The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 32

39. How are mast cell disease, Ehlers Danlos Syndrome and POTS connected? (Continued)

I’m answering this question in two parts because there is a lot of information to relay and it’s important that it is done clearly. This is the second part.

Mast cells are found throughout the body. There is no record of a person living without mast cells. They perform many essential functions. This is the reason why killing off all of a person’s mast cells is not a viable treatment for mast cell disease. While mast cells cause so many symptoms and problems for patients with mast cell disease, life is unsustainable without mast cells.

Let’s specifically consider just a few of the mast cell’s essential functions here and how they relate to POTS and EDS.

Mast cells help the body to regulate blood pressure and heart rate. Many of the mast cell’s chemicals do this so it happens in many different ways all stemming from mast cells. This means that when mast cells are not behaving appropriately, there are many ways in which this dysfunction can lead to not regulating blood pressure and heart rate correctly.

  • Histamine can affect blood pressure and heart rate differently depending upon how it acts on the body. If it uses the H1 receptors, it can cause low blood pressure. If it uses the H2 receptors, it elevates blood pressure. If it uses the H3 receptor, it can cause low blood pressure. When it does this at the H3 receptor, it’s because it tells the body not to release norepinephrine. Not releasing as much norepinephrine lowers heart rate and making the heart beat more weakly.
  • Prostaglandin D2 lowers blood pressure and causes fast heart beat. However, the molecule made by breaking down PGD2, called 9a,11b-PGF2 increases blood pressure.
  • Vasoactive intestinal peptide lowers blood pressure.
  • Heparin, chymase and tryptase can decrease blood pressure. They do this by helping to make a molecule called bradykinin. When this happens, a lot of fluid falls out of the blood stream and gets stuck in the tissues, causing swelling.
  • Thromboxane A2 increases blood pressure.
  • Many mast cell molecules affect the amount of angiotensin II. This molecule strongly drives the body toward high blood pressure. Some mast cell molecules that affect blood pressure this way include chymase and renin.

Another very essential function of mast cells is to make connective tissue. Mast cells help the body to shape itself correctly and to make tissue to heal wounds. When mast cells are not behaving appropriately, their dysfunction can interfere with making connective tissue and wound healing. It can cause wounds to heal very slowly or for there to be too much scar tissue. It can also cause the connective tissue to be too weak or too strong.

The interaction between POTS and mast cell disease

In POTS, the body is already predisposed toward not regulating blood pressure and heart rate correctly. When a person with POTS stands up, their body quickly causes the heart to beat very fast. When your body does this, it takes steps that cause mast cells to become activated. In turn, the mast cells release chemicals to try and regulate the heart rate. However, if you have mast cell disease, the mast cell may release the wrong chemicals, or too many chemicals, failing to regulate the heart rate. This in turn results in a situation where the body becomes very stressed. Stress activates mast cells, which results in more release of chemicals. Patients can very easily become trapped in a cycle where POTS and mast cell disease irritate each other.

POTS can be exacerbated by the use of medications that affect blood vessels. Medications that are vasodilators (that make the blood vessels bigger) are taken by many people, including mast cell patients. In some people, using medications that blocks the action of histamine or prostaglandins can help to improve symptoms of both POTS and mast cell disease. Conversely, some of the medications used to manage POTS, like beta blockers, can trigger mast cell reactions and raise the risk of anaphylaxis. However, some POTS treatments can also help alleviate mast cell symptoms, specifically the use of IV fluids.

A paper published in 2005 found that hyperadrenergic POTS was sometimes found in patients with mast cell activation disorders.

The interaction between EDS and POTS

POTS is a form of dysautonomia. Dysautonomia means dysfunction of the autonomic nervous system. This is the part of your nervous system that helps to control automatic functions like heart rate, blood pressure and digestion.

In EDS patients, the body does not make collagen correctly. Collagen is the most common connective tissue protein in the body. This can cause vascular laxity. Blood vessels change size depending upon how much blood they need to move through them. If they get larger, it is called vasodilation. When they get smaller, it is called vasoconstriction. When a person has vascular laxity, their vessels can get larger than they should and they can stay that way longer.

POTS is the most common form of orthostatic intolerance in HEDS. Orthostatic intolerance is when a patient has symptoms specifically as the result of standing up. All EDS patients have more autonomic symptoms than healthy people. Among patients with EDS, autonomic symptoms are more common and more severe in HEDS. 94% of HEDS patients have orthostatic symptoms, including lightheadedness, dizziness, palpitations, nausea, blurred vision, and anxiety. Dysautonomia is much worse in HEDS compared to CEDS and VEDS patients.

Patients with HEDS were found overall to have overactive sympathetic nervous systems. However, when their body needed to activate in response to regulate heart rate and blood pressure in response to changing position, their responses were not strong enough.

In EDS patients, the connective tissue does not support blood vessels enough. This makes the harder for the blood vessels to get the blood back to the right places when you stand up, exacerbating POTS.

The interaction between EDS and mast cell disease

Mast cells are involved in making and repairing connective tissue, which involves collagen. For this reason, there are many mast cells living in connective tissues. Mast cells are stimulated when the body is making or trying to make collagen. Because EDS causes the body to make collagen incorrectly, mast cells can become activated to try and make collagen and other connective tissue correctly. When mast cells in one place are activated a lot over a long time, they can activate other mast cells elsewhere, resulting in systemic symptoms.

The interactions among mast cell disease, POTS and EDS

It is undeniable that there is an association among mast cell disease, EDS and POTS. However, there is not much data published on this topic. There was a poster presented in 2015 that found some combination of EDS, POTS and MCAS in a group of 15 patients. This is a very small population and we need larger studies to understand incidence. There is ongoing work to tie this group of conditions to specific genetic markers. However, this also requires further investigation and more patients. In the absence of hard data, we are forced to use some early data and understanding of similar conditions to try and figure out exactly what happens. As more data comes out, this understanding may change.

This is very much a chicken and egg situation where it’s not clear exactly what begets what. EDS is a genetic disorder and considered primary. However, that does not necessarily mean POTS or mast cell disease is secondary in this scenario.

Regardless of which is the initiating condition, the relationship seems to be something like the following:

1. A patient has EDS. They make defective connective tissue. These defective tissues do not support the bodily organs and vessels properly.

2. A patient stands up. Blood quickly moves from the torso into the legs.

3. The blood vessels in the legs try become more narrow and more able to keep fluid in the bloodstream. However, in an EDS patient, the blood vessels are stretched out and not held in the right place because the connective tissue is too weak.

4. The blood vessels in the legs are not able to pump blood back to the heart quickly enough. The body interprets this as having low blood pressure.

5. The nervous system sends signals to increase heart rate to compensate for the “low” blood pressure.

6. The signals sent to increase heart rate activate mast cells.

7. Mast cells activate release mediators to try and regulate blood pressure and heart rate.

8. Mast cell mediators activate other mast cells, eventually affecting other parts of the body.

9. The molecules released by mast cells make blood vessels bigger and more leaky.

10. As fluid leaves the bloodstream and gets stuck in places where it can’t work (third spacing), blood pressure decreases and heart rate increases. This exacerbates POTS symptoms. The cycle repeats.

For more detailed reading, please visit these posts:

Cardiovascular manifestations of mast cell disease: Part 1 of 5

Cardiovascular manifestations of mast cell disease: Part 2 of 5

Cardiovascular manifestations of mast cell disease: Part 3 of 5

Cardiovascular manifestations of mast cell disease: Part 4 of 5

Cardiovascular manifestations of mast cell disease: Part 5 of 5

Hypermobility Type Ehlers Danlos Syndrome and Autonomic Dysfunction (Part 1)

Hypermobility Type Ehlers Danlos Syndrome and Autonomic Dysfunction (Part 2)

Hypermobility Type Ehlers Danlos Syndrome and Autonomic Dysfunction (Part 3)

Hypermobility Type Ehlers Danlos Syndrome and Autonomic Dysfunction (Part 4)

Hypermobility Type Ehlers Danlos Syndrome and Autonomic Dysfunction (Part 5)

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 1

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 2

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 3

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 4

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 5

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 6

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 7

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 31

39. How are mast cell disease, Ehlers Danlos Syndrome and POTS connected?

I’m answering this question in two parts because there is a lot of information to relay and it’s important that it is done clearly.

Let’s talk about what EDS and POTS are first.

Ehlers Danlos Syndrome (EDS) is a connective tissue disease. It can be, and often is, inherited. About 1 in 5000 people have some form of EDS.

There are several subtypes of EDS. The ones you hear about most are called classical, vascular, and hypermobility. The different forms of EDS used to be distinguished by numbers (like Type I, Type II, etc) but now they use descriptive terms instead. Types I and II EDS are now called classical EDS (cEDS); type IV EDS is now called vascular EDS (vEDS); and type III EDS is now called hypermobility type (hEDS or htEDS). There are also other rare variants of EDS.

Each of these subtypes has distinguishing features that make them unique from the other forms of EDS. All forms of EDS cause major systemic dysfunction of connective tissue, the pieces of you that hold your body together and keep everything in the right place. Generally, in EDS patients, their connective tissues tear easily and heal slowly. They usually (but do not always) show hypermobility in their joints (being double jointed or overly flexibility). Skin that is very stretchy or that heals very poorly is common.

Because you have connective tissues holding your whole body together, EDS can affect your entire body. All patients are at risk for symptoms that specifically impact their joints, muscles and bones. VEDS can significantly affect life span because it increases the risk of an aneurysm or a blood vessel bursting. HEDS patients often have cardiovascular, GI, and neurologic symptoms. CEDS patients often display the trademark skin stretchiness and many have extraordinary difficulties in healing incisions and wounds. Of course, many EDS patients have other symptoms, and there is a lot of symptom overlap among these forms. I am just generalizing here.

There is no cure and treatment is largely about managing symptoms and complications. EDS is usually diagnosed by a geneticist. There are genetic markers for most forms of EDS that can be found with genetic testing. However, the most common form of EDS, hypermobility type EDS (hEDS), does not have a known genetic marker. For this reason, geneticists often assess how hypermobile a patient is and then uses that to support the diagnosis of hEDS.

Postural orthostatic tachycardia syndrome (POTS) is a form of orthostatic intolerance, which means symptoms and problems caused specifically by standing up. POTS patients have a big jump in heart rate when they stand up (increase of 30 beats per minute or heart rate over 120 beats/minute in adults) that is not due to a drop in blood pressure. POTS is a form of dysautonomia, an umbrella term that covers several conditions in which the body is not able to control some of the body’s automatic functions like heart rate and blood pressure. (For those wondering, automatic is not a typo, and I did not mean to write autonomic, which is related here.)

There are multiple types of POTS. I’m just going to cover neuropathic POTS and hyperadrenergic POTS as they are the most applicable here. POTS can be a primary or secondary condition. It can cause very severely disabling symptoms and effects. It can cause a huge array of symptoms, including dizziness; fainting; exhaustion; inability to exercise; nausea; vomiting; major GI disturbances (both diarrhea and constipation); inappropriate sweating; chest pain; coldness, numbness, pain and weakness of extremities; and anxiety. Some patients are unable to stand up at all.

Neuropathic POTS, the most frequently described, is thought to be the result of the veins in the legs not being able to pump blood effectively. When you stand up from a sitting position or laying down, a lot of blood that was in your torso quickly moves into your legs. This happens to everyone. In most people, the veins in your legs are able to tighten and squeeze effectively to pump that blood out of the legs and get it back to your heart. In neuropathic POTS, your veins don’t seem to be able to do this as well so the blood gets stuck in your legs. Your body interprets this as having low blood pressure even though you have enough blood and it’s just not where your body expects it. In response to the “low blood pressure”, your heart starts beating very fast to try and get enough oxygenated blood to every place in your body that needs it.

Hyperadrenergic POTS is less common but relatively more common in mast cell patients. In this form, the body makes too much adrenaline (and often other similar molecules like noradrenaline). These molecules work together to cause the nervous system to tell the heart to beat way too fast in response to standing up and that blood moving into your legs. In patients with hyperadrenergic POTS, blood pressure is often increased while the heart rate is also increased instead of being normal or low as in neuropathic POTS.

The second part of this question (question 39) will be up in a day or two. Sorry for the length but I don’t think there’s a way to answer this question both clearly and with brevity.

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 4

Syncope, also called fainting, is the loss of consciousness caused by temporary loss of blood supply to the brain, followed by complete recovery. About 40% of people will faint in their lifetime and half of them will first faint as teenagers, around the age of 15. Fainting can be caused by orthostatic hypotension. Otherwise, it can occur for cardiac or neurologic reasons (also called reflex syncope). One type of reflex syncope is vagovagal syncope, which can be further divided into postural syncope (fainting upon standing) and emotional or phobic syncope (fainting due to unpleasant psychological stimuli).

Vagovagal syncope has been attributed to several things, but none have been definitively proven. Some patients have decreased presence of enzymes that mediate blood pressure, like norepinephrine transportase (NET). Some have insufficient circulation in the abdominal cavity. As vasovagal syncope is often preceded by lightheadedness, sweating, weakness, nausea and visual disturbances, it can be difficult to distinguish between VVS and POTS. However, VVS patients often go long periods without OI symptoms, which only occur immediately before syncope.   Postural syncope and POTS are also associated with increased rate and depth of breathing in order to meet oxygen needs during these episodes.

Ingestion of 16 ounces of water in five minutes is known to effectively treat OI episodes of all types. It begins to have effect in about twenty minutes. It is important that this water not have solutes; that is to say, it should be pure water. Effects can last for hours.

There are a number of precipitating factors that can induce OI symptoms in susceptible patients. Avoidance is a key treatment modality. These factors include large meals, sudden postural changes, laying down for extended periods of time, environmental heat, alcohol, vasodilators* and sympathomimetic drugs, such as methylphenidate. (*It is worth noting that mast cell disease is inherently vasodilatory).

For both orthostatic hypotension and neurogenic POTS patients, physical maneuvers and compression garments can decrease venous pooling of blood. Increasing both salt and water intake can be helpful to expand plasma volume; 1.5-2L is recommended for adults.

Medications that retain salt and water, such as fludrocortisone, may be tried as well. Pressor drugs with short half lives, such as midodrine and pyridostigmine, are also used in these patients. Droxidopa is used outside of the US. Other meds, such as clonidine, also see some utility. Exercise is also encouraged as a treatment option (will be detailed in a follow up post).

HyperPOTS is often treated with beta blockers. (WARNING: beta blockers interfere with the action of epinephrine and should be used cautiously in mast cell patients). Angiotensin receptor blockers like Cozaar have been used, as has droxidopa. Exercise is likewise suggested for treatment of this patient group.

Water ingestion is recommended for patients with vasovagal syncope. Additionally, physical maneuvers are advised upon the onset of OI symptoms.

 

References:

Stewart, Julian M. Update on the theory and management of orthostatic intolerance and related syndromes in adolescents and children. Expert Rev Cardiovasc Ther 2012 November; 10(11): 1387-1399.

Benarroch, Eduardo E. Postural tachycardia syndrome: a heterogenous and multifactorial disorder. Mayo Clinic Proceedings 2012; 87(12): 1214-1225.

 

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 3

POTS (postural orthostatic tachycardia syndrome) is one type of orthostatic intolerance. It is defined as the increase in heart rate of 30 beats/min or more when standing in the absence of orthostatic hypotension. There are a number of mechanisms that cause POTS.

Neuropathic POTS is caused by inefficient constriction of blood vessels in the lower limbs due to a defect in the sympathetic nervous system. In these patients , the heart does not sense the change in blood pressure correctly and does not pump out enough blood volume to accommodate the pressure change. Patients with this syndrome usually do not sweat in the feet. They have insufficient release of norepinephrine upon standing.

The orthostatic intolerance in neuropathic POTS is caused by the veins not constricting enough in the legs to maintain blood pressure upon standing. When executing the Valsalva maneuver, they are unable to raise blood pressure significantly. Blood is found to pool in the leg veins when these patients do not use pressure devices like compression stockings. These patients have “high blood flow”, meaning that the total peripheral resistance (the total pressure exerted by the blood vessels) is lower than expected when laying down or standing. This form of POTS may have an autoimmune link, but this though requires further investigation.

Hyperadrenergic POTS is caused by excessive cardiac response to stimulation by the sympathetic nervous system. In these patients, the nervous system tells the heart to beat faster and harder.  30-60% of patients have this form. These patients have serum plasma norepinephrine of 600 pg/mL or higher when standing. They have fluctuating or elevated blood pressure (both consistently or during crisis), and episodes of tachycardia, hypertension and hyperhidrosis. Of note, these episodes can be triggered by orthostatic stimuli (changing position) as well as physical or even emotional stimuli.

This category has also been referred to as “low volume” POTS, in which norepinephrine levels in serum can exceed 1000 pg/mL, and in which patients often have pale and cold skin, tachycardia while laying down, elevated blood pressure while laying down and increased neurologic signals to muscles while laying down. A genetic condition affecting the norepinephrine transporter (NET) gene is responsible for some cases of hyperadrenergic POTS. Hyperadrenergic POTS can be secondary to a number of conditions, including mast cell activation disease. One study found that 38% of patients with mast cell disease also had hyperPOTS.

POTS patients may have low plasma, red cell or total blood volumes. One study found 28.9% of POTS patients to be hypovolemic, meaning they had less volume in their blood stream than normal. In some of these patients, they have low renin activity and aldosterone when standing. Others may have high angiotensin II levels. These molecules are related to regulation of blood pressure. GI conditions that result in poor oral water intake from nausea or diarrhea can cause hypovolemia with orthostatic intolerance and tachycardia. For this population, the recommendation is to consider POTS as secondary the GI condition.

POTS patients present with persistent tachycardia, reduced stroke volume (amount of blood pushed out of the heart), loss of mass in the left ventricle (this part of the heart is smaller than normal), and reduced peak oxygen uptake when standing, during and after exercise. These markers are also present in physical deconditioning, which can also cause orthostatic intolerance regardless of why the deconditioning occurred. For this reason, POTS is often associated with conditions that provoke exercise intolerance, such as fibromyalgia, chronic fatigue syndrome and deconditioning.

 

References:

Stewart, Julian M. Update on the theory and management of orthostatic intolerance and related syndromes in adolescents and children. Expert Rev Cardiovasc Ther 2012 November; 10(11): 1387-1399.

Figueroa, Juan J., et al. Preventing and treating orthostatic hypotension: As easy as A, B, C. Cleve Clin J Med 2010 May; 77(5): 298-306.

Benarroch, Eduardo E. Postural tachycardia syndrome: a heterogenous and multifactorial disorder. Mayo Clinic Proceedings 2012; 87(12): 1214-1225.

Cheung, Ingrid, Vadas, Peter. A new disease cluster: mast cell activation syndrome, postural orthostatic tachycardia syndrome and Ehlers-Danlos syndrome. J All Clin Immunol 2015: 135(2); AB65.

Joyner, M., Masuki, S. POTS versus deconditioning: the same or different? Clin Auton Res 2008 Dec; 18(6): 300-307.