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.

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 3 of 5

Recurrent or perpetual elevation in blood pressure has been observed in multiple studies and may affect up to 31% of patients with mast cell activation disease (systemic mastocytosis, mast cell activation syndrome/disorder, monoclonal mast cell activation syndrome). Despite this high prevalence, many providers continue to believe that this symptom cannot be inherently from mast cell activation.

A number of mast cell mediators are vasoconstrictors, narrowing the blood vessels and elevating blood pressure. Histamine can both increase and lower blood pressure depending on which receptor it acts upon (H1: hypotension; H2: hypertension).

Several mediators participate in the angiotensin-renin pathway. Angiotensin II, the level of which is largely determined by mast cell mediators like renin, strongly elevates blood pressure. Chymase, involved in the angiotensin-renin pathway, can also either increase or lower blood pressure depending on concentration relative to other mediators present. Carboxypeptidase A can also affect angiotensin II level as well. Renin regulates the level of a molecule that becomes angiotensin II and can increase blood pressure this way.

Phospholipases, which help produce the molecule needed to make prostaglandins, leukotrienes and thromboxanes can contribute to either high or low blood pressure depending upon which molecule is made. Prostaglandin D2 (PGD2) is a vasodilator, lowering blood pressure; but its metabolite, 9a,11b-PGF2, increases blood pressure. (Author’s note: I personally believe this to be the reason for the rapid blood pressure fluctuations in mast cell patients, but do not have evidence to directly support this.) Thromboxane A2, a molecule related to prostaglandins and leukotrienes, increases blood pressure, as do leukotrienes.

Management of high blood pressure is complicated in mast cell patients by the interaction of common antihypertensives with mast cell activation. Beta blockers are contraindicated in mast cell patients because they interfere with epinephrine, both naturally produced and medicinally.  Use of beta blockers is a risk factor for fatal anaphylaxis.  Any patient on beta blockers that carries an epipen should also carry a glucagon pen, which can be administered prior to the epipen to increase efficacy.

ACE inhibitors interfere with angiotensin converting enzyme, which increases blood pressure through the angiotensin II pathway.  ACE inhibitors affect bradykinin levels, a mast cell mediator that is also mast cell activating.  For this reason, ACE inhibitors can increase mast cell reactivity and symptoms like angioedema.

Author’s note:  I extended this series to four posts to discuss heart failure in mast cell patients.  Following this series, I will be posting a series dedicated exclusively to Kounis Syndrome, including diagnosis and treatment.  Sit tight!

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.