Kounis syndrome

Kounis syndrome is a group of symptoms that manifests as unstable vasospastic or nonvasospastic angina and even as acute myocardial infarction and is triggered by the release of inflammatory mediators following an allergic insult [1]. The name was given by a group of scientists from USA [2] and Greece [3] because Professor Nicholas G Kounis, cardiologist from Greece, was the first to discover that the same inflammatory mediators, released during acute allergic episodes, are also increased in blood or urine of patients suffering from acute coronary syndromes and that a common pathophysiologic pathway exists between hypersensitivity and acute coronary episodes. Taking previously underrated, scattered and rarely diagnosed, clinical phenomena and presenting their pathophysiology, this scientist described in 1991, for the first time, the syndrome of "allergic angina" [4]. Allergic angina could progress to acute myocardial infarction which was named ‘‘allergic myocardial infarction’’ [5–7]. In 1995, Kovanen et al. examined specimens of coronary arteries from 20 patients who had died of acute myocardial infarction and found that the degree of mast cell degranulation was much higher (200 to 1 ratio) at the sites of plaque erosion or rupture than in adjacent areas or in the more distant unaffected areas [8]. He concluded that collagen-degrading proteases, from mast cells, could induce plaque erosion and/or rupture. Following this clinical description, Constantinides [9], in 1995, raised the possibility that ‘‘even ordinary allergic reactions could promote plaque disruption’’. This was based on Constantinides’s observation that circulating mast cell precursors could penetrate the open junctions between endothelial cells that line human atheromatous plaques in contrast to closed junctions over the normal arterial intima [10]. Braunwald [11], in 1998, categorized allergic angina in a subgroup of dynamic coronary occlusion lesions by quoting that ‘‘allergic reactions with mediators such as histamine or leukotrienes acting on coronary vascular smooth muscle’’ can induce vasospastic angina.

Today, allergic angina and allergic myocardial infarction constitute dangerous and life-threatening ubiquitous diseases that affect patients of any age, involve numerous and continuously increasing causes with broadening clinical manifestations, and cover a wide spectrum of mast cell–activation disorders that are referred to as Kounis syndrome. Furthermore, Kounis syndrome has familiarized physicians with these scattered, underrated and until now rarely diagnosed clinical phenomena and has enabled them to correctly diagnose and apply appropriate life saving therapeutic measures [12-17].

Kounis syndrome is defined as "the concurrence of acute coronary syndromes with conditions associated with mast cell activation, involving interrelated and interacting inflammatory cells, and including allergic or hypersensitivity and anaphylactic or anaphylactoid insults." "It is caused by inflammatory mediators such as histamine, neutral proteases, arachidonic acid products, platelet activating factor and a variety of cytokines and chemokines released during the activation process [18,19]. Inflammatory mediators including histamine, neutral proteases, arachidonic acid products, platelet activating factor and a variety of cytokines and chemokines are increased in blood or urine in both allergic episodes and acute coronary syndromes. The release of mediators during allergic insults has been incriminated as a cause of coronary artery spasm and/or atheromatous plaque erosion or rupture. A common pathway between allergic and non-allergic coronary syndromes seems to exist. Today, there is evidence that mast cells not only enter the culprit region before plaque erosion or rupture but they release their contents before an actual coronary episode. Kounis syndrome, as consequence, of the above pathophysiologic association is regarded as nature’s own experiment and magnificent natural paradigm showing novel way in an effort to prevent acute coronary syndromes. It has been shown that the same mediators, released during acute allergic episodes, are increased in blood or urine of patients suffering from acute coronary syndromes of nonallergic etiology [18,19]. Consequently, the same substances from the same cells are present in both acute allergic episodes and acute coronary syndromes. Does, therefore, Kounis syndrome represent a magnificent natural paradigm and nature’s own experiment in a final trigger pathway implicated in cases of coronary artery spasm and plaque rupture? Drugs and natural molecules which stabilize mast cell membrane and monoclonal antibodies that protect mast cell surface could emerge as novel therapeutic modalities capable of preventing acute coronary and cerebrovascular events [20].


Syndrome variants

Type I variant: includes patients with normal coronary arteries without predisposing factors for coronary artery disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm without increase of cardiac enzymes and troponins or coronary artery spasm progressing to acute myocardial infarction with raised cardiac enzymes and troponins

Type II variant: includes patients with culprit but quiescent pre-existing atheromatous disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm with normal cardiac enzymes and troponins or plaque erosion or rupture manifesting as acute myocardial infarction

Type III variant: includes patients with coronary thrombosis (including stent thrombosis) in whom aspirated thrombus specimens stained with hematoxylin-eosin and Giemsa demonstrate the presence of eosinophils and mast cells respectively

Treatment

Give corticosteroids and antihistamines
Give vasodilators such as nitrates and Ca-blockers
Apply acute coronary event protocol and give corticosteroids and antihistamines
Give vasodilators such as nitrates and Ca-blockers when appropriate
The use of mast cell stabilizers in association with steroids and antihistamines are recommended
Harvesting of intrastent thrombus together with histological examination of aspirated material and staining for eosinophils and mast cells should be undertaken.
When allergic symptoms are present following stent implantation, desensitization measures should be applied

It should be borne in mind that:

References

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2. Rich MW. Is vasospastic angina an inflammatory disease? Am J Cardiol. 2005;96:1612

3. Zavras GM, Papadaki PJ, Kokkinis CE, Kalokairinov K, Kouni SN, Batsolaki M, Gouvelou-Deligianni GV, Koutsojannis C. Kounis syndrome secondary to allergic reaction following shellfish ingestion. Int J Clin Pract. 2003 ;57:622-4

4. Kounis NG, Zavras GM. Histamine-induced coronary artery spasm: the concept of allergic angina. Br J Clin Pract 1991; 45:121–8

5. Zosin P, Miclea F, Munteanu M. Allergic myocardial infarction. Rom Med Review 1965;19:26 –8

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8. Kovanen PT, Kaartinen M, Paavonen T. Infiltrates of activated mast cells at the site of coronary atheromatous erosion or rupture in myocardial infarction. Circulation 1995;92:1083–1088

9. Constantinides P. Infiltrates of activated mast cells at the site of coronary atheromatous erosion or rupture in myocardial infarction. Circulatory 1995;92:1083

10. Constantinides P, Harkey M. Electron microscopic exploration of human endothelium in early and advanced atherosclerotic lesions. Ann N Y Acad Sci 1990; 898: 113-124

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12. Kounis NG. Kounis syndrome (allergic angina and allergic myocardial infarction): a natural paradigm? Int J Cardiol 2006; 110:7–14

13. Biteker M. Current understanding of Kounis syndrome. Expert Rev Clin Immunol. 2010; 6: 777-788

14. Lopez PR, Peiris AN. Kounis syndrome. South Med J. 2010; 103: 1148-1155

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16. Ridella M, Bagdure S, Nugent K, Cevik C. Kounis syndrome following beta-lactam antibiotic use: review of literature. Inflamm Allergy Drug Targets. 2009;8:11-6

17. Biteker M, Duran NE, Biteker FS, Civan HA, Kaya H, Gökdeniz T, Yildiz M, Ozkan M. Allergic myocardial infarction in childhood: Kounis syndrome. Eur J Pediatr. 2010;169: 27-9

18. Sakata V, Komamura K, Hirayama A, et al. Elevation of plasma histamine concentration in the coronary circulation in patients with variant angina. Am J Cardiol 1996;77:1121–6.

19. Cuculo A, Summaria F, Schiavino D, et al. Tryptase levels are elevated during spontaneous ischemic episodes in unstable angina but not after ergonovine test in variant angina. Cardiologia 1998; 43:189–93.

20. Kaartinen M, Penttila A, Kovanen PT. Accumulation of activated mast cells in the shoulder region of human coronary atheroma, the prediction site of atheromatous rupture. Circulation 1994;90:1669–78