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Kounis syndrome: Aspects on pathophysiology and management

Published:February 18, 2016DOI:https://doi.org/10.1016/j.ejim.2016.02.001
      We read with the great interest the excellent and concise review of Filippo Fassio et al. [
      • Fassio F.
      • Losappio L.
      • Antolin-Amerigo D.
      • Peveri S.
      • Pala G.
      • Preziosi D.
      • et al.
      Kounis syndrome: a concise review with focus on management.
      ] focused on Kounis syndrome and its treatment. Since the description of this syndrome has paved the possibility for prevention of the progression of coronary plaques to unstable lesions with inhibition of mast cell activation, that has been already achieved experimentally [
      • Nemmar A.
      • Hoet P.H.M.
      • Vermylen J.
      • Nemery B.
      • Hoylaerts M.F.
      Pharmacological stabilization of mast cells abrogates late thrombotic events induced by diesel exhaust particles in hamsters.
      ], we believe that the following observations and additions on its pathophysiology and management would be of value.
      • 1.
        Cardiovascular symptoms and signs associated with allergic, hypersensitivity, anaphylactic or anaphylactoid reactions involving mast cells and interrelated macrophages and T-lymphocytes have been described long before as “morphologic cardiac reactions,” “acute carditis,” or “lesions with basic characteristics of rheumatic carditis [
        • Nemmar A.
        • Hoet P.H.M.
        • Vermylen J.
        • Nemery B.
        • Hoylaerts M.F.
        Pharmacological stabilization of mast cells abrogates late thrombotic events induced by diesel exhaust particles in hamsters.
        ,
        • Clark E.
        Serum carditis: morphologic cardiac alterations in man associated with serum disease.
        ,
        • Wadsworth G.M.
        • Brown C.H.
        Serum reaction complicated by acute carditis.
        ,
        • Rich A.R.
        • Gregory J.E.
        Experimental evidence that lesions with basic characteristics of rheumatic carditis can result from anaphylactic hypersensitivity.
        ]. However, the detailed description of the “allergic angina syndrome” as coronary spasm, which represents a manifestation of endothelial dysfunction or microvascular angina and progresses to allergic acute myocardial infarction, was not described until 1991 [
        • Kounis N.G.
        Coronary hypersensitivity disorder: the Kounis syndrome.
        ].
      • 2.
        Kounis syndrome appears clinically as coronary spasm, acute thrombotic myocardial infarction, and stent thrombosis that can affect cerebral, mesenteric, and coronary arteries [
        • Kounis N.G.
        Coronary hypersensitivity disorder: the Kounis syndrome.
        ]. Coronary thrombosis, in Kounis syndrome, is the result of mediators deriving from mast cells that act on high- and low-affinity IgE receptors FCγRI, FCγTII, FCεRI, and FCεRII situated in platelet surface [
        • Hasegawa S.
        • Tashiro N.
        • Matsubara T.
        • Furukawa S.
        • Ra C.
        A comparison of FcepsilonRI-mediated RANTES release from humanplatelets between allergic patients and healthy individuals.
        ]. This process starts with platelet membrane extensions, known as tethers, that adhere transiently to the abnormal intima in an “on and off and start and stop” fashion via interaction of the glucoprotein Ib receptor with Von Willebrand factor. The tethering is followed by platelet rolling which is the result of interaction between glucoprotein VI receptor and collagen.
        Platelet activation is then taking place via stimulation of receptors for PAF, histamine, and the aforementioned high-affinity and low-affinity IgE receptors. During their activation platelets change shape from discoid to spiculated and release granules which contain, proinflammatory, prothrombotic, adhesive, and aggregatory mediators. Finally, platelet aggregation ensues by binding of glucoprotein IIb/IIIa receptor with fibrinogen and interaction, again, with Von Willebrand factor. Thrombin converts fibrinogen to fibrin which serves as a stable lάttice for the creation of thrombus [
        • Minai-Fleminger Y.
        • Levi-Schaffer F.
        Mast cells and eosinophils: the two key effector cells in allergic inflammation.
        ].
      • 3.
        Clinical and laboratory findings have confirmed that mast cell activation precedes acute coronary events and that mast cells not only enter the culprit lesion before plaque erosion or rupture but also release their contents before an actual coronary event. For example, it has been found that mast cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has already occurred but also the shoulder sites of coronary plaques that are susceptible to erosion or rupture which means they invade before an actual initial event. The same applies also for other inflammatory cells such as macrophages and T lymphocytes. This suggests that inflammatory cells infiltrate the lesions before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes. Furthermore, infiltrates of degranulated mast cells at the site of coronary atheromatous erosion or rupture, in patients who had died within 2 days after an acute coronary event, were found in a ratio of 200 to 1 compared with the nearby normal endothelial segments. It is known that circulating blood contains only mast cell precursors which take several days to weeks to differentiate into morphologically identifiable mast cells filled with cytoplasmic secretory granules [
        • Kovanen P.T.
        • Kaartinen M.
        • Paavonen T.
        Infiltrates of activated mast cells at the site of coronary atheromatous erosion or rupture in myocardial infarction.
        ]. Therefore, the mast cells must already have been present at the erosion or rupture sites ready to degranulate and release their content just before the acute coronary event.
      • 4.
        A challenging issue for the physicians is the ability to predict the risk of Kounis syndrome in patients suffering from allergic or anaphylactic episodes. We had previously suggested that a threshold level of mast cell content (tryptase, chymase, etc.) exists [
        • Kounis N.G.
        Coronary hypersensitivity disorder: the Kounis syndrome.
        ] above which it can provoke coronary artery spasm and/or plaque erosion or rupture. The magnitude of the initial allergic response, the patient's sensitivity, the patient's comorbidity, the site of antibody–antigen reaction, the allergen concentration, and the route of allergen entrance could be some additional factors. According to other reports, patients with increased serum baseline tryptase might have underlying clonal mast cell disorder, either systemic mastocytosis or monoclonal mast cell activation syndrome [
        • Akin C.
        • Scott L.M.
        • Kocabas C.N.
        • Kushnir-Sukhov N.
        • Brittain E.
        • Noel P.
        • et al.
        Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with “idiopathic” anaphylaxis.
        ]. Such patients are prone to developed immediate and severe hypersensitivity reaction to hymenoptera stings. Flow cytometric and KIT mutation analysis has shown, in these patients, mast cells expressing CD2 or CD25 in their surface and KIT mutation at codon 816, respectively. KIT is the mast receptor for the stem cell factor which is essential for mast cell development, proliferation, survival, adhesion, and homing. KIT mutations can lower the stimulus threshold for anaphylaxis, and create hyperresponsive mast cell phenotype resulting in the development of Kounis syndrome.
      • 5.
        Since opioids (codeine, meperidine, and morphine) which are the drugs of choice for the relief of chest pain in acute coronary syndromes could induce massive mast cell degranulation and therefore aggravate such an allergic reaction, attempts have been made to use intravenous paracetamol as an alternative treatment. Although paracetamol (acetaminophen, N-acetyl-para-amino-phenol) is a well-known analgesic and antipyretic drug, its intravenous use in critically ill patients, as patients with Kounis syndrome are, can induce severe hypotension due to reduction of both cardiac output and systemic vascular resistance and aggravate cardiogenic shock [
        • Krajčová A.
        • Matoušek V.
        • Duška F.
        Mechanism of paracetamol-induced hypotension in critically ill patients: a prospectiveobservational cross-over study.
        ]. Therefore, extremely caution should be applied on paracetamol administration in Kounis syndrome. Fentanyl and its derivatives do not affect cardiac output and show slight mast cell activation and are preferable.
      • 6.
        In conclusion, Kounis syndrome seems to be a complex acute coronary syndrome that requires early diagnosis, immediate decisions, and rapid treatment. Following the relieve of the acute shock and coronary event, a full cardiology work-up, including a 12-lead ECG, echocardiogram, and cardiac risk factor modification are necessary. An allergy work-up should be also followed to include the assessment of allergies to drugs, food, insect stings, and other environmental agents. Hematology tests, skin tests, and food challenges may be useful in identifying the culprit agent.

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      Linked Article

      • Kounis syndrome: A concise review with focus on management
        European Journal of Internal MedicineVol. 30
        • Preview
          Kounis syndrome is defined as the co-incidental occurrence of an acute coronary syndrome with hypersensitivity reactions following an allergenic event and was first described by Kounis and Zavras in 1991 as an allergic angina syndrome. Multiple causes have been described and most of the data in the literature are derived from the description of clinical cases – mostly in adult patients – and the pathophysiology remains only partly explained. Three different variants of Kounis syndrome have been defined: type I (without coronary disease) is defined as chest pain during an acute allergic reaction in patients without risk factors or coronary lesions in which the allergic event induces coronary spasm that electrocardiographic changes secondary to ischemia; type II (with coronary disease) includes patients with pre-existing atheromatous disease, either previously quiescent or symptomatic, in whom acute hypersensitive reactions cause plaque erosion or rupture, culminating in acute myocardial infarction; more recently a type-III variant of Kounis syndrome has been defined in patients with preexisting coronary disease and drug eluting coronary stent thrombosis.
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      • Author's reply: Kounis syndrome: Aspects on pathophysiology and management
        European Journal of Internal MedicineVol. 32
        • Preview
          We thank Kounis and coll. for their Letter to the Editor [1] commenting and congratulating for our recently published article “Kounis syndrome: A concise review with focus on management” [2].
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