Kounis Syndrome: A Potential Cause of
Simultaneous Multivessel Coronary Spasm and Thrombosis after Drug-Eluting Stent
Implanta

In the very interesting report¹ and editorial² published in the December 2006 issue of the Journal, the authors reported and commented on 13 patients who developed severe, diffuse coronary artery spasm after drug-eluting stent insertion. Five patients experienced diffuse multivessel spasm. Of these 5 patients, 2 died. The postmortem examination of one of the patients showed a few scattered mast cells in the adventitia of the left anterior descending coronary artery, possibly pointing to a hypersensitivity reaction to the stent components. The stent components currently in use should be considered as potential allergens capable of inducing the Kounis syndrome.³
This syndrome, described 15 years ago, involves the concurrence of acute coronary syndromes with conditions associated with activation of mast cells and interaction with T-cells and macrophages including allergic or hypersensitivity and anaphylactic or anaphylactoid reactions. All these inflammatory cells participate in a vicious inflammatory cycle, and via multidirectional signals, mast cells can enhance T-cell activation, T-cells can mediate mast cell proliferation and activation, inducible macrophage protein-1 can activate mast cells, mast cells can activate macrophages, and T-cells can regulate macrophage activity.³ Histamine, proteolytic enzymes such as tryptase and chymase, arachidonic acid metabolites, and a variety of chemokines and cytokines released during the activation of these interacting and interrelated cells have been incriminated for inducing the Kounis syndrome. The described patients seem to have suffered the type II variant of Kounis syndrome. Type II variant includes patients with culprit but quiescent, preexisting 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.⁴
The first patient in this series had received intravenous corticosteroids and antihistamines for possible anaphylactic reaction. She was also administered a singledose of epinephrine to treat refractory hypotension. It is known that, rarely, corticosteroids can induce allergic reactions and Kounis syndrome.³ Therapeutic epinephrine administration can enhance the endogenous catecholamine release and can have an adverse effect on the myocardium including chest pain and electrocardiographic changes in the absence of coronary stenosis.⁵ On the other hand, it should be emphasized that in a sulfite-allergic patient, epinephrine should be avoided because every commercially available epinephrine preparation contains sodium metabisulfite.⁶ Sodium metabisulfite is a commonly used food and drug preservative. Methoxamine, a potent alpha agonist, should be used as an alternative. Although this patient did not provide any history of sulfite allergy, she was allergic to aspirin. In atopic patients, IgE sensitization to an allergen should not be clinically evaluated on its own, but rather in the possible context of multi-allergen sensitization and exposure.⁷ Clinical studies have shown that allergic patients who are simultaneously exposed to several allergens have more symptoms than monosensitized individuals.⁷
Drug-eluting stent components include the metal stent itself, the polymer coating, and the impregnated drugs which for today are: the antimicrotubule antineoplastic agent paclitaxel for the Taxus^® brand (Boston Scientific Corp., Natick, Massachusetts), and the anti-inflammatory, immunosuppressive and antiproliferative agent rapamycin for the Cypher™ brand (Cordis Corp., Miami, Florida). Other investigative agents such as zotarolimus, everolimus, biolimus, tacrolimus, pimecrolimus, etc., are currently undergoing safety and efficacy trials either impregnated in metal stents or used in transplant recipients in order to prevent rejection. All drug-eluting stent components, either separately or synergistically, seem to be able to induce hypersensitivity reactions and hypersensitivity coronary events. Hypersensitivity inflammation is initiated by allergens cross-bridging their corresponding receptor-bound immunoglobin IgE antibodies on the mast cell or basophil cell surface. These cells degranulate and release their mediators when the critical number of bridged IgE antibodies reaches the order of 2,000 out of a maximal number of some 500,000–1,000,000 IgE antibodies on the cell surface. A recent study showed that IgE antibodies with different specificities can produce an additive effect, and even small amounts of corresponding allergens can trigger mediator release when the patient is simultaneously exposed to them.⁸ This seems to apply to drug-eluting stent components, where sensitization to a component should not be clinically evaluated on its own, but in the context of sensitization and exposure to the other components.
Five of the reported patients developed multivessel coronary artery spasm. There are also reports of simultaneous multivessel acute or subacute drug-eluting stent thrombosis.^9–11 In one of these reports, a patient underwent multivessel bifurcation stent placement after an acute myocardial infarction over a period of 1 week and developed subacute stent thrombosis of the 2 drug-eluting stents in the left anterior descending and the circumflex coronary arteries, leading to death.¹¹ These reports possibly suggest that simultaneous coronary spasm or thrombosis after drug-eluting stent implantation involves a more general pathology resulting from circulating inflammatory mediators. Ideally, in these cases, measurement of the levels of histamine, tryptase, chymase, and arachidonic acid products might shed light on the pathogenesis of these events.
At the present, coronary drug-eluting stents remain safe and effective when used in patients according to the approved indications. However, in atopic patients and in patients who have already experienced a first Kounis syndrome and who are going to undergo DES implantation, we recommend the following: (1) a detailed history of allergies and adverse drug reactions; (2) antibody testing and intradermal skin tests for every stent component where appropriate, monitoring the level of inflammatory mediators immediately after the insertion; (3) macrophage and T-cell activation studies; and (4) consideration of the use of corticosteroids and mast cell stabilizers, since the latter have abrogated late thrombotic events experimentally.¹²

Professor Nicholas G. Kounis, MD, PhD, FESC, FACC
Patras Highest Institute of Education and Technology
Patras, Greece
E-mail: ngkounis@otenet.gr

George N. Kounis, MD, MSc
Patras Highest Institute of Education and Technology

George D. Soufras, MD, PhD
Department of Cardiology, “Saint Andrews” General Hospital
Patras, Greece

References

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