Causes of POTS/Postural Orthostatic Tachycardia Syndrome

Part of the process of being diagnosed with POTS is wondering what caused it and if you did something to cause it and questioning in general.

The list of things that can go wrong in the body and cause POTS is quite extensive. In addition, there are disorders with symptoms like POTS. The secondary disorders are usually treatable and will in turn, treat your POTS symptoms. I would ideally like to make a separate post for each thing. But it will be more efficient to just make links to information within this post.

Adrenal disorders like Addison's disease is one of those conditions that has POTS-like symptoms, meaning that it mimics POTS. If you have an auto-immune disease, you can have an autoimmune type of Addison's disease. And to complicate that further, autoimmune thyroid disease can put you at risk for the autoimmune form of Addison's disease. Other things associated with it are hypoparathyroidism, hypopituitarism, pernicious anemia, testicular failure in men, diabetes type I, and vitiligo.

One of the problems with adrenal glands can be caused by a form of tumor called a Pheochromocytoma. This causes the adrenal glands to be overactive. This can lead to high blood pressure and cause symptoms such as

• Headaches
• Sweating
• Pounding of the heart
• Being shaky
• Being extremely pale

The hormones produced by the adrenal glands belong to a category called Catecholamines, which are released into the bloodstream in response to physical or emotional stress. The ones specific to the adrenal glands are epinephrine and norepinephrine, also called respectively adrenal and noradrenaline. The other catecholamine is dopamine. But it isn't produced by the adrenal glands. Dopamine is produced in the brain. It is a neurohormone that is released by the hypothalamus. Its action is as a hormone that is an inhibitor or prolactin release from the anterior lobe of the pituitary

Pheocychromatoma and paragangliomas cause an overproduction of these hormones. Blood and urine tests to measure the amounts can help detect a pheochromocytoma.

The urine test is a 24-hour urine collection. The blood test for catecholamines is sometimes done when a person has unexplained hypertension or sudden paroxysmal hypertension.

Anemia

People with Anemia can have symptoms like POTS and if they also have a folic acid deficiency, it will make their anemia and POTS symptoms worse.

Anemia patients sometimes exhibit the symptoms of POTS. Some patients may have a folic acid deficiency, which is contributing to their anemia and POTS symptoms.

Angiotensin II

Some people with POTS have an increased level of Angiotensin II. The renin-angiotensin-aldosterone system (RAAS) helps regulate blood volume by regulating sodium and water retention. Renin and aldosterone can be reduced in POTS patients. But this study found that Angiotensin II was increased. http://www.ncbi.nlm.nih.gov/pubmed/16262605. Angiotensin II is a hormone and it causes blood vessels to constrict.

There may be a gene called the angiotensin II type one receptor gene involved in POTS.

Autoimmune Diseases

Besides anemia and Addison's disease and thyroid disorders, there are several other autoimmune diseases that can cause POTS. See: Lupus, Sjogren's, Guillain-Barre. Sarcoidosis, Crohn's Disease

Pain and autonomic dysfunction in patients with sarcoidosis and small fibre neuropathy

Association of small fiber neuropathy with cardiac sympathetic dysfunction in sarcoidosis.

http://ihpotblogspot.blogspot.com/2016/09/slesystemic-lupus-erythematosis.html

http://ihpotblogspot.blogspot.com/2016/09/another-crossover-illness-with-pots.html

There is an antibody to neuronal nicotinic acetylcholine receptors of autonomic ganglia that has been discovered. Some POTS patients have higher levels of this antibody. Some patients that also had anhidrosis, constipation, urinary dysfunction, sicca syndrome and pupillary dysfunction had even higher levels. And those that had the highest levels of the antibody, had more severe autonomic dysfunction. And levels of the antibody lower when patients symptoms get better. This indicates cause and effect. Meaning that the antibody can cause POTS and POTS can cause an increase in the level of the antibodies. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2671239/

Cardiac Problems

Usually, doctors try to rule out cardiac disease before any diagnosis of POTS.

Problems with the electrical conduction of the heart such as atrioventricular conduction and ventricular repolarization can cause POTS in some patients. Sinus node abnormalities and abnormal P-waves can also cause it. Some patients undergo a procedure called ablation to treat these type of problems. But studies show that the long-term benefits were not good. And it really isn't recommended as a treatment.

In addition, if a patient has been misdiagnosed with sinus tachycardia, it will make their POTS worse to go through ablation. Heart rate-dependent electrocardiogram abnormalities in patients with postural tachycardia syndrome.

Spinal Problems

Cervical stenosis is when there is an area of the spinal canal that is too narrow, and it compresses the spinal cord and nerve roots. Some patients have had craniovertebral decompression which resulted in a decrease or cessation of their POTS symptoms. But other patients did not benefit from it.

Chiari malformation is when the cerebellar tonsils protrude down into the spinal cord. And it can cause the flow of cerebral spinal fluid to be restricted. Some patients have a procedure to correct the Chiari malformation. But not all of them get better afterward. Some doctors think that Chiari malformation causes all POTS, and some do not. Doctors from the NIH and The Chiari Institue say there is a connection between as well as a connection to EDS/Ehlers-Danlos syndrome. There are lots of links here on Chiari malformation and POTS: http://www.dinet.org/index.php/information-resources/pots-place/pots-useful-links

Syringomyelia is a medical condition caused by a cyst growing in the spinal cord. This sometimes causes POTS. Some people also have Chiari malformation. Many POTS patients also report a worsening of symptoms upon straining. One possible explanation of POTS in syringomyelia patients is partial sympathetic denervation of the legs.

Chemicals

Exposure to some chemicals might cause POTS in some patients. Here is a table of some of the possible chemicals: Chemicals and POTS

Alcohol-related peripheral neuropathy: nutritional, toxic, or both?

Associations between autonomic dysfunction and pain in chemotherapy-induced polyneuropathy.

Ehlers-Danlos Syndrome (EDS), a connective tissue disorder,is found in some POTS patients. Physicians propose that these syndromes occur together due to abnormal connective tissue in dependent blood vessels in those with EDS, which permits veins to distend excessively in response to ordinary hydrostatic pressures (Rowe, Barron, Calkins, Maumenee, Tong & Geraghty, 1999). Simply put, this connective tissue abnormality allows excessive amounts of blood to pool in these patients' lower limbs when they stand up.

There are a variety of types of Ehlers-Danlos syndrome. Classical and type III EDS were originally reported in orthostatic intolerance patients (Rowe et al., 1999). Many POTS patients with EDS have type III (Grubb, 2002).

There can be many symptoms and problems that are associated with the classical and hypermobile types of EDS. Mitral valve prolapse, gastric emptying or motility issues, dilation or rupture of the aorta, hiatal hernia, premature rupture of the membranes during pregnancy, poor wound healing, bruising, joint dislocation, etc.http://ihpotblogspot.blogspot.com/2016/09/joint-hypermobility-syndrome-and-eds.html

Joint Hypermobility Syndrome is a similar disorder. You can read more on them here:

Electrical injury

Electrical injury and being struck by lightning has reportedly occurred prior to the development of POTS in some cases. Lightning strike and autonomic failure -coincidence or causally related?

Liver Disease

A type of liver disease called compensated cirrhosis is when the liver is damaged but is able to compensate for it. This condition causes hypovolemia and vasodilation, POTS and pooling of blood in the lower extremities. Autonomic dysfunction in chronic liver disease

Mast-cell activation disorders

Some people with POTS or other orthostatic intolerance have flushing, palpitations, shortness of breath, chest pain, headache, lightheadedness, hypotension, or hypertension, and syncope

may play a role in the development of POTS in some individuals. Some patients with orthostatic intolerance suffer from episodes of flushing, palpitations, shortness of breath, chest discomfort, headache, lightheadedness, hypotension or hypertension and occasionally syncope, and it is sometimes brought on by an increase in activity. They may also have fatigue, sleepiness, increased urination, and sometimes diarrhea after they have an attack. There are tests for an increase in urinary methylhistamine, which is a marker of mast cell activation, that can be done to find MCAS.

You can read more about MCAS here: A Tale of Two Syndromes – POTS and MCAS

Neuropathy

Some people with neuropathy have POTS. It may be caused by autonomic neuropathy in the cardiovascular system. There may also be sympathetic denervation in the legs. The Neuropathic Postural Tachycardia Syndrome

Nitric Oxide deficit

Nitric Oxide (NO) controls blood vessel size with through changes in blood flow and blood vessels during inflammation and blood vessel leakiness. If you have a deficit of nitric oxide, you may develop POTS. Nitric oxide and regulation of heart rate in patients with postural tachycardia syndrome and healthy subjects

Researchers have found that NO levels can be increased by blocking the most important receptor for angiotensin-II. This may lead to treatments in the future in select groups of POTS patients.

Norepinephrine transporter deficiency

Norepinephrine transporter deficiency causes POTS is some people. These patients have an irregularity in how norepinephrine is used in the body. Under normal conditions, the body recycles norepinephrine. For some people, the protein that causes norepinephrine to be recycled doesn't work properly. And excess norepinephrine is spilled over. They then have depleted levels of norepinephrine if their neurons continue to be stimulated. They go from having excessive amounts of norepinephrine to having no norepinephrine, at which point they crash.Orthostatic Intolerance and Tachycardia Associated with Norepinephrine-Transporter Deficiency

Some patients have hypermethylation of the norepinephrine transporter (NET) gene promoter. When this happens, the gene for the protein that transports norepinephrine (NET) is turned off because its promoter is turned off. 

Nutcracker Phenomenon

This is a condition is which the left renal vein is congested because it is being compressed by the aorta and the superior mesenteric artery. It may cause a disruption in the renin-angiotensin system. And it also may disrupt the sympathetic adrenal system and overproduction of catecholamines.

Nutcracker phenomenon or nutcracker syndrome?

Thyroid disease

Thyroid disease can sometimes cause symptoms that are similar to those of POTS.

Tumors

When the body tries to get rid of a tumor by producing antibodies to attack it, sometimes they also attack part of the nervous system. This is called Paraneoplastic Syndrome. This is a rare condition. If the autonomic nervous system is attacked, then the result can be POTS or dysautonomia. Some people get better after the tumor is removed. Some people have to have intravenous immunoglobulin or other immune modulating treatments to try and reduce the harmful antibody levels.

Medscape: Paraneoplastic Autonomic Neuropathy

Screening for tumours in paraneoplastic syndromes: report of an EFNS Task Force

Physical Trauma, Surgery, and Pregnancy

Trauma such as surgery, pregnancy, bariatric surgery, and Traumatic Brain Injury, car accidents, etc. have been shown to precipitate POTS

Autonomic dysfunction presenting as postural tachycardia syndrome following traumatic brain injury.

Postural tachycardia syndrome - current experience and concepts

The Neurological Complications of Nutritional Deficiency following Bariatric Surgery

Viruses

It is estimated that 50% of patients with POTS have a recent history of some sort of virus when they become ill. It has been associated with Epstein-Barr virus. It is believed that viruses may affect the autonomic nervous system directly or that they may cause an autoimmune response that results in POTS.Postural Orthostatic Tachycardia Syndrome (POTS): A Diagnostic Dilemma

Vitamin Deficiencies

People with digestive problems, that are common in people with dysautonomia, frequently have B12 deficiency.

University of Chicago Peripheral Neuropathy Center - Vitamin B12 Deficiency

Don't forget to check out the videos at the bottom of the blog. You have to scroll down to the bottom. There is a good one on norepinephrine transporters and one on the sympathetic nervous system. 

Catecholamines

                                                                                         

Right now the thing on my mind is catecholamines. I just did a 24-hour urine study to check my catecholamine levels. So, I've been trying to understand them.

As part of our ability to survive as a species, the human body needs to be able to change internal things from one minute to the next, rather quickly and without our involvement, and regardless of what is happening in the environment outside the body, but also in response to it.

Changes in temperature, the humidity, and barometer or any danger we may find ourselves in, require the body to react quickly in order to maintain homeostasis (the body being in a stable state, normal operation). The hypothalamus does this through the Autonomic Nervous System and the endocrine glands.

The Autonomic Nervous System or ANS is one of the systems in our body that responds to changes in position. Around 25% to 30% of our blood volume is in the upper chest when we are laying down. But when we stand up between 300 and 800 mL of the blood moves to the lower body and extremities, helped along by gravity. This is a 25% to 30% drop in volume. Half of this happens during the first few minutes after we stand up.This causes a drop in the blood flow going back to the heart. That in turn, cause a drop in arterial pressure.

In order for you to remain standing and maintain adequate blood flow to the brain, several systems in your body have to be regulated.One of which is your blood pressure. Your blood pressure as to stabilize within about a minute after you stand up.

In Hyperadrenergic POTS, there is an abnormally large increase in plasma norepinephrine and a RISE of blood pressure instead of a drop when you stand up. The criteria for Hyperadrenergic POTS is an increase in systolic blood pressure >10 mmHg during 10 minutes of head-up tilt(HUT), as well as an increase of plasma norepinephrine, >600 pg/mL.

Patients usually have a rise in heart rate like other POTS patients, but also have symptoms like palpitations,anxiety, tachycardia and tremulousness. When a ganglionic blockade called trimethaphan is administered, they have a larger drop in BP than other patients, and their upright plasma norepinephrine levels are higher than non-hyperadrenergic POTS patients. When upright, individuals may experience a sense of anxiety, tremor, and cold sweaty hands and feet. Also, in a good portion of individuals, there is a significant urge to pass urine after even a short period of time upright (I wonder if this is why I have to run to the bathroom as soon as I stand up?). True migraine headaches are also common.

NMH or Orthostatic Tachycardia  is most likely to occur if you have a decrease in norepinephrine and an increase in epinephrine. POTS is the opposite, it is most likely to result from an increase in norepinephrine and a decrease in epinephrine.


An interesting article I read on Medscape.com said that people with Hyperadrenergic POTS have exaggerated pressor and sometimes tachycardia response to both orthostatic and other types of stress. It said it's important for them to minimize the reduction of blood flow back to the heart and pulse pressure. This can be helped by volume expansion, i.e. staying hydrated, and wearing an abdominal binder, which reduces vein capacity. Physical counter-maneuvers help too. Counter maneuvers are when you contract certain muscles in order to help blood flow back to the heart.

One really interesting thing the article said was that Inderal(propranolol0, which is a non-β-selective lipophilic agent, at about 10mg a day may work better than atenolol, which is a β-selective lipophilic agent. I happen to be on atenolol right now. Some people have such high BP jumps when they stand, (as much as 250/150 mmHg), that they have to be given phenobarbital. Sometimes they are helped
by clonidine or drugs in the same class.

I found the following on a Vanderbilt University website: "Some studies have labeled patients with “Hyperadrenergic POTS” if the patient’s upright plasma norepinephrine level is >600 pg/ml.  Other studies label patients with “Neuropathic POTS”if the QSART sweat test is abnormal.  Someone in the first study might say “I have hyperadrenergic POTS”, while the person in the second study might say “I have neuropathic POTS”.  The truth is that at least some (if not many) of those patients will have both abnormalities.  Often, these terms are not used to describe mutually exclusive subtypes, but to describe specific findings."

One related condition is pheochromocytoma (a norepinephrine producing tumor) and tests may be needed to differentiate between pheochromocytoma and hyperadrenergic POTS.

Another condition that is similar to Hyperadrenergic POTS is Norepinephrine Transporter (NET) Deficiency. It is thought to be an abnormality in a gene that leads to too much norepinephrine circulating in the body. It can be treated with a class of antidepressants called SNRIs, which will block these transporters. However, some people experience an increase in HR and can't take them.

Inappropriate sinus tachycardia or IST has similar symptoms to Hyperadrenergic POTS. IST patients have a high HR when they are laying down (around 90-100bpm), and slight exertion or emotional stress will cause rapid acceleration. Both conditions can overlap and may have the same underlying causes. Treatment options are similar.

I found an excellent explanation of what adrenergic receptors are at Dysautonomia International. "Think of adrenergic receptors like a TV antenna (if you are old enough to remember when TVs had antennas!). If the TV antenna picks up a signal, it transmits a message across the screen. In adrenergic receptors, the “signals” are chemicals present in the body called catecholamines (primarily epinephrine and norepinephrine). The “message” is what the catecholamine tells the receptor to do. For example, constrict a blood vessel or make the heart beat faster."

Some people have been found to have auto-antibodies called adrenergic receptor auto=antibodies. So instead of only fighting off a virus or something, their bodies have made auto-antibodies that have  attacked and damaged important sites on certain cell membrane proteins and altered their normal cell function. There are two kinds of adrenergic receptor auto-antibodies. One affects the blood pressure and causes it to drop and the other effects the HR and causes it to raise.

Orthostatic HYPERtension: What Is That?

I recently had a short stay in the hospital for low blood pressure and a slow heart rate(also called Bradycardia). I had a few EKG's, an Echocardiogram, and a Stress Test. The doctors took me off of my beta blocker that I have been on for years. When my blood pressure leveled out, they sent me home.

My doctor was out of town at the time and not expected to be back for a few weeks. A few days after I got home, I started having dizzy spells (Syncope). So, I started checking my blood pressure and it was high. I decided I didn't want to go back to the hospital and would wait it out and see what my doctor said when she got back. Since I had gone from really low BP and heart rate to having high BP and HR, I decided to look up how to do a "Poor Man's Tilt Table Test". You can read more on how to do this here. And there is a link to the right on what a tilt table test is.

I had some help doing it, but we did three of them. All three of them caused my BP and HR to raise over the requisite 30 beats above the resting BP and HR.

I knew what Orthostatic Hypotension was. It is sometimes also called Neurally Mediated Hypotension.But with it, your blood pressure drops 25 mmHg, without the increase in HR that I was having. When my husband was diagnosed, they didn't separate out Orthostatic Hypotension from POTS. And depending on who was talking to us, they were using the two terms interchangeably. Now they are two distinct diagnoses, although you can have both.

 I was pretty concerned because I had never heard of BP going up to the degree mine was when I stood up.  So, I did a google search.

I found out that there is a subclass of orthostatic intolerance that causes this called ORTHOSTATIC HYPERTENSION. This is what I could find out about it. There wasn't much information available.

In general, it is simply when your BP rises upon standing. Orthostatic hypertension was defined as either an increase in DBP (diastolic)  from <90 mmHg to ≥90 mmHg or an increase in SBP(systolic) from <140 mmHg to ≥140 mmHg.

Studies have shown that people who have Mast Cell Activation Syndrome and POTS sometimes have Orthostatic Hypertension. People with baroreflex failure also have bouts of it. Another rare condition  called norepinephrine transporter deficiency can also cause this increase in blood pressure on standing. And pheochromocytoma can also cause it. And finally, diabetes can cause it. Diabetics are prone to having neuropathy (nerve damage), and it is likely that neuropathy has some connection to Orthostatic Hypertension.

Patients usually have venous pooling in the lower legs. This means that a large amount of blood collects in your lower legs when you stand up. This causes a decrease in the cardiac output of your heart. That in turn, causes your sympathetic nervous system to become activated. And then your arteries become severely constricted. This is similar to the POTS occurs. POTS happens because of dysautonomia in the lower legs which results in venous pooling. But the difference is that POTS patients don't always have symptoms of Orthostatic Hypertension.

Different studies have used different criteria for diagnosing Orthostatic Hypertension.
One study used the following:  ≥20 mmHg increase in SBP upon assuming an upright posture ( head-up tilting to 70 degrees) from the supine position.

Generally, this result needs to be reproducible because people with conditions like essential hypertension (regular high blood pressure) or diabetes have more variation in blood pressure readings than otherwise healthy people.

Aside from the rise in BP when you stand there are other tests that need to be run in order to diagnose underlying causes. Your doctors need to know if there is something that needs to be corrected with surgery, or if you have baroflex failure.

To treat it, the most obvious line of treatment is to treat your high blood pressure, if you have it. Activation of the sympathetic nervous system should be controlled with things like alpha-1 adrenergic receptor antagonists such as prazosin, or central alpha-2 adrenergic receptor agonists such as clonidine.

More on this subject can be found here: Orthostatic Hypertension: When Pressor Reflexes Overcompensate