cardiovascular symptoms

Cardiovascular manifestations of mast cell disease: Part 5 of 5

Low blood pressure causing lightheadedness or fainting is a classic manifestation of mast cell disease with as many as 22-55% of patients having experienced it at least one. For comparison, the control group demonstrated a frequency of 5%.  Some patients experience this symptom often while others only rarely experience it or never do.

A staggering amount of mast cell mediators can induce low blood pressure; indeed, this is the reason why low blood pressure is the hallmark sign of severe allergic reaction and anaphylaxis.  Histamine can induce hypotension through the H1 receptor.  Heparin makes histamine and tryptase less susceptible to degradation, allowing longer action.

Many mediators are vasodilating, widening the blood vessels. Vasoactive intestinal peptide (VIP) is a vasodilator.  PGD2 is also a very potent in this capacity. PGE2 is not released in large amounts by mast cells, but has the same effect. Platelet activating factor decreases blood pressure in multiple ways: by decreasing the force of heart muscle contraction, by slowing heart rate and by widening blood vessels. IL-6 and nitric oxide are also vasodilating.

Some mediators lower blood pressure by their participation in the bradykinin pathway.  Bradykinin is a potent stimulator of fluid loss from the blood to the tissues, causing low blood pressure and angioedema. Heparin can serve as an initiator for the production of bradykinin. Tryptase and chymase both participate in bradykinin formation.

Mast cell medications can be very effective in increasing blood pressure by decreasing fluid loss from the blood to the tissues.  As PGD2 can be a strong vasodilator, COX inhibitors like NSAIDs that interfere with prostaglandin production can help to increase blood pressure.  Aspirin, 81-325mg once or twice daily, is sometimes recommended for adults that are not sensitive to the medication.  Early data on the use of omalizumab (Xolair) in SM patients indicates that it may prevent episodes of sudden onset low blood pressure.

References:

Kolck UW, et al. Cardiovascular symptoms in patients with systemic mast cell activation disease. Translation Research 2016; x:1-10.

Gonzalez-de-Olano D, et al. Mast cell-related disorders presenting with Kounis Syndrome. International Journal of Cardiology 2012: 161(1): 56-58.

Kennedy S, et al. Mast cells and vascular diseases. Pharmacology & Therapeutics 2013; 138: 53-65.

 

Cardiovascular manifestations of mast cell disease: Part 4 of 5

Heart failure is uncommon in mast cell patients, but is noteworthy as a condition that involves mast cell activation.  One study of adults with SM found 12 patients out of 548 had congestive heart failure.  A small study with 18 MCAS patients found that persistent mast cell activation did not affect such parameters as systolic left ventricular function, systolic and diastolic left ventricular diameter, or shortening fraction.  These markers are often tied to heart failure. In that same study, 12/18 MCAS patients did exhibit a diastolic left ventricular dysfunction.  This defect is a sensitive indicator of changes to the myocardium, muscle around the heart and can be found using Doppler imaging. Five of those MCAS patients also showed hypertrophy in the left ventricle, a thickening of tissue that can be linked to heart damage.

Importantly, these findings were not linked to chronic heart failure in this population.  Mast cell patients should be aware that while these anatomical changes of the left ventricle may be present, there is not currently any indication that their increase the frequency of symptomatic heart failure in this population.  Mast cells are heavily involved in tissue remodeling and it is possible that local mast cell activation can lead to laying of additional tissue or scarring.  Tryptase, chymase and matrix metalloproteinases, all released by mast cells, participate in tissue remodeling and fibrosis.

Tryptase has been associated with both heart failure and atherosclerosis, involved in coronary disease and syndromes.  A number of other mediators can also contribute to heart failure, including histamine, platelet activating factor, IL-4, IL-6, IL-10, TNF, fibroblast growth factor (FGF) and transforming growth factor beta (TGFB).

Treatment of heart failure in mast cell patients is not terribly different from that of the general population.  Diuretics are often used first, including furosemide. Angiotensin receptor antagonists like losartan are good choices for mast cell patients since ACE inhibitors and beta blockers should be avoided wherever possible.  Calcium channel blockers like verapamil can be used. Spironolactone or similar medications may provide additional benefit. Ivabradine, a newer medication that works by affecting the funny current (Author’s note: Not a joke!  My favorite pathway name), is also a consideration.  Digoxin is appropriate for atrial fibrillation (afib) where other attempts to correct rhythm have failed.

References:

Kolck UW, et al. Cardiovascular symptoms in patients with systemic mast cell activation disease. Translation Research 2016; x:1-10.

Gonzalez-de-Olano D, et al. Mast cell-related disorders presenting with Kounis Syndrome. International Journal of Cardiology 2012: 161(1): 56-58.

Kennedy S, et al. Mast cells and vascular diseases. Pharmacology & Therapeutics 2013; 138: 53-65.

Cardiovascular manifestations of mast cell disease (Part 2 of 5)

Abnormalities of heart rate and rhythm can occur due to action of several mast cell mediators. Histamine binds at histamine receptors numbered in the order of identification: H1, H2, H3 and H4. Histamine binding at H1 receptors on cardiomyocytes (heart muscle cells) slows the heart rate, while histamine binding at H2 receptors increasing heart rate and the force of heart contraction.

As I mentioned in the previous post, histamine binding at the H3 receptor decreases the release of norepinephrine. Another mast cell product, renin, modulates angiotensin II, which can increase norepinephrine release.  Increased levels of norepinephrine triggers increases in heart rate and force of contraction.  This means that whether or not mast cell activation causes tachycardia depends largely on how much renin and histamine are released. Much less histamine is necessary to trigger the H3 inhibition of norepinephrine release relative to the amount needed to affect heart rate through H1 and H2 receptors.

Prostaglandin D2, a mast cell mediator, can also cause tachycardia.  Of note, prostaglandin D2 is not stored in mast cell granules.  It is made following mast cell activation and is considered part of the “late phase allergy response”, which can occur several hours after exposure to a trigger.

Tachycardia is a common symptom for mast cell patients.  The recommendation in a recent review article is to treat when the heart rate is perpetually over 100-120 bpm, or when it is extremely distressing to the patient. There are a number of options for treatment. As it can be caused directly by mast cell behavior, mast cell medications such as antihistamines (H1 and H2) should be adjusted for maximum effect. Renin inhibitors, such as aliskiren (Tekturna in the US), can be used to treat supraventricular tachycardia (SVT) in mast cell patients, as can angiotensin receptor blockers like losartan, valsartan and others. Patients on renin inhibitors or angiotensin receptor blockers can also decrease blood pressure.

Calcium channel blockers, like verapamil, are also an option.  The medication ivabradine treats tachycardia in patients who have a regular heart rhythm and does not affect blood pressure.  Ivabradine is not used to treat atrial fibrillation. β-blockers are contraindicated in mast cell patients because it interferes with the action of epinephrine, making patients more likely to have reactions and epinephrine less likely to treat effectively.

References:

Kolck UW, et al. Cardiovascular symptoms in patients with systemic mast cell activation disease. Translation Research 2016; x:1-10.

Gonzalez-de-Olano D, et al. Mast cell-related disorders presenting with Kounis Syndrome. International Journal of Cardiology 2012: 161(1): 56-58.

Kennedy S, et al. Mast cells and vascular diseases. Pharmacology & Therapeutics 2013; 138: 53-65.

Cardiovascular manifestations of mast cell disease (Part 1 of 5)

Mast cells are present in the cardiovascular system under normal conditions both in the heart and near vasculature, often in spaces close to nerve endings.  They perform a variety of necessary functions including participating in the pathway to generate the hormone angiotensin II, which encourages an increase in blood pressure.  Mast cells in the heart and vasculature are usually positive for both chymase and tryptase in granules. Mast cells in the cardiovascular system have also been tied to a number of conditions, including atherosclerosis, arrhythmias and aneurysm.

Mast cell patients may experience a number of cardiovascular symptoms or events. 29% of SM patients and at least 20% of MCAS patients report palpitations and supraventricular tachycardia.  31% of patients with mast cell activation disease (MCAS, MMAS, SM) experience episodic or chronic elevation in arterial blood pressure due to mast cell activation. Ventricular fibrillation, cardiac arrest and Kounis Syndrome can occur in mast cell patients due to mast cell activation.  Few cases of heart failure in SM patients have been reported.

Kounis Syndrome is an acute coronary syndrome provoked by mast cell mediator release. In one series, ten mast cell patients (5 MCAS, 3 MMAS, 2 ISM) suffered acute coronary syndromes.  These patients reported “oppressive” chest pain of the type commonly seen in ischemic cardiac events.  The triggers for these events were diverse: venom immunotherapy, mepivacaine, exercise, penicillin, general anesthesia, wasp sting, metamizole and moxifloxacin.  In seven patients, the echocardiogram was normal.  In the remaining, left ventricular hypertrophy, anteroseptal hypokinesia, medioapical hypokinesia, inferoseptal akinesis, lateral apical akinesia and left ventricular ejection fraction of 40% were found on echo. Only six patients had elevation of troponin, a test commonly used to diagnose heart attack and acute coronary syndromes.

Mast cell mediators exhibit a wide range of effects on the cardiovascular and nervous systems. Mast cell mediators can affect release of norepinephrine by sympathetic nervous system, contributing to arrhythmias.  In some instances, release of norepinephrine has been linked to sudden cardiac death, although not linked specifically to mast cell patients. Histamine actually decreases norepinephrine release by binding to H3 receptors on nerve endings.

As mentioned above, mast cells participate in modulating the level of angiotensin II. Mast cells release renin, which leads to the formation of angiotensin II. Angiotensin II then binds to AT1 receptors on sympathetic nerve endings, raising blood pressure. Angiotensin II can also cause arrhythmias without involving the nervous system.

References:

Kolck UW, et al. Cardiovascular symptoms in patients with systemic mast cell activation disease. Translation Research 2016; x:1-10.

Gonzalez-de-Olano D, et al. Mast cell-related disorders presenting with Kounis Syndrome. International Journal of Cardiology 2012: 161(1): 56-58.

Kennedy S, et al. Mast cells and vascular diseases. Pharmacology & Therapeurics 2013; 138: 53-65.

Mast cells in vascular disease: Part 3

Aneurysms are formed when elastic tissue is degraded by proteases and MMPs; the vessel is thinned due to smooth muscle loss; and the endothelium is broken down, resulting in inflammation. There is a significant body of evidence linking aneurysm formation and growth to mast cell activity.

A number of studies have found that mast cells are present in larger numbers in vasculature near aneurysms. Mast cells are increased in cerebral arteries of patients who died from subarachnoid hemorrhage. In particular, mast cell number is higher in arteries close to the rupture site. Mast cell count has been linked previously to aneurysm instability. Another study found that activated mast cells were increased in the aortas of patients who died from abdominal aortic aneurysms. Increased mast cells are also found in ascending aortic aneurysms. Mast cell density is a predictor for occurrence of ascending aortic aneurysm.

Chymase activity has been heavily implicated in aneurysm physiology. One study found that levels of angiotensin II were unlikely to induce development of aneurysm, but that degradation of the vessel by chymase may weaken the aneurysm and increase risk of rupture. Increased chymase activity was found in an additional fourteen patients having aortic aneurysms repaired. In thoracic aortic aneurysm patients, chymase positive mast cells were found in inflamed areas. Chymase may participate in the generation of reactive oxygen species. In abdominal aortic aneurysm samples, most players in the renin-angiotensin system, including chymase and cathepsins, are increased.

Serpin A3, a protease inhibitor, normally regulates activity of elastase, chymase and cathepsin G. It is thought that deficiency of this molecule may worsen damage caused by chymase.

Mast cell proteases, like tryptase and chymase, may be involved in the formation of aneurysms. Erosion of the endothelium occurred in the thrombosed region of the vessel, followed by decreased oxygen supply to the underlying vessel. Tryptase and chymase may participate in rupture of the vessel and intravascular hemorrhage. Adrenomedullin, a mast cell mediator, is found to be strongly expressed in mast cells to local to aneurysms. Adrenomedullin suppresses formation of the extracellular matrix.

Serum tryptase levels in abdominal aortic aneurysms correlated well with growth of aneurysm as well as risk of complications during repair. Tryptase deficient mice were completely protected against developing this type of aneurysm. Tryptase deficiency reduced expression of cathepsins, as well as activation of endothelial cells and movement of monocytes. Tryptase induces release of cathepsins that trigger apoptosis, so this may be a mechanism.

5-lipoxygenase is the enzyme that drives leukotriene formation. Mice deficient in this molecule were protected against aneurysm formation. They also had less inflammation and apoptosis, lower IL-6 and IFN-γ. Mast cell degranulation augmented aneurysm formation while mast cell stabilizer cromolyn decreased it. Another study found that treatment with tranilast, another mast cell stabilizer, decreased the diameter of the aorta.

Leukotriene C4 and 5-lipoxygenase are increased in patients with abdominal aortic aneurysms, but leukotriene B4 is not. Leukotrienes increase release of MMPs and encourage matrix degradation. Leukotrienes may be a therapeutic target to slow aneurysm progression.

References:

Kennedy, Simon, et al. Mast cells and vascular diseases. Pharmacology & Therapeutics 138 (2013) 53-65.

Bot, Ilze, et al. Mast cells: Pivotal players in cardiovascular diseases. Current Cardiology Reviews, 2008, 4, 170-178.

 

Mast cells in vascular disease: Part 2

Chymase is a mediator produced and released by mast cells. It is an enzyme that converts angiotensin I to angiotensin II, which is important in regulating blood pressure. Chymase can also activate TGF-b1, IL-1b and degrade some of the proteins that hold cells together in tissues.

Release of chymase by local mast cells is a large factor in plaque instability. This is thought to be by raising amount of angiotensin II and degrading a structure that stabilizes the plaque. Chymase also causes apoptosis, or cell death, of smooth muscle cells, which lie underneath the plaque. It was recently discovered that activation of the toll like receptor 4 (TLR4) on the surface of the mast cell causes the mast cell to release IL-6. IL-6 then binds to the mast cell and causes it to make and release chymase.

Chymase and tryptase also interfere with cholesterol transport. In plaques, macrophages eat cholesterol and become foam cells. When the foam cells try to release the cholesterol, chymase and tryptase can prevent this, which stabilizes the plaque and makes it larger.

Mast cell activation is also known to affect plaque behavior. In mast cells that could not be activated by IgE, the size of the plaque and cell death around it were reduced. IgE levels are higher in patients who suffer acute coronary syndromes compared with those who don’t, with IgE levels peaking seven days after the event. Patients with hyper-IgE syndrome are much more likely to have coronary artery dilation or aneurysm, although atherosclerosis was not common. A whole body MRI detected impaired vascular integrity in these patients. These patients are expected to be more prone to mast cell activation.

In mastocytosis patients, no increase in atherosclerosis has been reported, though cardiovascular symptoms are not unusual. Some mastocytosis patients demonstrate vascular instability. Two cases of strokes due to cranial artery dissection have been published.

Mice that lack substance P, a neuropeptide that activates mast cells, have better cardiac function than expected. In mouse models, adding substance P to a plaque could cause hemorrhage only if the mouse had mast cells. This indicates that mast cell activation is important in plaque rupture.

 

References:

Simon Kennedy, Junxi Wu, Roger M. Wadsworth, Catherine E. Lawrence, Pasquale Maffia. Mast cells and vascular diseases. Pharmacology & Therapeutics 138 (2013) 53–65.

Ramalho, L. S., Oliveira, L. F., Cavellani, C. L., Ferraz, M. L., de Oliveira, F. A., Miranda Corrêa, R. R., et al. (2012). Role of mast cell chymase and tryptase in the progression of atherosclerosis: study in 44 autopsied cases. Ann Diagn Pathol 17, 28–31.

Meléndez, G. C., Li, J., Law, B. A., Janicki, J. S., Supowit, S. C., & Levick, S. P. (2011). Substance P induces adverse myocardial remodelling via a mechanism involving cardiac mast cells. Cardiovasc Res 92, 420–429.

Guo, T., Chen,W. Q., Zhang, C., Zhao, Y. X., & Zhang, Y. (2009). Chymase activity is closely related with plaque vulnerability in a hamster model of atherosclerosis. Atherosclerosis 207, 59–67.

 

Mast cells in vascular disease: Part 1

Atherosclerosis is a very specific type of artery hardening that occurs due to accumulation of white blood cells and their inflammation of the vessel. Atherosclerosis can cause heart attacks, formation of blood clots and obstruction of major vessels. There are a number of risk factors, including tobacco smoking, high LDL cholesterol, diabetes, vitamin B6 deficiency, high C reactive protein, and many others.

Atherosclerosis is now known to be an immunoinflammatory condition, one which results from inflammation mediated by immune cells. In recent years, mast cells have been found to play an important role in the formation of atherosclerotic lesions, progression and destabilization of the lesion, which in turn causes the more significant clinical effects. In 2004, 66% of men and 47% of women in the US had heart attack or sudden cardiac death as their first symptom of atherosclerotic heart disease.

Endothelial cells line the blood vessels and form the endothelium. In atherosclerotic plaques, monocytes from the blood burrow into the endothelium. They turn into macrophages, a different kind of cell. These macrophages eat certain kinds of cholesterol and start a cycle in inflammation in the vessel wall. Platelets then stick to the inflamed places.

Mast cells are known to have a number of behaviors that affect plaque pathology. Mast cells near plaques release tryptase, which activates endothelial cells through the PAR-2 receptor. This causes a series of events that produces platelet activating factor (PAF). PAF increases the permeability and contraction of the nearby smooth muscle, which can lead to vascular events.

Increased densities of mast cells have been found in the tissue layer overlaying plaques that ruptured. It has been hypothesized that mast cell released histamine could cause coronary spasm, making the plaque more likely to rupture. In a study that looked at 44 autopsy samples of aorta with atherosclerotic lesions, there was a direct correlation found between levels of tryptase and chymase, the amount of collagen in the plaque, and the size of the endothelium involved.

Mast cells that store basic fibroblast growth factor (bFGF) are found in small vessels inside plaques. Histamine may cause leakage from those tiny vessels, which can further make the plaque more likely to rupture.   In histamine deficient mice, the plaque area was reduced in size, and expression of genes for NF-kB, matrix metalloproteinases (MMPs), and inflammatory cytokines involved in plaque progression. Histamine is also involved in acute coronary vasospasm that may result in heart attack; this is called Kounis Syndrome.

 

References:

Simon Kennedy, Junxi Wu, Roger M. Wadsworth, Catherine E. Lawrence, Pasquale Maffia. Mast cells and vascular diseases. Pharmacology & Therapeutics 138 (2013) 53–65.

Ramalho, L. S., Oliveira, L. F., Cavellani, C. L., Ferraz, M. L., de Oliveira, F. A., Miranda Corrêa, R. R., et al. (2012). Role of mast cell chymase and tryptase in the progression of atherosclerosis: study in 44 autopsied cases. Ann Diagn Pathol 17, 28–31.

Lappalainen,H., Laine, P., Pentikäinen,M. O., Sajantila,A.,& Kovanen, P. T. (2004).Mast cells in neovascularized human coronary plaques store and secrete basic fibroblast growth factor, a potent angiogenic mediator. Arterioscler Thromb Vasc Biol 24, 1880–1885.

Kounis, N. G., Mazarakis, A., Tsigkas, G., Giannopoulos, S., & Goudevenos, J. (2011). Kounis syndrome: a new twist on an old disease. Future Cardiol 7, 805–824.

Cardiovascular symptoms of MCAS

MCAS patients often have a number of cardiovascular symptoms.  In true mast cell disease fashion, these symptoms often represent both ends of the spectrum.
Heart palpitations are the most common cardiac complaint, with true rhythmic abnormalities being fairly rare.  Tachycardia is also very common, but occasionally slow heart rate (bradycardia) is reported.  In bradycardic patients, no obvious cause for this can be identified.  Both low and high blood pressure can be seen, many times in the same patient, sometimes even following one after the other in a short period of time.  These changes in blood pressure often have no clear trigger.
True syncope (fainting) is uncommon in MCAS, but presyncope (lightheadedness, weakness, dizziness or vertigo) affects the majority of patients.  These presyncope episodes can be distinct from POTS symptoms, and may not be related to position.  Some patients experience as many as several episodes a day.  When tested for POTS with tilt table, MCAS patients may or may not be positive.  However, when treated for POTS, mast cell patients in general only see mild reduction in their presyncope episodes, with little improvement in their other symptoms.
MCAS patients often complain of chest pain, which may or may not reveal ECG abnormalities.  This type of pain is generally localized specifically to the chest and does not radiate down the arm.  Chest pain must be carefully evaluated due to the potential for two rare cardiac syndromes.  Additionally, mast cell disease can indirectly cause congestive heart failure by the long term action of histamine. 
Takotsubo syndrome, or stress-induced cardiomyopathy, is caused by sudden weakening of the myocardium that causes ballooning of the left ventricle.  It can cause acute heart failure, ventricular arrhythmias, and acute heart failure.  Angiography shows that there is no coronary artery defect to explain the left ventricular abnormalities.  If the patient survives, the left ventricle typically returns to normal after about eight weeks.  This does not occur as a result of an allergic reaction, but is sometimes seen in patients with idiopathic anaphylaxis.  In 75% of patients, serum catecholamines are elevated, a finding sometimes seen in MCAS patients.  Due to severe emotional stress frequently being the trigger for the cardiac event, Takotsubo syndrome is also known as broken heart syndrome.
Kounis syndrome is also known as allergic angina or allergic myocardial infarction.  In these patients, there are no obstructive lesions in the coronary artery.  Patients suffer severe chest pain or heart attack as an extension of an allergic reaction.  Kounis syndrome is caused by mast cell activation causing vasospasm of the coronary artery.  It is not known if the mast cells effecting this pathology are normally developed mast cells or improperly developed, such as seen in mastocytosis and MCAS.  This syndrome accounts for about 0.002% of all acute heart attacks.  (An in depth post on Kounis syndrome is on the way.)
MCAS patients often experience coronary and peripheral atherosclerosis.  Some have pain due to narrowing of the vessels.  Sclerosis and poor healing is seen in many MCAS patients.  Due to the importance of mast cells in angiogenesis, long term mast cell activation can contribute to aneurysms, hemorrhoids, varicosities, hemangiomas, arteriovenous malformations and telangiectasias. 
Edema is a common finding.  Most MCAS patients who have edema have no heart abnormalities and do not have pitting edema, indicating that the edema is likely not from heart disease.  MCAS patients often have widespread edema that can shift to different parts of the body.  There is usually no detectable low albumin.  This is thought to be due to third spacing. 

References:
Afrin, Lawrence B. Presentation, diagnosis and management of mast cell activation syndrome.  2013.  Mast cells.
Molderings GJ, Brettner S, Homann J, Afrin LB. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J. Hematol. Oncol.2011; 4:10-17.
Ribatti D, Crivellato E. Mast cells, angiogenesis, and tumour growth. Biochim. Biophys. Acta Mol. Basis Dis. 2012 Jan; 1822(1): 2-8.
Glowacki J, Mulliken JB. Mast cells in hemangioma and vascular malformations.  Pediatrics 1982; 70(1):48-51.
Ribatti D, Crivellato E. Mast cells, angiogenesis, and tumour growth. Biochim. Biophys. Acta Mol. Basis Dis. 2012 Jan; 1822(1):2-8.
Glowacki J, Mulliken JB. Mast cells in hemangioma and vascular malformations. Pediatrics 1982; 70(1):48-51.
Kolck UW, Alfter K, Homann J, von Kügelgen I, Molderings GJ. Cardiac mast cells: implications for heart failure. JACC 2007 Mar 13; 49(10):1106-1108.

Third spacing

The human body essentially keeps fluids in two spaces called compartments.  The first compartment is inside of cells.  This is called intracellular fluid.  It holds about 60% of the body’s fluids.  The second compartment is outside of the cells in the extracellular fluid, which holds about 40% of the body’s fluids.  This second compartment includes spaces like the interstitial compartment and the intravascular compartment.  The interstitial compartment is the fluid that surrounds the cells in tissues.  The intravascular component is mostly blood. 

Third spacing is when body fluids collect somewhere that is not in one of the two compartments where your body can use it.  When fluids are inside cells, your body can use it for chemical reactions.  When fluids are in the interstitial and intravascular compartments, your body can use it for lubrication, chemical reactions and moving chemicals from one place to another.  Fluid in third spaces is outside of the circulatory system and cannot be used by the body.
A common third space is in the abdominal cavity.  When fluid becomes trapped between the tissues and organs of the abdomen, it is called “ascites.”  When fluid accumulates in the interstitial area around the lungs, it is called “pulmonary edema.”  When fluid is found between the layers of the skin or mucous membranes, it is called “angioedema.”
Third spacing is a problem for multiple reasons.  The first is that it compresses the structures around the fluid, like when angioedema puts pressure on the throat and makes it difficult to breathe.  The fluid sometimes affects organ function.  Another reason third spacing is problematic is because it can cause the fluid level in the circulatory system to drop.  This means the amount of blood moving through the body is less than it should be, which decreases blood pressure and increases heart rate.  This can be very dangerous.  If there is not enough blood for the heart to pump, it will stop pumping.
People with a lot of third spacing often have symptoms of dehydration.  This includes things like excessive thirst, fatigue, and reduced urine output. 
Third spacing occurs as a result of anaphylaxis.  It is also a common problem for people with mast cell disease in the absence of anaphylaxis due to “leaking” of chemicals like histamine that push fluid out of the blood vessels and into the tissues.  Fluid replacement is very important to staying stable.
There is a lot of anecdotal information that suggests that IV fluids are helpful to counteracting third spacing in people with mast cell disease.  I get 2L of fluids overnight three times a week, and it has helped immensely.  For me, the IV fluids have stabilized my blood pressure, decreased my heart rate and keep my GI tract moving.  My abdominal pain has improved significantly since starting the IV fluids. My energy is better.  I don’t think that it has been formally written up in article form, but this is a treatment that is quickly gaining momentum in the mast cell community.