta Blocker, just i case...

But it seems so hard to tell what one you have! I was sure I was post-viral, but now my younger brother and sister are having symptoms. Yet the study said they've only seen the NET-gene situation in one family...but other POTS/Dysautonomia run in families, right?

Also, how do you get tested for: norepinephrine

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Yeah its a really interesting read.

I dont know any POTS people who have been tested for MAST cell disorders.

Despite the fact that only one kindred have been found with a polymorhpism of the actual NET gene, In another test done by my local specialist, I was one of a few POTS patients that was tested and found to have low NET gene expression inb my arm biospy.

Whether the low NET is the cause or consequence of POTS remains to be demonstrated. It was implied that my low expression was the result of a hypermethylated gene promoter - where the gene looks fine but has been turned up by an epigenetic mechanism like in some cancers.

You can get your NET function tested by getting an MIBG scan of your heart that measures NE reuptake.

My POTS seems pretty run of the mill in terms of symptoms - im also easily over stimulated, can get jittery on standing and get anxiety as an occasional symptom. I feel better in hot weather than cold which i think is a little unusual.

As for J.Stewarts three catagories I dont have venous pooling or edema in my legs. So i guess id be in the low or normal flow groups??

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very ineresting ramakentesh, thanks for sharing!

considering what he wrote about treatment, i like this doctor a lot!

corina :(

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Thank you so much for posting these! I have an appointment with my Doctor tomorrow morning and was looking for a good summary of the current state of research/theories for POTS and this fits the bill to a T!

I want to get tested for "Other patients with POTS have episodic flushing and increased urinary levels of methylhistamine, a primary urinary metabolite of histamine. These patients are thought to have a coexisting mast cell activation disorder that is associated with shortness of breath, headache, lightheadedness, diarrhea, nausea, and vomiting." before I go on a Beta Blocker, just i case...

.....

I asked an expert in the field this same question so that I could discuss the test with my Doctor tomorrow to see if thinks it is a good idea to rule this out in my case as well. The researcher said " [the test] is called a urinary methyl histamine level. We usually ask subjects to wait until a bad flushing episode. At the onset of the episode, the patient is instructed to void and discard. The patients should then collect a 4 hour urine sample and send this to the laboratory. The rationale is to collect an ?enriched? urine sample. This is more often negative than not, but this method is designed to optimize the yield."

Of course the last section "This is more often negative than not," concerns me ... but it's worth a try. And I'd much rather get some kind of empirical data because I'm not likely to try anti-histimines without any indication that it could help.

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I am going to talk to my doctor about this too - sounds like a simple enough test, I guess...! And I really, really need to take a Beta Blocker because I've been SOO tachy lately. But want to be safe about it.

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.....

I asked an expert in the field this same question so that I could discuss the test with my Doctor tomorrow to see if thinks it is a good idea to rule this out in my case as well. The researcher said " [the test] is called a urinary methyl histamine level. We usually ask subjects to wait until a bad flushing episode. At the onset of the episode, the patient is instructed to void and discard. The patients should then collect a 4 hour urine sample and send this to the laboratory. The rationale is to collect an ?enriched? urine sample. This is more often negative than not, but this method is designed to optimize the yield."

Of course the last section "This is more often negative than not," concerns me ... but it's worth a try. And I'd much rather get some kind of empirical data because I'm not likely to try anti-histimines without any indication that it could help.

Great article! EM, it is very difficult to "catch" high methylhistamine after an episode. Masto specialists often base a DX, in part, by how you respond to H-1 and H-2 Blockers and, more importantly, how you react without them. MCAD is controversial in the allergy/immunology world. The criteria for a DX is emerging. There are currently no definitive laboratory markrs for even proving anaphylaxsis. Serum tryptase sometimes raises, but not always. A DX is often based on detailed history and clinical evidence. My gut tells me that if you aren't using antihistamines now, you're pretty unlikely to have MCAD. Most folks are pretty dependent on them years prior to a DX. Try an OTC zyrtec and zantac one morning to see how you feel. If you do notice a marked improvement......you might be on to something.

All the best-

Julie

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"Norepinephrine transporter protein deficiency

Another recent autonomic condition producing a complex form of POTS is norepinephrine transporter (NET) protein deficiency. This has been reported in only a single family.17 Investigators have identified a single point mutation in the NET protein with both central and peripheral effects on vascular regulation. Despite its rarity, the illness has furnished an ideal monogenetic model for autonomic illness, and appropriate animal knock-out models have been constructed and investigated. An NET-deficient mouse was recently shown to have near-normal resting arterial pressure and heart rate, likely due to increased sympathoinhibition.18 However, when engaged in awake activities, these mice exhibited excessive tachycardia and elevated blood pressure."

Ernie- is that your family???

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