KS was first described in 1991 by Kounis and Zavras as the simultaneous appearance of acute coronary events and anaphylactic or anaphylactoid allergic reactions.1

In an editorial published in 1998, Braunwald described that vasospastic angina could be induced by allergic reactions, with mediators such as histamine and leukotrienes acting upon the smooth muscle of the coronary arteries.2 In this context, allergic angina and allergic acute infarction have been recognized as KS.3 Even today the syndrome is little known, and most of the available information comes from the description of clinical cases (almost 300 in the literature to date)–mostly corresponding to adults, with some isolated pediatric cases.4 Multiple causes have been described, including drugs, insect stings, foods, environmental exposures and medical conditions, among others.5,6

Recent data from the ARIAM study7 indicate that acute myocardial infarction with transient ST-segment elevation, which probably would include most cases of KS, accounts for 4.6% of all cases of ACS admitted to the Intensive Care Unit (ICU), though only a very small proportion of cases would have KS as the underlying cause.

KS has been divided into two subtypes8:

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  Type I (without coronary disease): chest pain during an acute allergic reaction in patients without risk factors or coronary lesions, in which the allergic event induces coronary spasm that causes chest pain and electrocardiographic changes secondary to ischemia, while the cardiac enzymes may be either normal or reflect progression towards acute myocardial infarction. The explanation for this type would be endothelial dysfunction and/or microvascular angina.

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  Type II (with coronary disease): chest pain during an acute allergic reaction in patients with pre-existing atheroma disease (whether known or otherwise). Acute mediator release in such cases may induce atheroma plaque erosion or rupture, clinically resulting in acute myocardial infarction.

In recent years a third type has been proposed comprising patients with drug-eluting stent thrombosis,9 where Giemsa and hematoxylin–eosin staining reveals the presence of mast cells and eosinophils, respectively.10

To date, three conditions have been related to KS:

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  Takotsubo myocardiopathy11 (stress-induced myocardiopathy affecting the left ventricle, producing hyperkinesia of the ventricle base and hypokinesia of the apex and midzone). These alterations would be caused by the action of inflammatory mediators in the same way as in KS.

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  Coronary vascular disease in allogenic heart transplantation.

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  Hypersensitivity myocarditis. In both cases there is an allergic cause–affecting the coronaries in the case of KS and the heart muscle and conduction system in the case of myocardiopathy. Clinically the two conditions may be indistinguishable–the differential diagnosis requiring magnetic resonance imaging (MRI) and in some cases cardiac biopsy.12

A number of agents can give rise to KS, as reflected in Table 1.

In the case of insect stings and bites (bees and wasps), the venom contains proteins, peptides and vasoactive amines that can cause direct cardiotoxicity but also behave as allergens, with activation of the mast cells.13

In theory, any drug is able to trigger an allergic reaction, and thus potentially may cause KS. In practice, the drug substances most often associated with the syndrome are betalactams, nonsteroidal antiinflammatory drugs (NSAIDs), general anesthetics and iodine contrast media.14–16

Foods (shellfish and kiwi), latex, and snake venom are other potential causes.

As regards the related diseases, mention must be made of mastocytosis, characterized by clonal mast cell proliferation and clinically associated to repeated anaphylactic episodes. The patients show high serum tryptase levels outside the anaphylactic episodes, and the definitive diagnosis is based on the bone marrow biopsy findings.

Foreign bodies can also cause allergic reactions and KS, including conventional or drug-eluting stents.17,18 In a recent review, Chen et al.10 found patients with epicutaneous or patch tests positive for the metal components of the stents (nickel and molybdenum) to have a greater tendency to suffer stent thrombosis than those without such positive tests. On the other hand, new coronary events following drug-eluting stent placement may represent not only a local phenomenon but also a generalized hypersensitivity reaction including the release of mediators capable of inducing thrombotic and/or vasoconstrictive phenomena. The literature describes cases of severe diffuse spasm and simultaneous spasm in several coronary arteries following the implantation of such stents. The induction of coronary spasm in an artery other than the vessel in which the stent has been positioned, as well as multiple thrombosis located not only in the coronary arteries, supports this theory.19 The histological findings in patients who died as a result of stent thrombosis show eosinophilic infiltrates and poor intima healing, and the extracted thrombi are seen to contain neutrophil and eosinophil infiltrates.20 Furthermore, these and other patients receive antiplatelet drugs such as acetylsalicylic acid (ASA) (aspirin) and clopidogrel, which are potentially antigenic.21

Allergens such as foods, insect venom, iodine contrast media or drugs induce mast cell degranulation, resulting in the release locally and into the systemic bloodstream of a number of vasoactive mediators (histamine, leukotrienes, serotonin) and proteases (tryptase, chymase).22

Histamine and the leukotrienes are potent coronary vasoconstrictors, while tryptase and chymase activate the metalloproteinases, inducing collagen degradation and erosion of the atheroma plaque–which in turn initiates the coronary event.

Cardiac histamine acts upon four types of receptors, each of which can contribute to the severity of allergic myocardial damage. The H1 receptors mediate coronary vasoconstriction, while the H2 receptors to a lesser degree intervene in coronary relaxation. The interaction between both receptor activities induces a drop in diastolic blood pressure and an increase in pulse pressure. The H3 receptors in turn inhibit noradrenalin release, while the H4 receptors regulate mast cell, eosinophil and lymphocyte chemotaxis–producing a change in eosinophil shape and favoring molecular adhesion.23 Likewise, histamine can activate platelets, enhance the aggregation response of other agonists such as adrenalin or thrombin,23,24 and reduce tissue factor expression and activity–this enzyme being a key element in the coagulation cascade, favoring the final formation thrombin.

The diagnosis of KS is eminently clinical, and is based on the identification of signs and symptoms suggestive of an acute allergic reaction and a coronary event coinciding in time. The patient presents a coronary syndrome that can manifest as malaise with chest pain of anginal characteristics, and simultaneously also shows symptoms typical of an anaphylactic reaction: hypotension in the context of contact with a known allergen, skin manifestations (rash, urticaria, angioedema), respiratory alterations (dyspnea, wheezing, dysphonia, stridor) and/or digestive disorders (abdominal pain, nausea, vomiting).

Coronary syndrome includes unstable angina with or without evidence of vasospasm and/or acute myocardial infarction, accompanied by electrocardiographic alterations and/or cardiac enzyme elevations. The most frequent symptoms and the electrocardiographic alterations are described in Table 2.

The clinical history is essential for establishing a cause–effect relationship in time with the possible triggering factor. In this sense, and in addition to the usual information, we must explore the possible allergic antecedents of the patient (allergy to latex, fruit, drug substances and situations such as insect stings or the recent use of medications that may have gone unnoticed, such as NSAIDs).

There is no diagnostic test pathognomonic of KS. When the syndrome is suspected, we must do the following:

• 1.

  Electrocardiogram (ECG): Although the most frequent ECG finding is ST-segment elevation in the four anterior and inferior leads, the tracing may be normal or show only nonspecific findings. The right coronary artery is the vessel most often affected by vasospasm, though the reason for this is not clear (Table 2).

• 2.

  Laboratory tests: These tests on one hand are used to assess cardiac damage and are the tests usually requested in the case of patients with ACS (cardiac enzymes, blood count, cholesterol levels, D-dimer), and on the other hand they are used to evidence a possible allergic reaction (levels of tryptase,27 histamine, arachidonic acid products, interleukins, tumor necrosis factor (TNF), complement, eosinophilia, total IgE and specific IgE). The guides recommend the determination of tryptase, histamine, complement, eosinophils and total IgE. Normality of these parameters does not rule out the possibility of a prior allergic reaction.

  According to the Spanish Galaxia guide, tryptase concentration is the most useful parameter for diagnosing anaphylaxis, offering a sensitivity of 73% and a specificity of 98%. These percentages moreover increase if the parameter is evaluated on a serial basis. A minimum of three determinations is recommended: on starting drug treatment immediately after the reaction; two hours after symptoms onset; and again after 24hours. The tryptase levels usually return to normal between 6 and 9hours after the reaction.

  Serum tryptase is a more practical marker of mast cell activity than plasma histamine. This is because the half-life of histamine is 60minutes, with a maximum peak 5–10minutes after the start of the reaction, versus 90minutes in the case of tryptase–a fact that facilitates use of the latter. Measurement of methylhistamine in 24-hour urine also can be performed.

  The absence of specific IgE antibodies or of total IgE elevation does not discard mast cell degranulation, since in principle degranulation occurs when the allergic reaction is mediated by IgE–and this is not always the case.

  Other inflammatory markers such as the leukotrienes and thromboxanes are unable to differentiate this syndrome from a traditional ischemic event, since they show significant elevations in acute myocardial infarction of non-allergic origin.

• 3.

  Echocardiogram: Echocardiography can differentiate the syndrome from other causes of chest pain such as pericarditis or aortic dissection. The echocardiogram reveals segmental contractility alterations in most of the patients; these alterations usually disappear within a few days or weeks, without complications following the acute phase.

• 4.

  Arteriography: This technique may be required to evaluate the coronary anatomy, treat vasospasm with intracoronary drugs, or perform angioplasty where indicated. In those patients in which type II KS is suspected, intracoronary ultrasound also should be performed to identify occult coronary disease.

• 5.

  Vascular biopsy: This technique reveals mast cell infiltration at the site of spasm, in the ruptured plaque, and also in zones susceptible to atheromatosis.28 However, the myocardial biopsy findings are typically normal.

• 6.

  At discharge it is advisable to refer the patient to the specialist for full allergological evaluation.

At present there are no specific clinical practice guides referred to KS, and most of the information on the treatment of this syndrome comes from individual case reports or case series. The indicated management is that specific to ACS and anaphylaxis, with the added complication that the drugs used, while clearly indicated in application to these disorders considered separately, may present contraindications when administered jointly in one same patient. This aspect is particularly relevant in relation to the use of adrenalin. As a result, the treatment of KS merits a series of special considerations, as described below.29

Although some studies have found the prognosis to be better in type I KS, in both types the prognosis depends on the magnitude of the initial allergic reaction, the patient sensitivity, comorbidity, location of the antigen–antibody reaction, the concentration of the allergen, and its penetration route.37

The prognosis is very good beyond the acute phase, during which the patient may develop lung edema, arrhythmias and very rarely thrombi–though death is very rare. Long-term follow-up confirms the good prognosis, with a low incidence of heart failure, and should include an echocardiogram four weeks after patient discharge, to confirm the normalization of left ventricle function.38

Full resolution of the contractility alterations within a matter of weeks is characteristic of the syndrome, and other possible diagnoses must be discarded if such resolution does not occur.

Although no recurrences have been reported, repeat exposure to the allergen could cause a new episode.

KS is underdiagnosed, and further studies are needed to better understand its epidemiology, clinical characteristics and diagnosis, as well as to better define the opportune preventive and therapeutic measures. Treatment of the allergic reaction may suffice in type I syndrome, though in type II KS it is moreover obligatory to treat the ACS through dilatation of the coronary arteries. Vasodilator drugs, including nitrates and calcium antagonists, must be regarded as first line options in this case.

Eduardo Palencia-Herrejon has received economical compensation for teaching and consulting activities from Astra Zeneca, Baxter, Edwards, Lilly, Pfizer and GSK.