The Provider Primer Series: Relevance of mast cells in common health scenarios (continued)

Reason for care Post op care
Role of mast cells Mast cells are inherently activated following surgery as they drive tissue remodeling, angiogenesis, and wound repair.[i]

Mast cells are involved in the transmission of pain stimuli.[iii]

Impact of condition on mast cells Mechanical trauma or pressure, such as dressing a wound or palpating the area, can directly induce degranulation and mast cell activation[ii].

Pain can trigger mast cell activation.[iii]

Psychological and physical stress can trigger an inflammatory response that involves mast cell activation.[iv]

Notes regarding condition treatment NSAIDS can trigger mast cell degranulation and cannot be taken by some mast cell patients.[iv]

Codeine and derivatives can trigger mast cell degranulation[v].

Vancomycin, gyrase inhibitors and cefuroxime should be avoided where possible due to risk of mast cell activation.[vi]

Amide caine anesthetics are preferred over ester caines.[vi]

ACE inhibitors and β-adrenergic receptor antagonists (beta blockers) should be avoided. In particular, beta blockers directly interfere with the action of epinephrine and can impede anaphylaxis management.[vi]

Fentanyl and fentanyl derivatives are the preferred narcotic for mast cell patients due to low risk of degranulation. Hydromorphone and oxycodone are suggested by some authors and see use in mast cell patients.[vi]

Benzodiazepines can provide anxiolytic and anticonvulsive support in mast cell patients are needed.[vi]

IV contrast poses significant to mast cell patients due to the high risk of systemic degranulation. If required, premedication is advised.[vi]

Adhesive allergy is not unusual and patients may require specific occlusive dressings, tapes, or wound glue.

Notes regarding mast cell treatment Antihistamines and mast cell stabilizers can be helpful in mitigating common post op symptoms such as opiate induced itching and nausea. COX inhibitors can help with pain management.[vii]
Special considerations for mast cell patients Mast cells are the largest reservoir of endogenous heparin. Patient should be monitored for coagulopathy.[viii]

Mast cells contribute significantly to post operative ileus.[ix]

Intestinal manipulation directly results in mast cell degranulation.[ix]

 

Reason for care Hypertension
Role of mast cells Mast cell mediators can impact blood pressure. Histamine acting on H2 receptor can promote hypertension.[xi]

Renin, chymase, and carboxypeptidase A all participate in hypertension by dysregulation of angiotensin II.[xi]

9a,11b-PGF2, the degradation product of prostaglandin D2, thromboxane A2, and leukotrienes increase blood pressure.[xi]

Impact of condition on mast cells Dysregulation of angiotensin II and renin levels can affect mast cell behavior.[x]
Notes regarding condition treatment ACE inhibitors and β-adrenergic receptor antagonists (beta blockers) should be avoided. In particular, beta blockers directly interfere with the action of epinephrine and can impede anaphylaxis management. Alternatives include calcium channel blockers, renin inhibitors, and ivabradine, among others.[vi]
Notes regarding mast cell treatment Several mast cell medications can impact levels of histamine, renin, and angiotensin II, all of which can affect blood pressure.
Special considerations for mast cell patients Mast cell patients taking β-adrenergic receptor antagonists (beta blockers) should carry a glucagon pen to increase efficacy of epinephrine in anaphylaxis.[xi]

As many as 31% of patients with mast cell disease demonstrate elevated arterial blood pressure secondary to mast cell activation. These elevations may be episodic or chronic.[xi]

Mast cell patients may also have hyperadrenergic postural orthostatic tachycardia syndrome (hyperPOTS), a condition that can cause hypertension.[xii]

 

Reason for care Heart disease
Role of mast cells Renin, chymase, and carboxypeptidase A all participate in hypertension by dysregulation of angiotensin II, contributing to evolution of arrhythmia.[xi]

Prostaglandin D2, VIP, PAF, IL-6 and nitric oxide are all vasodilating and can contribute to tachycardia.[xi]

Tryptase, histamine, PAF, IL-10, TNF, IL-4, IL-6, FGF, and TGFB can contribute to heart failure.[xi]

Mast cells participate in the formation, destabilization and rupture of atherosclerotic lesions.[xiii]

Histamine release is associated with acute coronary syndromes such as Kounis Syndrome, commonly known as “allergic MI” or “allergic angina”.[xiv]

Leukotriene C4, adrenomedullin, tryptase and chymase participate in the formation, destabilization and rupture of aneurysms.[xiii]

Impact of condition on mast cells Heart disease, especially heart failure, can disrupt release of catecholamines including norepinephrine.[xv] Norepinephrine dysregulation can impact mast cell behavior.

Dysregulation of angiotensin II and renin levels can affect mast cell behaviorx

Notes regarding condition treatment NSAIDS can trigger mast cell degranulation. Some mast cell patients are unable to take them.xx

Acetaminophen is generally recommended for use in mast cell patients.[iv]

ACE inhibitors and β-adrenergic receptor antagonists (beta blockers) should be avoided. In particular, beta blockers directly interfere with the action of epinephrine and can impede anaphylaxis management. Alternatives include calcium channel blockers, renin inhibitors, and ivabradine, among others.[vi]

Notes regarding mast cell treatment COX inhibitors are routinely taken by mast cell patients and may provide relief of prostaglandin induced symptoms.[vi]

Several mast cell medications can impact levels of histamine, renin, and angiotensin II, all of which can affect blood pressure.

Epinephrine can provoke myocardial ischemia, prolong QT interval, and exacerbate coronary vasospasm and arrhythmia.[xiv]

Special considerations for mast cell patients Over 20% of systemic mastocytosis and mast cell activation syndrome patients experience palpitations and supraventricular tachycardia.[xi]

Prostaglandin D2 can cause tachycardia. PGD2 is associated with late phase allergic response and symptoms may be delayed for several hours after allergic event.[xi]

One study showed that 12/18 mast cell activation syndrome patients showed diastolic left ventricular dysfunction.[xi]

Mast cell patients may also have postural orthostatic tachycardia syndrome (POTS), a condition that can cause blood pressure and heart rate irregularities.[xii]

 

Reason for care Chest pain
Role of mast cells Mast cells participate in the formation, destabilization and rupture of atherosclerotic lesions.[xiii]

Histamine release is associated with acute coronary syndromes such as Kounis Syndrome, commonly known as “allergic MI” or “allergic angina”.[xiv]

Leukotriene C4, adrenomedullin, tryptase and chymase participate in the formation, destabilization and rupture of aneurysms.[xiii]

Mast cells participate in esophageal inflammation in several models, including from acid reflux.[xvi]

Mast cells contribute to GI dysmotility which can cause esophageal spasms.[xvii]

Mast cells are involved in the transmission of pain stimuli.[iii]

Impact of condition on mast cells Pain can trigger mast cell activation.[iii]

Psychological and physical stress can trigger an inflammatory response that involves mast cell activation.[iv]

Notes regarding condition treatment NSAIDS can trigger mast cell degranulation. Some mast cell patients are unable to take them.xx

Acetaminophen is generally recommended for use in mast cell patients.[iv]

Fentanyl and fentanyl derivatives are the preferred narcotic for mast cell patients due to low risk of degranulation. Hydromorphone and oxycodone are suggested by some authors and see use in mast cell patients.[vi]

Benzodiazepines can provide anxiolytic and anticonvulsive support in mast cell patients are needed.[vi]

ACE inhibitors and β-adrenergic receptor antagonists (beta blockers) should be avoided. In particular, beta blockers directly interfere with the action of epinephrine and can impede anaphylaxis management. Alternatives include calcium channel blockers, renin inhibitors, and ivabradine, among others.[vi]

Notes regarding mast cell treatment COX inhibitors are routinely taken by mast cell patients and may provide relief of prostaglandin induced symptoms.[vi]
Special considerations for mast cell patients Mast cell patients may experience GI dysmotility which can cause esophageal spasms.[xviii]

Mast cell patients sometimes have eosinophilic esophagitis, causing esophageal spasms, food impaction, and pain.[xix]

Over 20% of systemic mastocytosis and mast cell activation syndrome patients experience palpitations and supraventricular tachycardia.[xi]

Prostaglandin D2 can cause tachycardia. PGD2 is associated with late phase allergic response and symptoms may be delayed for several hours after allergic event.[xi]

One study showed that 12/18 mast cell activation syndrome patients showed diastolic left ventricular dysfunction.[xi]

Mast cell patients can present with Kounis Syndrome. Management of Kounis Syndrome relies upon addressing both cardiovascular aspects of the episode as well as allergic aspects.[xiv]

Costochondritis can occur in mast cell patients and may present as chest pain.

Mast cell patients may also have postural orthostatic tachycardia syndrome (POTS), a condition that can cause blood pressure and heart rate irregularities.[xii]

IV contrast poses significant to mast cell patients due to the high risk of systemic degranulation. If required, premedication is advised.[vi]

References:

[i] Douaiher J, et al. (2014). Development of mast cells and importance of their tryptase and chymase serine proteases in inflammation and wound healing. Adv Immunol, 122, 211-252.

[ii] Zhang D, et al. (2012). Mast-cell degranulation induced by physical stimuli involves the activation of transient receptor-potential channel TRPV2. Physiol Res, 61(1), 113-124.

[iii] Chatterjea D, Martinov T. (2015). Mast cells: versatile gatekeepers of pain. Mol Immunol, 63(1),38-44.

[iv] Dewachter P, et al. (2014). Perioperative management of patients with mastocytosis. Anesthesiology, 120, 753-759.

[v] Brockow K, Bonadonna P. (2012). Drug allergy in mast cell disease. Curr Opin Allergy Clin Immunol, 12, 354-360.

[vi] Molderings GJ, et al. (2016). Pharma,ological treatment options for mast cell activation disease. Naunyn-Schmiedeberg’s Arch Pharmol, 389:671.

[vii] Molderings GJ, et al. (2011). Mast cell activation disease: a concise, practical guide to diagnostic workup and therapeutic options. J Hematol Oncol, 4(10).

[viii] Carvalhosa AB, et al. (2015). A French national survey on clotting disorders in mastocytosis. Medicine (Baltimore), 94(40).

[ix] Peters EG, et al. (2015). The contribution of mast cells to postoperative ileus in experimental and clinical studies. Neurogastroenterol Motil, 27(6), 743-749.

[x] Biscotte SM, et al. (2007). Angiotensin II mediated activation of cardiac mast cells. The FASEB Journal, 21(6).

[xi] Kolck UW, et al. (2016). Cardiovascular symptoms in patients with systemic mast cell activation disease. Translation Research, x, 1-10.

[xii] Shibao C, et al. (2005). Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension, 45, 385-390.

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

[xiv] Kounis NG. (2016). Kounis Syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management. Clin Chem Lab Med, 54(10), 1545-1559.

[xv] Florea VG, Cohn JN. (2014). The autonomic nervous system and heart failure. Circulation Research, 114, 1815-1826.

[xvi] Morganstern JA, et al. (2008). Direct evidence of mast cell participation in acute acid-induced inflammation in mice. J Pediatr Gastroenterol Nutr, 46(2), 134-138.

[xvii] De Winter BY, et al. (2012). Intestinal mast cells in gut inflammation and motility disturbances. Biochimica et Biophysica Acta – Molecular Basis of Disease, 1822(1), 66-73.

[xviii] De Winter BY, et al. (2012). Intestinal mast cells in gut inflammation and motility disturbances. Biochimica et Biophysica Acta – Molecular Basis of Disease, 1822(1), 66-73.

[xix] Nurko S, Rosen R. (2010). Esophageal dysmotility in patients with eosinophilic esophagitis. Gastrointest Endosc Clin N Am, 18(1), 73-ix.

Take home points: July 2015

Mast cell interactions with B and T cells
• Mast cells communicate with other cells by:
o Releasing chemicals to tell another cell to do something
o Other cells releasing chemicals to tell mast cells to do something
o Moving right up against other cells, which allows the cells to “talk”
• B cells are white blood cells that make antibodies and protect against infections.
o Mast cells can tell B cells to make IgE, an allergy antibody.
o When mast cells touch B cells, the mast cells can release IL-6 which tells B cells to live longer.
o Mast cells can tell B cells to make IgA, an antibody.
• T cells are white blood cells that have many functions.
o T cells and mast cells are found close together in many inflammatory conditions, like ulcerative colitis.
o Activated T cells can activate mast cells.
o Mast cells can tell T cells to proliferate and produce inflammatory molecules.
o A kind of T cell called Treg (T reg, like in regulatory) cells can make mast cells harder to activate and interfere with degranulation.

Mast cells in kidney disease
• Kidney disease is often not identified until 60-70% of functional kidney cells have been damaged beyond repair.
• Mast cells are rare in healthy kidneys.
o Damaged kidneys can have up to 60x the normal amount of mast cells.
o Mast cell count is not related to disease severity.
• Atopic disease, like atopic dermatitis and allergic asthma, is linked to idiopathic nephrotic disease, kidney disease of unknown origin.
o The nephrotic disease and atopic disease could be manifestations of the same overarching condition.
o In patients with both, IgE levels are high.
• Tryptase is elevated in some patients with kidney damage.
• Mast cells are responsible for bringing other inflammatory cells to the damaged kidney.
• Mast cells can cause fibrosis in kidneys.
• In some roles, mast cells can protect kidneys from damage.

Regulation of mast cells by IgE and stem cell factor (SCF)
• Mast cells are mostly regulated in two ways
• IgE binds to the IgE receptor (FceRI) on mast cells and activates them
o Activation by IgE results in degranulation and secretion of mediators
o IgE induces mediator release by affecting the amount of calcium inside mast cells
• Stem cell factor (SCF) binds to the CKIT receptor on mast cells and tells them to stay alive
o SCF also increases degranulation and production of cytokines
o SCF helps mast cells to adhere to other cells

Mast cells in vascular disease: Part 3
• Mast cells are involved in the formation and growth of aneurysms
• Activated mast cell populations are increased in vessels that rupture
• Chymase, a mast cell mediator, can degrade vessels and increase risk of rupture
• Leukotrienes contribute to aneurysm formation

Kounis Syndrome: Stress (Part 4 of 4)

The phenomenon we now called Kounis Syndrome has previously been called by names like morphologic cardiac reactions, acute carditis and lesions with basic characteristics of rheumatic carditis. It is sometimes still referred to as allergic angina or allergic myocardial infarction/heart attack depending upon the presentation. Allergic angina, which affected patients as microvascular angina, was first noted to progress to allergic heart attack in 1991.

In a small study done at a hospital, 31 patients with anaphylaxis or non-anaphylactic severe allergic reactions had higher serum troponin I than healthy control patients.  Among those 31 patients, those that experienced anaphylaxis had the highest troponin I overall.  This report, and similar findings, indicates that cardiovascular damage may be a frequent component of anaphylaxis, well beyond what is reported.

Mast cell patients often struggle to identify which is the chicken and which is the egg in the many instances of comorbid conditions. There is no such confusion here – mast cell activation causes Kounis Syndrome.  Tryptase increases in peripheral blood during a spontaneous heart attack.  However, when coronary spasm is induced with medications, there is no such increase in tryptase.  In instances where Kounis Syndrome was caused by disruption of an atherosclerotic plaque, mast cells entered the lesion and released mediators prior to the initiation of the coronary event.

Stress is well known to induce mast cell degranulation.  It has been documented in dozens of papers from various disciplines in the last twenty years. Corticotropin releasing hormone (CRH) is a stress hormone that can bind to the CRHR-1 receptor on mast cells, inducing the manufacture of VEGF. At the same time as CRH is released, neurotensin can also be released.  Experimental work has shown that stress induced mast cell degranulation can be compromised if the neurotensin receptor is blocked.

Reactive oxygen species can activate mast cells and induce sensory nerves to release substance P.  Substance P is a potent mast cell degranulator, inducing secretion of histamine and release of VEGF and other inflammatory mediators. These multiple activation pathways triggered by stress result in mast cell mediator release, which can induce coronary hypersensitivity syndromes such as Kounis Syndrome.

References:

Kounis NG, et al. Kounis Syndrome (allergic angina and allergic myocardial infarction). In: Angina Pectoris: Etiology, Pathogenesis and Treatment 2008.

Lippi G, et al. Cardiac troponin I is increased in patients admitted to the emergency department with severe allergic reactions. A case-control study. International Journal of Cardiology 2015, 194: 68-69.

Kounis NG, et al. The heart and coronary arteries as primary target in severe allergic reactions: Cardiac troponins and the Kounis hypersensitivity-associated acute coronary syndrome. International Journal of Cardiology 2015, 198: 83-84.

Fassio F, et al. Kounis syndrome: a concise review with focus on management. European Journal of Internal Medicine 2016; 30:7-10.

Kounis Syndrome: Aspects on pathophysiology and management. European Journal of Internal Medicine 2016.

Kounis NG. Kounis syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management. Clin Chem Lab Med 2016

Kounis NG. Coronary hypersensitivity disorder: the Kounis Syndrome. Clinical Therapeutics 2013, 35 (5): 563-571.

Alevizos M, et al. Stress triggers coronary mast cells leading to cardiac events. Ann Allergy Asthma Immunol 2014; 112 (4): 309-315.

Kounis Syndrome: Treatment (Part 3 of 4)

Kounis Syndrome treatment requires amelioration of both allergic and cardiovascular symptoms.

  • Type I KS patients may only need treatment for allergic aspects without ever progressing to heart attack.
  • Type II and III KS patients are recommended to follow acute coronary event protocol recommended by ACS.
Treatment of allergic aspects of Kounis Syndrome
Drug class Medication Dosage Notes
H1 inverse agonist Diphenhydramine 1-2 mg/kg

50mg IV is a frequent dosage used for mast cell patients experiencing anaphylaxis symptoms

Can cause hypotension and decrease blood flow through coronary artery if given bolus; should be given slowly
H2 antagonist Ranitidine 1 mg/kg
Famotidine 40mg IV is a frequent dosage used for mast cell patients experiencing anaphylaxis symptoms
Corticosteroid Methylprednisolone or other Methylprednisolone 120 mg IV is a frequent dosage used for mast cell patients experiencing anaphylaxis symptoms Corticosteroids are not used for immediate effect, but to prevent biphasic reactions.Corticosteroid treatment in active heart attack patients has not been found to be harmful.Corticosteroids were recommended as early as 2008 by Kounis for several reasons: inhibition of eicosanoid synthesis, decreasing amount of prostaglandins, leukotrienes and thromboxanes that can be made; reduction of inflammation by increasing death receptor CD95 on some cells; synthesis of annexins, proteins that modulate inflammatory cells and their actions

 

 

Fluid support IV fluids Crystalloid normal saline; avoid colloid solution Use with caution to avoid pulmonary edema
Epinephrine Epinephrine IM dose: 0.2-0.5mg every 5-15 minutes Can contribute to myocardial ischemiaCan prolong the QTc interval

Can cause coronary vasospasm and arrhythmias, especially if given IV

Glucagon is an alternative in patients for whom epinephrine is inappropriate

 

 

Treatment of coronary syndrome in Kounis Syndrome
Drug class Medication Dosage Notes
Nitroglycerin Nitroglycerin Sublingual: 0.3-0.4 mg every five minutesIV: 5-10mcg/min, increased by 10 mcg/min every 5 minutes Causes dilation of coronary vesselsIncreases bloodflow to counteract myocardial ischemia
Calcium channel blocker Diltiazem, verapamil Example  ER dosing for verapamil: 80mg orally every eight hours, immediate release Vasodilators
NSAID Aspirin 160-325 mg Prevent clot formation
P2Y12 receptor inhibitor Clopidogrel 75mg daily Taken with aspirin to prevent clot formation; some medical bodies recommend P2Y12 inhibitors with aspirin, while others recommend aspirin alone
Glycosaminoglycan Heparin IV: 5000 IU bolus, followed by infusion of heparin until PTT 1.5-2.5 above normal Type III patientsHeparin may cause allergic reaction, especially in bolus
Opioid Fentanyl 1-2 mcg/kg Drug of choice for pain management, causes small amount of mast cell degranulation, other opiates risk large scale degranulationDoes not affect cardiac output
N/A Stent placement if vessel narrowed by atherosclerosis N/A

 

Notes:

Beta blockers are contraindicated in Kounis Syndrome for the same reason they are contraindicated in mast cell patients – they block the action of epinephrine, which complicates treatment of anaphylaxis.

IV acetaminophen is generally well tolerated by mast cell patients but is not appropriate for Kounis Syndrome. Acetaminophen reduces cardiac output and systemic vascular resistance which can cause severe low blood pressure and aggravate cardiogenic shock.

References:

Kounis NG, et al. Kounis Syndrome (allergic angina and allergic myocardial infarction). In: Angina Pectoris: Etiology, Pathogenesis and Treatment 2008.

Lippi G, et al. Cardiac troponin I is increased in patients admitted to the emergency department with severe allergic reactions. A case-control study. International Journal of Cardiology 2015, 194: 68-69.

Kounis NG, et al. The heart and coronary arteries as primary target in severe allergic reactions: Cardiac troponins and the Kounis hypersensitivity-associated acute coronary syndrome. International Journal of Cardiology 2015, 198: 83-84.

Fassio F, et al. Kounis syndrome: a concise review with focus on management. European Journal of Internal Medicine 2016; 30:7-10.

Kounis Syndrome: Aspects on pathophysiology and management. European Journal of Internal Medicine 2016.

Kounis NG. Kounis syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management. Clin Chem Lab Med 2016

Kounis NG. Coronary hypersensitivity disorder: the Kounis Syndrome. Clinical Therapeutics 2013, 35 (5): 563-571.

Kounis Syndrome: Diagnosis (Part 2 of 4)

Separating the symptoms of the coronary syndrome from those caused by the coincident allergic reaction is difficult.  Acute chest pain is the hallmark symptom of Kounis Syndrome. While other symptoms may be present, such as nausea, fainting, and shortness of breath, they can also be attributed to the allergic reaction.  Likewise, many of the clinical markers for KS may also appear during anaphylaxis, including cold extremities, very fast or very low heart rate, low blood pressure, palpitations, and sweating. Given the significant overlap in presentation with allergic symptoms, KS is not often diagnosed, though it likely affects a larger population than represented in literature.

Troponins and cardiac enzymes like creatinine kinase are important markers for coronary syndrome, but they are not always elevated in KS. Measurement of mast cell mediators like histamine or tryptase is not always accurate due to the short lifetime of these molecules in the body.  Released histamine is only present in blood for about eight minutes, while tryptase has a half-life of about ninety minutes.

An electrocardiogram (EKG) should be performed as part of the diagnostic process.  A number of signs have been seen in KS patients, including atrial or ventricular fibrillation, bigeminal rhythm, heart block, nodal rhythm, sinus bradycardia or tachycardia, ST segment depression or elevation, T-wave flattening or inversion, QRS or QT prolongation, and ventricular ectopics.  Beyond EKG, there are additional markers that may be present with Kounis Syndrome.  A chest x-ray may show an enlarged heart.  Echocardiogram may show dilated cardiac chambers. Angiography of the coronary artery can reveal spasm or thrombosis. In coronary biopsies, infiltration by mast cells and eosinophils may be found.  Elevation of eosinophils in the blood may also be present.

Having no history of coronary artery disease can make diagnosis more complicated for KS Type I patients, who also may have normal troponins and EKG. Dynamic cardiac MRI with gadolinium can show a subendocardial lesion in patients with KS Type I. Newer imaging techniques such as SPECT have been able to identify myocardial ischemia in KS Type I where coronary angiography had showed no irregularities.

References:

Kounis NG, et al. Kounis Syndrome (allergic angina and allergic myocardial infarction). In: Angina Pectoris: Etiology, Pathogenesis and Treatment 2008.

Lippi G, et al. Cardiac troponin I is increased in patients admitted to the emergency department with severe allergic reactions. A case-control study. International Journal of Cardiology 2015, 194: 68-69.

Kounis NG, et al. The heart and coronary arteries as primary target in severe allergic reactions: Cardiac troponins and the Kounis hypersensitivity-associated acute coronary syndrome. International Journal of Cardiology 2015, 198: 83-84.

Fassio F, et al. Kounis syndrome: a concise review with focus on management. European Journal of Internal Medicine 2016; 30:7-10.

Kounis Syndrome: Aspects on pathophysiology and management. European Journal of Internal Medicine 2016.

Kounis NG. Kounis syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management. Clin Chem Lab Med 2016

Kounis NG. Coronary hypersensitivity disorder: the Kounis Syndrome. Clinical Therapeutics 2013, 35 (5): 563-571.

Kounis Syndrome: Subtypes and effects of mast cell mediators (Part 1 of 4)

Kounis Syndrome (KS) is an acute coronary syndrome that arises as a direct result of mast cell degranulation during an allergic or anaphylactic reaction.

KS usually presents as chest pain during an acute allergic or anaphylactic reaction. There are three recognized variants:

Type I: Patient has no predisposing coronary artery disease.

There are two possible outcomes:

  • Coronary artery spasm with no appreciable increase in cardiac enzymes or troponins
  • Coronary artery spasm that evolves to acute myocardiac infarction (heart attack) with accompanying increase in cardiac enzymes or troponins

Type II: Patient has history of coronary artery disease. There are two possible outcomes:

  • Coronary artery spasm with no appreciable increase in cardiac enzymes or troponins
  • Plaque erosion or rupture that evolves to acute myocardiac infarction (heart attack) with accompanying increase in cardiac enzymes or troponins

Type III: Patient has history of coronary artery disease and a drug eluting coronary stent. There are two possible outcomes:

  • Coronary artery spasm with no appreciable increase in cardiac enzymes or troponins
  • Thrombosis that evolves to acute myocardiac infarction (heart attack) with accompanying increase in cardiac enzymes or troponins

A number of mast cell mediators have effects that can cause coronary spasm or thrombosis.  Beyond their direct effects, they also perpetuate an inflammatory cycle that results in activation and infiltration by inflammatory cells

Mediator Effect
Histamine Coronary vasoconstriction, activation of platelets, increase expression of tissue factor
Chymase Activation of interstitial collagenase, gelatinase, stromelysin resulting in plaque rupture, generation of angiotensin II, a powerful vasoconstrictor
Cathepsin D Generation of angiotensin II, a powerful vasoconstrictor
Leukotrienes (LTC4, LTD4, LTE4) Powerful vasoconstrictor, levels increased during acute unstable angina
Tryptase Activation of interstitial collagenase, gelatinase, stromelysin resulting in plaque rupture
Thromboxane Platelet aggregation, vasoconstriction
PAF Vasoconstriction, aggregation of platelets
Platelets Vasoconstriction, thrombosis

 

References:

Kounis Syndrome (allergic angina and allergic myocardial infarction). Kounis NG, et al. In: Angina Pectoris: Etiology, Pathogenesis and Treatment 2008.

Lippi G, et al. Cardiac troponin I is increased in patients admitted to the emergency department with severe allergic reactions. A case-control study. International Journal of Cardiology 2015, 194: 68-69.

Kounis NG, et al. The heart and coronary arteries as primary target in severe allergic reactions: Cardiac troponins and the Kounis hypersensitivity-associated acute coronary syndrome. International Journal of Cardiology 2015, 198: 83-84.

Fassio F, et al. Kounis syndrome: a concise review with focus on management. European Journal of Internal Medicine 2016; 30:7-10.

Kounis Syndrome: Aspects on pathophysiology and management. European Journal of Internal Medicine 2016.

Symptoms, mediators and mechanisms: A general review (Part 1 of 2)

Skin symptoms    
Symptom Mediators Mechanism
Flushing Histamine (H1), PGD2 Increased vasodilation and permeability of blood vessels

Blood is closer to the skin and redness is seen

Itching Histamine (H1), leukotrienes LTC4, LTD4, LTE4, PAF Possibly stimulation of itch receptors or interaction with local neurotransmitters
Urticaria Histamine (H1), PAF, heparin, bradykinin Increased vasodilation and permeability of blood vessels and lymphatic vessels

Fluid is trapped inappropriately between layers of skin

Angioedema Histamine (H1), heparin, bradykinin, PAF Increased vasodilation and permeability of blood vessels and lymphatic vessels

Fluid is trapped inappropriately between layers of tissue

 

Respiratory symptoms    
Symptom Mediators Mechanism
Nasal congestion Histamine (H1), histamine (H2), leukotrienes LTC4, LTD4, LTE4 Increased mucus production

Smooth muscle constriction

Sneezing Histamine (H1), histamine (H2), leukotrienes LTC4, LTD4, LTE4 Increased mucus production

Smooth muscle constriction

Airway constriction/ difficulty breathing Histamine (H1), leukotrienes LTC4, LTD4, LTE4, PAF Increased mucus production

Smooth muscle constriction

 

Cardiovascular symptoms    
Symptom Mediators Mechanism
Low blood pressure Histamine (H1), PAF,  PGD2, bradykinin Decreased force of heart contraction

Increased vasodilation and permeability of blood vessels

Impact on norepinephrine signaling

Change in heart rate

Presyncope/syncope (fainting) Histamine (H1), histamine (H3), PAF, bradykinin Increased vasodilation and permeability of blood vessels

Decrease in blood pressure

Dysfunctional release of neurotransmitters

High blood pressure Chymase,  9a,11b-PGF2, renin, thromboxane A, carboxypeptidase A Impact on renin-angiotensin pathway

Impact on norepinephrine signaling

Tightening and decreased permeability of blood vessels

Tachycardia Histamine (H2), PGD2 Increasing heart rate

Increasing force of heart contraction

Impact on norepinephrine signaling

Arrhythmias Chymase, PAF, renin Impact on renin-angiotensin pathway

Impact on norepinephrine signaling

 

Gastrointestinal symptoms    
Symptom Mediators Mechanism
Diarrhea Histamine (H1), histamine (H2), bradykinin, serotonin Smooth muscle constriction

Increased gastric acid secretion

Dysfunctional release of neurotransmitters

Gas Histamine (H1), histamine (H2), bradykinin Smooth muscle constriction

Increased gastric acid secretion

Abdominal pain Histamine (H1), histamine (H2), bradykinin, serotonin Smooth muscle constriction

Increased gastric acid secretion

Dysfunctional release of neurotransmitters

Nausea/vomiting Histamine (H3), serotonin Dysfunctional release of neurotransmitters
Constipation Histamine (H2), histamine (H3), serotonin (low) Dysfunctional release of neurotransmitters

 

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.