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.

 

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.