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| GUEST EDITORIAL |
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| Year : 2014 | Volume
: 60
| Issue : 3 | Page : 227-229 |
Anaphylactic cardiac collapse, sudden death and the Kounis syndrome
NG Kounis1, GD Soufras2, G Hahalis3
1 Department of Medical Sciences, Patras Highest Institute of Education and Technology, Patras 26221, Greece
2 Department of Cardiology, Saint Andrews State General Hospital, Rio, Patras, Greece
3 Department of Cardiology, University of Patras Medical School, Rio, Patras, Greece
| Date of Web Publication | 14-Aug-2014 |
Correspondence Address:
Prof. N G Kounis
Department of Medical Sciences, Patras Highest Institute of Education and Technology, Patras 26221
Greece
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0022-3859.138704
How to cite this article:
Kounis N G, Soufras G D, Hahalis G. Anaphylactic cardiac collapse, sudden death and the Kounis syndrome. J Postgrad Med 2014;60:227-9 |
Sudden death is a contemporary plague and accounts for more than 300,000 deaths every year in the United States [1] and for 275,000 deaths in Europe. [2] Frequently sudden death is attributed to cardiac involvement but there are other causes of sudden death, which are not anticipated. The identification of those in the population who are at higher risk of sudden death remains a major challenge for the physicians because half of the victims are asymptomatic. Sudden death is occasionally associated with anaphylactic shock and its early diagnosis is lifesaving. The heart and coronary arteries in particular, seem to be primarily affected in anaphylaxis. [3] Measurement of eosinophils and mast cells in coronary arteries and in other organs such as spleen combined with serum tryptase measurement could diagnose anaphylaxis and anaphylactic death with a high degree of certainty. Since anaphylactic death cannot be diagnosed by autopsy alone and counting mast cells in the lung and airways have failed to give consistent results, the search for other tissues infiltrated by allergic inflammatory cells could prove of paramount importance in diagnosing anaphylactic sudden death. Physicians should pay attention on this matter.
| :: Eosinophis, Mast Cells and Basophils in Anaphylaxis | |  |
Eosinophils are bone marrow-derived granulocytic leukocytes, which normally reside in tissues and express H4 histamine receptors. They are not normally found in extravascular tissue compartments and migrate there, only during late-phase allergic responses. Mast cells are also bone marrow deriving cells and enter the systemic circulation as mononuclear cell precursors that express messenger ribonucleic acid for stem cell factor and have KIT receptors for the stem cell factor. They migrate into all the tissues, including the brain, which does not suffer from allergic reactions because immunoglobulin E antibodies do not cross the blood-brain barrier and they differentiate and mature there. This process takes several days to weeks. On contrary basophils develop in bone marrow from granulocyte cell precursors and entering the circulation only when are fully matured. Eosinophils, mast cells and basophils are important effector cells in the allergic response and they have been implicated in the pathogenesis of anaphylaxis. Histamine H4 eosinophil receptors facilitate eosinophil chemotaxis toward mast cells, which are the major producers of histamine. Eosinophils respond to histamine in changing cell shape, up-regulation of adhesion molecules and chemotaxis and these responses are mediated by the H4 receptor expressed on eosinophils. The role of mast cells in anaphylactic reactions has been classically confined to its early/acute phase, whereas the late/chronic phase of allergic inflammation is usually attributed to the effects of infiltrating eosinophils and leukocytes including basophils. Both mast cells and eosinophils co-exist in high numbers in the inflamed tissue during the late/chronic stages of allergic inflammation and are highly likely to interact with each other by numerous and complex pathways. [4] There are bidirectional interactions between mast cells and eosinophils which stimulate each other's functions and probably perpetuate an allergic event. [5],[6] Soluble mediators secreted by mast cells and eosinophils modulate reciprocal interactions between these cells in the so-called "allergic effector unit". [4] Basic proteins and lipid mediators of eosinophils have been found to activate mast cells and mast cell mediators and metabolites were shown as eosinophil stimulators. [6] Therefore, blood borne inflammatory cells and in particular, eosinophils, mast cells and basophils are recruited into particular inflamed tissues while the anaphylactic inflammatory response progresses. Lung and spleen tissues are easily infiltrated by the above inflammatory cells. The heart and especially the coronary arteries are also targets of anaphylaxis [3] and the question which arises is: Are the coronary arteries infiltrated by allergic inflammatory cells during an anaphylactic insult?
| :: Anaphylaxis and Anaphylaxis-Associated Kounis Syndrome | | |
It is well-known that allergy, hypersensitivity and anaphylaxis can affect the coronary arteries and induce the Kounis hypersensitivity associated acute coronary syndrome. [7],[8] This syndrome is a combination of acute coronary syndromes with conditions associated with mast cell activation, involving interrelated and interacting inflammatory cells, such as macrophages ans T-lymphocytes and includes anaphylactic or anaphylactoid and allergic or hypersensitivity insults. It is caused by preformed and newly synthesized inflammatory mediators released during the anaphylactic process. A subset of platelets bearing FCγRI, FCγRII, FCεRI and FCεRII receptors are also involved in the activation cascade. [9]
Three variants of Kounis syndrome have been described so far: In type I variant coronary spasm, in normal or nearly normal coronary arteries, associated with anaphylactic reaction can progress to myocardial infarction. In type II variant culprit but quiescent pre-existing atheromatous disease combined with anaphylactic reaction can result in acute myocardial infarction. In type III variant, hypersensitivity to any implanted intracoronary stent components can result in devastating intrastent thrombosis.
Therefore, anaphylaxis can affect the coronary arteries and coronary artery involvement manifesting as coronary spasm and/or acute myocardial infarction are the main causes leading to sudden death due to deadly cardiac arrhythmias and in particular ventricular fibrillation. [10],[11]
| :: Kounis Syndrome: The Primary Cause of Anaphylactic Shock? | | |
So far, it is believed that, during anaphylactic episodes, the main contributors to coronary hypoperfusion leading to myocardial damage, are systemic vasodilatation, reduced venous return, leakage of plasma and volume loss due to increase vascular permeability and diminished cardiac output. However, in experimental anaphylaxis with ovalvumin sensitized guinea pigs [12],[13] soon after administration of antigen the left ventricular end diastolic pressure rises significantly indicating pump failure, the arterial blood pressure rises also significantly and the cardiac output decreases by 90%. In these experiments, contemporary electrocardiograms showed acute myocardial ischemia. It was concluded that the rapid increase in left ventricular end diastolic pressure suggests that decreased venous return and volume loss due to an increase of vascular permeability are unlikely to be the primary causes of the documented depression of cardiac output and the view that the registered anaphylactic damage might be due to peripheral vasodilation can be definitely excluded. Although differentiating global myocardial hypoperfusion from a primary cardiac myocardial suppression due to mast cell mediator action is clearly challenging, combined myocardial suppression and peripheral vasodilatation, seem to occur simultaneously.
In the clinical setting, there are reports [14],[15] according to which patients with anaphylactic cardiac shock do not respond to fluid replacement but needed anti allergic and current myocardial infarction protocol treatment thus denoting that the heart and especially the coronary arteries are primarily affected. Therefore, the coronary arteries should be always searched in any case of anaphylactic death.
| :: Diagnosis of Anaphylactic Death | | |
Diagnosing the cause of sudden death is challenging task but anaphylaxis is rarely suspected. Frequently, sudden death cases are attributed to myocardial involvement but unrecognized anaphylaxis may accompany up to 13% of sudden unexpected deaths in adults. [16] However, anaphylaxis is frequently associated with myocardial involvement due to coronary artery spasm and thrombosis manifesting as Kounis type I and Kounis type II variant. There are reports of sudden death due to coronary artery spam in which the coronaries are involved. In a patient with repeated episodes of coronary spasm, who died suddenly following cessation of his treatment, the number of adventitial mast cells was found increased. [17] In this patient, histologic sections in all three major coronary arteries including the area of spasm were stained with toluidine blue and showed increased mast cells. In the same report, two additional subjects with sudden cardiac death had also increased mast cell in their coronaries with the highest counts in the atherosclerotic and hemorrhagic plaques. Furthermore, coronary arteries of cardiac patients are hyperreactive and contain stores of amines deriving from inflammatory cells that are the main culprits in inducing coronary spasm. [18] Type I and type II variants of Kounis syndrome have led to coronary artery spasm and sudden death in two patients with drug-eluting stents. It is known that drug-eluting stent components include the metal strut, which is made from stainless steel containing nickel, the polymer coating and the eluted drugs all of which have antigenic properties. [19] In these patients, histological examination of left anterior descending coronary artery and Giemsa stain for mast cells with positive control showed a few scattered mast cells in the tunica adventitia. [20],[21] In the present issue of the journal, Venkatesan P et al. have reported a case of acute myocardial infarction following the intravenous administration of tissue plasminogen activator. [22] They also state that it is unlikely to be Kounis syndrome. The proof of Kounis syndrome would lie in the histological examination of the heart and especially of coronary arteries could reveal the presence of inflammatory cells such as mast cells and eosinophils, which would help in elucidating the cause of sudden death.
| :: Conclusion | | |
Clinical and experimental evidence indicates that, during sudden anaphylactic death the heart and especially the coronary arteries are the primary target. We believe that Kounis syndrome, type I and type II variants should be always suspected in any case of sudden death and histological examination of the heart and coronary arteries with staining for eosinophils and mast cells should be always performed.
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