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Coronary Hypersensitivity Disorder: The Kounis Syndrome
Clinical Therapeutics/Volume 35, Number 5, 2013 · Atopic Clinical Entities Update
Review Article
Coronary Hypersensitivity Disorder: The Kounis Syndrome Nicholas G. Kounis, MD, PhD Department of Medical Sciences, Patras Highest Institute of Education and Technology, Patras, Greece ABSTRACT Background: When allergy or hypersensitivity and anaphylactic or anaphylactoid insults lead to cardiovascular symptoms and signs, including acute coronary events, the result might be the recently defined nosologic entity Kounis syndrome. Vasospastic allergic angina, allergic myocardial infarction, and stent thrombosis with occluding thrombus infiltrated by eosinophils and/or mast cells are the 3 reported variants of this syndrome. Objective: The purpose of this review was to highlight and consolidate the recent literature on allergic angina and allergic myocardial infarction and to propose new therapeutic modalities for stabilizing mast cells. Methods: A search for current literature on the pathophysiology, causality, clinical appearance, variance, prevention, and treatment of Kounis syndrome was conducted. Results: Kounis syndrome is caused by inflammatory mediators such as histamine; neutral proteases, including tryptase, chymase, and cathepsin-D; arachidonic acid products; platelet-activating factor; and a variety of cytokines and chemokines released during the mast-cell activation. Platelets with Fc ␥ receptor (Fc␥R) ⌱, Fc␥RII, FcRI, and FcRII also have a role in the activation cascade. The same mediators released from the similar inflammatory cells are involved in acute coronary events of nonallergic etiology. These cells are not only present in the involved region before plaque erosion or rupture but also release their contents just before an acute coronary event. Pro-inflammatory mediators similar to those found in Kounis syndrome are found in some cases with nonallergic etiology, suggesting that this is a more general problem. The acute coronary and cerebrovascular events in Kounis syndrome may be prevented by the inhibition of mast-cell degranulation. Substances and natural molecules that protect the mast-cell surface and stabilize the mast-cell membrane are emerging as novel agents in the prevention of acute coronary and other arterial events.
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Conclusions: The 3 reported variants of Kounis syndrome—vasospastic allergic angina, allergic myocardial infarction, and stent thrombosis with occluding thrombus—are caused by inflammatory mediators. Agents that inhibit mast-cell degranulation may be efficacious in preventing the acute coronary and cerebrovascular events of Kounis syndrome. (Clin Ther. 2013; 35:563–571) © 2013 Elsevier HS Journals, Inc. All rights reserved. Key words: acute coronary events, inflammatory mediators, Kounis syndrome, mast-cell stabilizers.
INTRODUCTION The first reports associating cardiovascular symptoms and signs with hypersensitivity and anaphylactic insults were published ⬎6 decades ago.1–3 However, a detailed description of the allergic angina syndrome, which could progress to acute allergic myocardial infarction, was not described until 1991.4 Today, allergic angina and allergic myocardial infarction are 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.5– 8
DEFINITION Kounis syndrome is defined as the concurrence of acute coronary syndromes such as coronary spasm, acute myocardial infarction, and stent thrombosis, with conditions associated with mast-cell and platelet activation involving interrelated and interacting inflammatory cells in the setting of allergic or hypersensitivity and anaphylactic or anaphylactoid insults. It is caused by inflammatory mediators such as histamine, neutral Accepted for publication February 25, 2013. http://dx.doi.org/10.1016/j.clinthera.2013.02.022 0149-2918/$ - see front matter © 2013 Elsevier HS Journals, Inc. All rights reserved.
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Clinical Therapeutics proteases, arachidonic acid products, platelet-activating factor (PAF), and a variety of cytokines and chemokines released during the activation process.6,8 –10 A subset of platelets bearing Fc ␥ receptor (Fc␥R) I, Fc␥RII, FcRI, and FcRII are also involved in the activation cascade.11 All of these inflammatory cells participate in an inflammatory cycle and activate each other via multidirectional signals. Recently, Kounislike syndromes that affect the cerebral12 and mesenteric arteries13 have been described. It is anticipated that the heart and the entire arterial system is vulnerable to allergic, hypersensitivity, anaphylactic, and/or anaphylactoid events.
PATHOPHYSIOLOGY The main inflammatory cells—the mast cells—interact with other macrophages and T lymphocytes to cause Kounis syndrome. Mast cells can activate macrophages14,15 and may enhance T-cell activation.16,17 Inducible macrophage protein 1a may activate mast cells,18 while CD169⫹ macrophages activate CD8 T cells.19 T cells may mediate mast-cell activation and proliferation20,21 and regulate macrophage activity.22 Although mast cells are numerically a minority in this inflammatory cascade, they influence decisively the inflammatory process. During hypersensitivity, degranulation of mast cells takes place and a variety of stored and newly formed inflammatory mediators are released locally and into the systemic circulation. These mediators include biogenic amines such as histamine, chemokines, enzymes such as the neutral proteases chymase, tryptase, cathepsin-D, peptides, proteoglycans, cytokines, growth factors and arachidonic-acid products such as leukotrienes, thromboxane, prostacyclin, PAF, and tumor necrosis factor ␣. Most of these mediators have important cardiovascular activity. Histamine induces coronary vasoconstriction, induces tissue factor expression, and activates platelets. All 3 neutral proteases can activate matrix metalloproteinases, which can degrade the collagen cap and induce plaque erosion and rupture.23 Tryptase exerts a dual action on the coagulation cascade with both thrombotic and fibrinolytic properties.24 Furthermore, chymase and cathepsin-D might act as enzymes to convert angiotensin I into angiotensin II, a major vasoconstricting substance.25 Leukotrienes are also powerful vasoconstrictors, and their biosynthesis is enhanced in the acute phase of unstable angina.26,27 Thromboxane is a potent mediator of platelet aggrega-
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tion and has vasoconstricting properties,28,29 and PAF, in myocardial ischemia, acts as a proadhesive signaling molecule via the activation of leukocytes and platelets to release leukotrienes or as a direct vasoconstrictor.30
CAUSALITY Several causes have been described to induce Kounis syndrome, and their number is increasing rapidly. These causes include various drugs, environmental exposures, and several conditions. The most recently described offenders are the scombroid syndrome31 (also called histamine fish poisoning) and exposure to gelatin succinylated/sodium chloride/sodium hydroxide (Gelofusine),32 latex,33 or the drug losartan34 in those who are hypersensitive or allergic. Fish flesh contains the amino acid histidine, and when fish infected with gram-negative bacteria containing the enzyme histidine decarboxylase is ingested, then this enzyme converts histidine into histamine, which may induce Kounis syndrome. Gelofusine is a bovine gelatin administered to maintain intravascular volume. Gelofusine is a component of various vaccines for children and constitutes the main cause of sensitization in children. Exposure to such allergens may occur directly or through the saliva of people (eg, kissing)35 or pets (eg, licking by dogs).36
CLINICAL MANIFESTATIONS The main clinical symptoms and signs of Kounis syndrome are associated with subclinical, clinical, acute, or chronic allergic reactions accompanied by cardiac symptomatology. A variety of ECG changes, ranging from ST-segment elevation or depression to any degree of heart block and cardiac arrhythmias, may be observed resembling digitalis intoxication. A high index of suspicion regarding this syndrome is of paramount importance. Although it is not a rare disease, its diagnosis is spare and easily overlooked.37 Kounis syndrome is becoming increasingly encountered in clinical practice, and it is anticipated that many more causative factors will be implicated in the future. Kounis syndrome has mostly been reported in southern Europe, especially in Spain, Italy, Greece, and Turkey. This geographic variation could be attributed to increased awareness of physicians of the existence of Kounis syndrome; climate and environmental conditions resulting in pollen cross-reactivity; and hymenoptera exposures, overconsumption of medicines, and/or inadequacy of preventative measures.8 Kounis syndrome has been re-
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N.G. Kounis ported in association with a mutation in E148q, the gene of familial Mediterranean fever.38
KOUNIS SYNDROME AND STENT THROMBOSIS The life-saving implantation of coronary stents has become the most frequently performed therapeutic procedure in medicine.39 Two kinds of stents are used— drug-eluting stents and bare-metal stents, which have a platform made of stainless steel (a combination of nickel, chromium, titanium, manganese, and molybdenum). The currently used, or second-generation, drug-eluting stents carry the misleading term cobaltchromium or platinum-chromium stents but have platforms that contain nickel and other metals. These stents are covered with polymer coatings that serve as drug carriers and permit controlled drug release. The released drugs have antiproliferative properties and include the everolimus and zotarolimus substances that inhibit the mammalian target of rapamycin and prevent re-endothelialization, thus avoiding the need for restenosis. A randomized clinical trial reported an incidence of 0.2% to 0.5% per year, with a death rate up to 40%.40 The stented and thrombotic areas may be infiltrated by inflammatory cells, including eosinophils, macrophages, T cells, and mast cells.9 That is why the author has insisted that stent thrombosis is mainly a manifestation of Kounis syndrome.41 Allergic inflammation goes through 3 phases.42
VARIANTS OF KOUNIS SYNDROME Three variants of Kounis syndrome have been described8: the type I variant includes normal or nearly normal coronary arteries without risk factors for coronary artery disease, and with the acute release of inflammatory mediators that may induce either coronary artery spasm without increased cardiac enzymes and troponins or coronary artery spasm progressing to acute myocardial infarction with raised cardiac enzymes and troponins. The type II variant includes culprit but quiescent preexisting atheromatous disease in which the acute release of inflammatory mediators may induce either coronary artery spasm with normal cardiac enzymes and troponins or coronary artery spasm together with plaque erosion or rupture manifesting as acute myocardial infarction. The type III variant includes coronary artery stent thrombosis in which aspirated thrombus specimens stained with he-
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matoxylin-eosin and Giemsa demonstrate the presence of eosinophils and mast cells, respectively.
Innate Release of Pro-inflammatory Molecules Pro-inflammatory mediators similar to those found in Kounis syndrome are found in some cases with nonallergic etiology, suggesting that this is a more general problem.
Histamine Increased histamine levels in the great cardiac vein have been reported in patients with attacks of variant angina without correlation with an allergic event.43 One study reported that the blood histamine concentration associated with enhanced oxidative stress in patients with nonallergic acute coronary syndromes was ⬎2-fold that in age- and sex-matched controls.44 In another report, the blood histamine level was significantly greater in patients with various types of nonallergic-etiology ischemic heart disease, such as unstable angina and acute myocardial infarction, compared with that in healthy control subjects.45
Tryptase Persistent tryptase elevation has been detected in patients with nonallergic acute coronary syndromes, with a higher concentration in a subgroup with ST-segment depression, both in the acute phase and at follow-up.46 In another report, serum tryptase and chymase concentrations were greater in a group with nonallergic acute myocardial infarction and unstable angina pectoris than in a group without substantial coronary disease.47 Elevated tryptase levels have been observed in patients with nonallergic significant chronic coronary artery disease as a result of chronic low-grade inflammatory activity present in the atherosclerotic plaques.48 In a group with unstable angina, the tryptase level was 5-fold higher after 5 minutes, 10-fold higher after 15 and 60 minutes, and 2-fold lower in the symptom-free period immediately after the onset of chest pain with ECG signs of ischemia.49
Arachidonic Acid Products Concentrations of thromboxane and leukotrienes were significantly greater in nonallergic patients with unstable angina than in patients with stable angina and in patients with nonischemic chest pain.50 Thromboxane and leukotriene concentrations in the systemic arterial circulation have been reported to be significantly higher in the acute stage of nonallergic myocardial infarction than in the circulation of normal controls.51
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Interleukin-6 Levels of interleukin-6, derived from inflamed coronary plaques and areas of myocardial necrosis, are reported to have been elevated in patients with nonallergic acute coronary syndromes.52,53
Is the Release of Allergic Inflammatory Mediators the Cause of an Acute Coronary Event, or the Result of Damaged and Inflamed Myocardial Tissue After the Acute Coronary Event? Clinical findings have supported that inflammatory 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 acute coronary event. It has been reported that mast cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred, but also the shoulder sites of coronary plaques susceptible to erosion or rupture, which means they invade before an acute initial event.54 The same applies also for other inflammatory cells, such as macrophages and T lymphocytes, suggesting that inflammatory cells infiltrate the lesions before erosion or rupture and that they are not a part of an inflammatory response to rupture initiated by other processes. In patients who had died within 2 days after an acute coronary event, infiltrates of degranulated mast cells at the site of coronary atheromatous erosion or rupture were found in a ratio of 200:1 compared with the nearby normal endothelial segments.55 Circulating blood contains only mast-cell precursors, which require several days or weeks to differentiate into morphologically identifiable mast cells filled with cytoplasmic secretory granules.56,57 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. In another report,50 concentrations of arachidonic acid products, such as leukotrienes and thromboxane, were significantly greater in patients with unstable angina than in patients with stable angina and in patients with nonischemic chest pain. Stress test–induced myocardial ischemia in the patients with stable angina was not accompanied by any change in leukotriene or thromboxane concentrations up to 6 days after a positive exercise-test result. The investigators in that report concluded that this lack of change in leukotriene and thromboxane concentrations rules out a role of ischemia per se in the induction of increased eicosanoid products.
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Histamine concentration in the great cardiac vein was reported to have been elevated in 8 of 11 patients with variant angina attacks43 and in 0 of 8 control subjects. In the same patients, the investigators did not observe any histamine elevation during or after acetylcholine-induced coronary artery spasm, suggesting that histamine was present in the aforementioned 8 patients to induce the variant angina attacks. In contrast, elevation of plasma histamine levels was antecedent to the angina attacks in 3 patients. In addition, high levels of histamine were observed even in the absence of ST-segment elevation in the same group of patients. Tryptase levels were elevated during spontaneous ischemic episodes in patients with unstable angina,49 but not after ergonovine-induced ischemia in patients with variant angina, suggesting that a primary, yet-unknown stimulus activates mast cells in patients with episodes of unstable angina.
Is the Ischemic Myocardial Damage a Primary Event During Anaphylactic Events? In the author’s view, the heart may be the primary site and target of anaphylaxis resulting in the development of Kounis syndrome.58 So far it is believed that, during anaphylactic episodes, systemic vasodilatation, reduced venous return, leakage of plasma, and volume loss due to increased vascular permeability, and the ensuing depression of cardiac output, contribute to coronary hypoperfusion with subsequent myocardial damage. However, differentiating global myocardial hypoperfusion from a primary cardiac myocardial suppression due to mast-cell mediator activity is clearly challenging. Combined myocardial suppression and peripheral vasodilatation may occur simultaneously. In an experimental model of anaphylaxis in ovalvumin-sensitized guinea pigs,59 it was reported that soon after antigen administration, ECG showed signs of acute myocardial ischemia; the left ventricular enddiastolic pressure was increased significantly, indicating pump failure; the arterial blood pressure was also increased significantly; and cardiac output was decreased by 90%. The blood pressure started declining steadily after 4 minutes. It was concluded that the rapid increase in left ventricular end-diastolic pressure suggested that decreased venous return and volume loss due to an increase in vascular permeability were unlikely to have been the primary causes of the documented depression in cardiac output, and the view that the registered anaphylactic damage might be due to peripheral
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N.G. Kounis vasodilation was definitively excluded. In isolated guinea pig hearts undergoing anaphylaxis after an intra-aortic injection of antigen, a prompt and prolonged decrease in coronary blood flow, an abrupt heart rate increase that peaked within 2 minutes, and a transient increase in ventricular contractile force, followed by a prolonged decrease, were observed.8 These findings are in accordance with those from other reports that anaphylactic cardiac damage may be dissociated temporarily into 2 sets of events: (1) initial primary cardiac reaction caused by the intracardiac release of histamine and (2) a subsequent cardiovascular reaction secondary to the systemic release of mediators.60 In the clinical setting, there are reports according to which patients with anaphylactic cardiac shock did not respond to fluid replacement but recovered with current protocol for myocardial infarction and antiallergy treatment, thus denoting that the heart is primarily affected.32,61
Why Kounis Syndrome Occurs Less Often Than Do Allergic, Hypersensitivity, and Anaphylactic Events The author has suggested that a threshold level of mast-cell content (eg, tryptase, chymase) exists,10 above which coronary artery spasm and/or plaque erosion or rupture is induced. Furthermore, the magnitude of the initial allergic response, the patient‘s sensitivity, the patient‘s comorbidities, the site of antibody–antigen reaction, the allergen concentration, and the route of allergen entrance may represent additional factors. Indeed, recent reports have suggested that patients with increased serum baseline tryptase are at a greater risk for immediate and severe hypersensitivity reaction to hymenoptera sting.62 Such patients were reported to have had underlying clonal mast-cell disorder— either systemic mastocytosis or monoclonal mast-cell activation syndrome.63 In these patients, bone marrow aspiration showed mast-cell aggregates and spindle-shaped mast cells. Flow-cytometric analysis of mast cells revealed mast cells expressing CD2 or CD25 on their surfaces, and on KIT mutation analysis, KIT mutation at codon 816 was found. KIT is the mast receptor for the stem-cell factor that is essential for mast-cell development, proliferation, survival, adhesion, and homing. Therefore, patients with an elevated baseline serum tryptase concentration or KIT mutations may have a lower stimulus threshold for anaphylaxis, as well as a
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hyper-responsive mast-cell phenotype,64 resulting in the development of Kounis syndrome. The following additional findings support the existence of Kounis syndrome. Common allergic symptoms such as allergic rhinoconjunctivitis and wheezing were reported to have been significantly associated with an increased risk for ischemic heart disease (IHD) in the National Health and Nutrition Survey III on noninstitutionalized civilian population in the United States, 1988 –1994.65 In another report, eosinophil counts were significantly increased in patients with vasospastic angina pectoris and might predict the severity of the disease. After medical treatment and relief of chest symptoms, the eosinophil count was decreased significantly to the same level as those in a control group.66 In clinical reports, the absolute number of eosinophils and the eosinophil:leukocyte ratio in the peripheral blood were significantly elevated in patients with coronary artery disease.67 Coronary vasospasm associated with eosinophilia has been reported to respond poorly to conventional vasodilator treatment and, although the risk for recurrence of coronary events is high, the majority of patients responded to treatment that suppressed eosinophilia, such as corticosteroids.68 Subcutaneous allergen-specific immunotherapy for immunoglobulin E–mediated allergic diseases has been associated with lower risks for acute myocardial infarction and autoimmune disease.69 Air pollution has been associated with an increased incidence of deaths from cardiovascular disease70 and Kounis syndrome.71 The use of inhaled corticosteroids has been associated with a reduced risk for myocardial infarction in patients with asthma and in particular in those with more severe disease.72 In reports on several experimental models, diesel exhaust particles triggered mast-cell degranulation and histamine release.73
TREATMENT Treatment of Kounis syndrome is challenging because it needs to address both cardiac and allergic symptoms simultaneously, and the drugs administered may worsen the allergy and aggravate heart function.74 In patients with the type I variant, treatment of the allergic event alone may abolish symptoms. The use of hydrocortisone 1 to 2 mg/kg/d IV and H1 and H2 antihistamines, such as diphenhydramine (1–2 mg/kg) and ranitidine (1 mg/kg), is adequate. The administration of vasodilators such as calcium channel blockers and nitrates may abolish hypersensitivity-induced vasospasm. However, nitroglycerine
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Clinical Therapeutics may cause hypotension and tachycardia, which may further complicate allergic reactions. In patients with the type II variant, treatment should be started with an acute coronary event protocol, together with corticosteroids and antihistamines. Vasodilators such as nitrates and calcium channel blockers are given when appropriate. However, the administration of -blockers may exaggerate coronary spasm due to unopposed activity of ␣-adrenergic receptors. Epinephrine, which is the drug of choice and may save lives in anaphylaxis, may aggravate ischemia and worsen coronary vasospasm in Kounis syndrome. In severe cases, sulfite-free epinephrine given intramuscularly is preferable because it has a faster onset of action and maintains a more stable concentration compared with the subcutaneous route (recommended IM dose, 0.2– 0.5 mg [1:1000]). Aqueous solution is preferable. In patients with a history of IHD who receive -blockers, epinephrine may be ineffective. It may also induce more vasospasm due to an unopposed ␣-adrenergic effect. Glucagon may be considered. Opioids such as morphine, codeine, and meperidine given to relieve acute chest pain should be administered with extreme caution in patients with Kounis syndrome because they may induce massive mast-cell degranulation and aggravate allergic reaction. Acetaminophen (paracetamol) is not recommended, especially by intravenous administration, because it might cause severe hypotension due to a reduction in cardiac output. Fentanyl and its derivatives are weak mast-cell triggers. In patients with the type III variant, the current acute myocardial infarction protocol, together with urgent aspiration of intrastent thrombus, followed by histologic examination of aspirated material and staining for eosinophils (hematoxylin and eosin) and mast cells (Giemsa) should be undertaken. In patients in whom allergic symptoms develop after stent implantation, the administration of antihistamines together with corticosteroids and mast-cell stabilizers may relieve the symptoms. If symptoms persist, the underlying cause should be ascertained and desensitization measures should be applied. If these measures fail, stent extraction seems unavoidable.75 Unfortunately, these are not clinically effective. The medical literature abounds with the earlier-mentioned reports that the same mediators deriving from similar cells and capable of inducing arterial spasm and atheromatous plaque erosion and rupture are found in both allergic and nonallergic acute coronary events. One treatment option might be
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the prevention of the coronary plaque from becoming unstable using inhibition of mast-cell degranulation, which has been already achieved experimentally.73,76 Recently, mast-cell inhibitors—specifically, the mast-cell stabilizer disodium cromoglycate (cromolyn), was reported not to inhibit human mast cells.77,78 However, the flavonoid quercetin was reported to have been more efficacious than cromolyn in blocking mast-cell cytokines in humans.79 This potential option is promising in the effort to prevent Kounis syndrome. A dietary supplement containing a combination of mast-cell inhibitors and natural flavonoids80 may be another option.
CONCLUSIONS The 3 reported variants of Kounis syndrome—vasospastic allergic angina, allergic myocardial infarction, and stent thrombosis with occluding thrombus— are caused by inflammatory mediators. Agents that inhibit mast-cell degranulation may be efficacious in preventing the acute coronary and cerebrovascular events of Kounis syndrome.
ACKNOWLEDGMENTS Dr. Kounis was responsible for the literature search, data interpretation, figure creation, and writing of the manuscript.
CONFLICTS OF INTEREST The author has indicated that he has no conflicts of interest with regard to the content of the article.
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population. Atherosclerosis. 2011; 215:494 – 499. Deliargyris EN, Upadhya B, Sane DC, et al. Mast cell tryptase: a new biomarker in patients with stable coronary artery disease. Atherosclerosis. 2005;178:381–386. 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 –193. Takase B, Maruyama T, Kurita A, et al. Arachidonic acid metabolites in acute myocardial infarction. Angiology. 1996;47:649 – 661. Cipollone F, Ganci AA, Greco M, et al. Modulation of aspirin in sensitive eicosanoid biosynthesis by 6-methylprednisolone in unstable angina. Circulation. 2003;107:55– 61. Deliargyris EN, Raymond RJ, Theoharides TC, et al. Sites of interleukin-6 release in patients with acute coronary syndromes and in patients with congestive heart failure. Am J Cardiol. 2000;86:913–918. Huang M, Pang X, Karalis K, et al. Stress-induced interleukin-6 release in mice is mast cell-dependent and more pronounced in Apolipoprotein E knockout mice. Cardiovasc Res. 2003;59:241–249. 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 –1678. 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. Irani AA, Nilsson G, Miettinen U, et al. Recombinant human stem cell factor stimulates differentiation of mast cells from dispersed human fetal liver cells. Blood. 1992;80: 3009 –3021.
57. Valent P, Spanbloshe E, Sperr WR, et al. Induction of differentiation of human mast cells from bone marrow and peripheral blood mononuclear cells by recombinant human stem cell factor (CSF)/kit ligand (KL) in long-term culture. Blood. 1992;80:2337–2245. 58. Kounis NG, Davlouros P, Hahalis G, et al. The heart seems to be the primary site and the target of anaphylaxis resulting in the development of Kounis syndrome. Intern Emerg Med. 2012;7(Suppl 2):S119 – S120. 59. Felix SB, Baumann G, Berdel WE. Systemic anaphylaxis separation of cardiac reactions from respiratory and peripheral vascular events. Res Exp Med. 1990;190:239 –252. 60. Zavecz JH, Levi R. Separation of primary and secondary cardiovascular events in systemic anaphylaxis. Circ Res. 1977;40:15–19. 61. Kajander OA, Virtanen MP, Sclarovsky S, et al. Iatrogenic inverted takotsubo syndrome following intravenous adrenaline injections for an allergic reaction. Int J Cardiol. 2012 Oct 15. [Epub ahead of print] 62. Bonadonna P, Perbellini O, Passalacqua G, et al. Clonal mast cell disorders in patients with systemic reactions to Hymenoptera stings and increased serum tryptase levels. J Allergy Clin Immunol. 2009;123:680 – 686. 63. Akin C, Scott LM, Kocabas CN, et al. Demonstration of an aberrant mastcell population with clonal markers in a subset of patients with ‘idiopathic’ anaphylaxis. Blood. 2007; 110:2331–2333. 64. Metcalfe DD, Schwartz LB. Assessing anaphylactic risk? Consider mast cell clonality. J Allergy Clin Immunol. 2009;123:687– 688. 65. Kim J, Purushottam B, Chae YK, et al. Relation between common allergic symptoms and coronary heart disease among NHANES III participants. Am J Cardiol. 2010;106:984 – 987.
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N.G. Kounis 66. Umemoto S, Suzuki N, Fujii K, et al. Eosinophil counts and plasma fibrinogen in patients with vasospastic angina pectoris. Am J Cardiol. 2000;85:715–719. 67. Nadimi AE, Ahmadi J, Mehrabian M. Peripheral eosinophil count and allergy in patients with coronary artery disease. Acta Med Indones. 2008;40:74 –77. 68. Wong CW, Luis S, Zeng I, et al. Eosinophilia and coronary artery vasospasm. Heart Lung Circ. 2008;17: 488 – 896. 69. Linneberg A, Jacobsen RK, Jespersen L, et al. Association of subcutaneous allergen-specific immunotherapy with incidence of autoimmune disease, ischemic heart disease, and mortality. J Allergy Clin Immunol. 2012;129:413– 419. 70. Brunekreef B, Hoek G, Fischer P, et al. Relation between airborne pollen concentrations and daily cardiovascular and respiratory-disease mortality. Lancet. 2000;355: 1517–1518. 71. Hahalis G, Kounis GN, Soufras GD, et al. Diesel exhaust, thrombus formation, and Kounis syndrome: a potential association. Inhal Toxicol. 2009;21:431– 432. 72. Suissa S, Assimes T, Brassard P, et al. Inhaled corticosteroid use in asthma and the prevention of myocardial infarction. Am J Med. 2003; 115:377–381. 73. Nemmar A, Hoet PH, Vermylen J, et al. Pharmacological stabilization of mast cells abrogates late thrombotic events induced by diesel exhaust particles in hamsters. Circulation. 2004;110:1670 –1677. 74. Cevik C, Nugent K, Shome GP, et al. Treatment of Kounis syndrome. Int J Cardiol. 2010;143:223–226. 75. Atoui R, Mohammadi S, Shum-Tim D. Surgical extraction of occluded stents: when stenting becomes a problem. Interact Cardiovasc Thorac Surg. 2009;9:736 –738. 76. Bot I, de Jager SC, Zernecke A, et al. Perivascular mast cells promote athero-
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genesis and induce plaque destabilization in apolipoprotein E-deficient mice.Circulation.2007;115:2516–2525. 77. Oka T, Kalesnikoff J, Starkl P, et al. Evidence questioning cromolyn’s effectiveness and selectivity as a ’mast cell stabilizer’ in mice. Lab Invest. 2012;92:1472–1482. 78. Vieira Dos Santos R, Magerl M, et al. Topical sodium cromoglicate relieves allergen- and histamine-induced dermal pruritus. Br J Dermatol. 2010;162:674 – 676.
79. Weng Z, Zhang B, Asadi S, Sismanopoulos N, et al. Quercetin is more effective than cromolyn in blocking human mast cell cytokine release and inhibits contact dermatitis and photosensitivity in humans. PLoS One. 2012;7:e33805. 80. Theoharides TC, Sismanopoulos N, Delivanis DA, et al. Mast cells squeeze the heart and stretch the gird: their role in atherosclerosis and obesity. Trends Pharmacol Sci. 2011; 32:534 –542.
Address correspondence to: Nicholas G. Kounis, MD, 7 Aratou Street, Queen Olgas Square, Patras 26221, Greece. E-mail: [email protected]
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Coronary Hypersensitivity Disorder: The Kounis Syndrome Nicholas G. Kounis, MD, PhD Department of Medical Sciences, Patras Highest Institute of Education and Technology, Patras, Greece ABSTRACT Background: When allergy or hypersensitivity and anaphylactic or anaphylactoid insults lead to cardiovascular symptoms and signs, including acute coronary events, the result might be the recently defined nosologic entity Kounis syndrome. Vasospastic allergic angina, allergic myocardial infarction, and stent thrombosis with occluding thrombus infiltrated by eosinophils and/or mast cells are the 3 reported variants of this syndrome. Objective: The purpose of this review was to highlight and consolidate the recent literature on allergic angina and allergic myocardial infarction and to propose new therapeutic modalities for stabilizing mast cells. Methods: A search for current literature on the pathophysiology, causality, clinical appearance, variance, prevention, and treatment of Kounis syndrome was conducted. Results: Kounis syndrome is caused by inflammatory mediators such as histamine; neutral proteases, including tryptase, chymase, and cathepsin-D; arachidonic acid products; platelet-activating factor; and a variety of cytokines and chemokines released during the mast-cell activation. Platelets with Fc ␥ receptor (Fc␥R) ⌱, Fc␥RII, FcRI, and FcRII also have a role in the activation cascade. The same mediators released from the similar inflammatory cells are involved in acute coronary events of nonallergic etiology. These cells are not only present in the involved region before plaque erosion or rupture but also release their contents just before an acute coronary event. Pro-inflammatory mediators similar to those found in Kounis syndrome are found in some cases with nonallergic etiology, suggesting that this is a more general problem. The acute coronary and cerebrovascular events in Kounis syndrome may be prevented by the inhibition of mast-cell degranulation. Substances and natural molecules that protect the mast-cell surface and stabilize the mast-cell membrane are emerging as novel agents in the prevention of acute coronary and other arterial events.
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Conclusions: The 3 reported variants of Kounis syndrome—vasospastic allergic angina, allergic myocardial infarction, and stent thrombosis with occluding thrombus—are caused by inflammatory mediators. Agents that inhibit mast-cell degranulation may be efficacious in preventing the acute coronary and cerebrovascular events of Kounis syndrome. (Clin Ther. 2013; 35:563–571) © 2013 Elsevier HS Journals, Inc. All rights reserved. Key words: acute coronary events, inflammatory mediators, Kounis syndrome, mast-cell stabilizers.
INTRODUCTION The first reports associating cardiovascular symptoms and signs with hypersensitivity and anaphylactic insults were published ⬎6 decades ago.1–3 However, a detailed description of the allergic angina syndrome, which could progress to acute allergic myocardial infarction, was not described until 1991.4 Today, allergic angina and allergic myocardial infarction are 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.5– 8
DEFINITION Kounis syndrome is defined as the concurrence of acute coronary syndromes such as coronary spasm, acute myocardial infarction, and stent thrombosis, with conditions associated with mast-cell and platelet activation involving interrelated and interacting inflammatory cells in the setting of allergic or hypersensitivity and anaphylactic or anaphylactoid insults. It is caused by inflammatory mediators such as histamine, neutral Accepted for publication February 25, 2013. http://dx.doi.org/10.1016/j.clinthera.2013.02.022 0149-2918/$ - see front matter © 2013 Elsevier HS Journals, Inc. All rights reserved.
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Clinical Therapeutics proteases, arachidonic acid products, platelet-activating factor (PAF), and a variety of cytokines and chemokines released during the activation process.6,8 –10 A subset of platelets bearing Fc ␥ receptor (Fc␥R) I, Fc␥RII, FcRI, and FcRII are also involved in the activation cascade.11 All of these inflammatory cells participate in an inflammatory cycle and activate each other via multidirectional signals. Recently, Kounislike syndromes that affect the cerebral12 and mesenteric arteries13 have been described. It is anticipated that the heart and the entire arterial system is vulnerable to allergic, hypersensitivity, anaphylactic, and/or anaphylactoid events.
PATHOPHYSIOLOGY The main inflammatory cells—the mast cells—interact with other macrophages and T lymphocytes to cause Kounis syndrome. Mast cells can activate macrophages14,15 and may enhance T-cell activation.16,17 Inducible macrophage protein 1a may activate mast cells,18 while CD169⫹ macrophages activate CD8 T cells.19 T cells may mediate mast-cell activation and proliferation20,21 and regulate macrophage activity.22 Although mast cells are numerically a minority in this inflammatory cascade, they influence decisively the inflammatory process. During hypersensitivity, degranulation of mast cells takes place and a variety of stored and newly formed inflammatory mediators are released locally and into the systemic circulation. These mediators include biogenic amines such as histamine, chemokines, enzymes such as the neutral proteases chymase, tryptase, cathepsin-D, peptides, proteoglycans, cytokines, growth factors and arachidonic-acid products such as leukotrienes, thromboxane, prostacyclin, PAF, and tumor necrosis factor ␣. Most of these mediators have important cardiovascular activity. Histamine induces coronary vasoconstriction, induces tissue factor expression, and activates platelets. All 3 neutral proteases can activate matrix metalloproteinases, which can degrade the collagen cap and induce plaque erosion and rupture.23 Tryptase exerts a dual action on the coagulation cascade with both thrombotic and fibrinolytic properties.24 Furthermore, chymase and cathepsin-D might act as enzymes to convert angiotensin I into angiotensin II, a major vasoconstricting substance.25 Leukotrienes are also powerful vasoconstrictors, and their biosynthesis is enhanced in the acute phase of unstable angina.26,27 Thromboxane is a potent mediator of platelet aggrega-
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tion and has vasoconstricting properties,28,29 and PAF, in myocardial ischemia, acts as a proadhesive signaling molecule via the activation of leukocytes and platelets to release leukotrienes or as a direct vasoconstrictor.30
CAUSALITY Several causes have been described to induce Kounis syndrome, and their number is increasing rapidly. These causes include various drugs, environmental exposures, and several conditions. The most recently described offenders are the scombroid syndrome31 (also called histamine fish poisoning) and exposure to gelatin succinylated/sodium chloride/sodium hydroxide (Gelofusine),32 latex,33 or the drug losartan34 in those who are hypersensitive or allergic. Fish flesh contains the amino acid histidine, and when fish infected with gram-negative bacteria containing the enzyme histidine decarboxylase is ingested, then this enzyme converts histidine into histamine, which may induce Kounis syndrome. Gelofusine is a bovine gelatin administered to maintain intravascular volume. Gelofusine is a component of various vaccines for children and constitutes the main cause of sensitization in children. Exposure to such allergens may occur directly or through the saliva of people (eg, kissing)35 or pets (eg, licking by dogs).36
CLINICAL MANIFESTATIONS The main clinical symptoms and signs of Kounis syndrome are associated with subclinical, clinical, acute, or chronic allergic reactions accompanied by cardiac symptomatology. A variety of ECG changes, ranging from ST-segment elevation or depression to any degree of heart block and cardiac arrhythmias, may be observed resembling digitalis intoxication. A high index of suspicion regarding this syndrome is of paramount importance. Although it is not a rare disease, its diagnosis is spare and easily overlooked.37 Kounis syndrome is becoming increasingly encountered in clinical practice, and it is anticipated that many more causative factors will be implicated in the future. Kounis syndrome has mostly been reported in southern Europe, especially in Spain, Italy, Greece, and Turkey. This geographic variation could be attributed to increased awareness of physicians of the existence of Kounis syndrome; climate and environmental conditions resulting in pollen cross-reactivity; and hymenoptera exposures, overconsumption of medicines, and/or inadequacy of preventative measures.8 Kounis syndrome has been re-
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N.G. Kounis ported in association with a mutation in E148q, the gene of familial Mediterranean fever.38
KOUNIS SYNDROME AND STENT THROMBOSIS The life-saving implantation of coronary stents has become the most frequently performed therapeutic procedure in medicine.39 Two kinds of stents are used— drug-eluting stents and bare-metal stents, which have a platform made of stainless steel (a combination of nickel, chromium, titanium, manganese, and molybdenum). The currently used, or second-generation, drug-eluting stents carry the misleading term cobaltchromium or platinum-chromium stents but have platforms that contain nickel and other metals. These stents are covered with polymer coatings that serve as drug carriers and permit controlled drug release. The released drugs have antiproliferative properties and include the everolimus and zotarolimus substances that inhibit the mammalian target of rapamycin and prevent re-endothelialization, thus avoiding the need for restenosis. A randomized clinical trial reported an incidence of 0.2% to 0.5% per year, with a death rate up to 40%.40 The stented and thrombotic areas may be infiltrated by inflammatory cells, including eosinophils, macrophages, T cells, and mast cells.9 That is why the author has insisted that stent thrombosis is mainly a manifestation of Kounis syndrome.41 Allergic inflammation goes through 3 phases.42
VARIANTS OF KOUNIS SYNDROME Three variants of Kounis syndrome have been described8: the type I variant includes normal or nearly normal coronary arteries without risk factors for coronary artery disease, and with the acute release of inflammatory mediators that may induce either coronary artery spasm without increased cardiac enzymes and troponins or coronary artery spasm progressing to acute myocardial infarction with raised cardiac enzymes and troponins. The type II variant includes culprit but quiescent preexisting atheromatous disease in which the acute release of inflammatory mediators may induce either coronary artery spasm with normal cardiac enzymes and troponins or coronary artery spasm together with plaque erosion or rupture manifesting as acute myocardial infarction. The type III variant includes coronary artery stent thrombosis in which aspirated thrombus specimens stained with he-
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matoxylin-eosin and Giemsa demonstrate the presence of eosinophils and mast cells, respectively.
Innate Release of Pro-inflammatory Molecules Pro-inflammatory mediators similar to those found in Kounis syndrome are found in some cases with nonallergic etiology, suggesting that this is a more general problem.
Histamine Increased histamine levels in the great cardiac vein have been reported in patients with attacks of variant angina without correlation with an allergic event.43 One study reported that the blood histamine concentration associated with enhanced oxidative stress in patients with nonallergic acute coronary syndromes was ⬎2-fold that in age- and sex-matched controls.44 In another report, the blood histamine level was significantly greater in patients with various types of nonallergic-etiology ischemic heart disease, such as unstable angina and acute myocardial infarction, compared with that in healthy control subjects.45
Tryptase Persistent tryptase elevation has been detected in patients with nonallergic acute coronary syndromes, with a higher concentration in a subgroup with ST-segment depression, both in the acute phase and at follow-up.46 In another report, serum tryptase and chymase concentrations were greater in a group with nonallergic acute myocardial infarction and unstable angina pectoris than in a group without substantial coronary disease.47 Elevated tryptase levels have been observed in patients with nonallergic significant chronic coronary artery disease as a result of chronic low-grade inflammatory activity present in the atherosclerotic plaques.48 In a group with unstable angina, the tryptase level was 5-fold higher after 5 minutes, 10-fold higher after 15 and 60 minutes, and 2-fold lower in the symptom-free period immediately after the onset of chest pain with ECG signs of ischemia.49
Arachidonic Acid Products Concentrations of thromboxane and leukotrienes were significantly greater in nonallergic patients with unstable angina than in patients with stable angina and in patients with nonischemic chest pain.50 Thromboxane and leukotriene concentrations in the systemic arterial circulation have been reported to be significantly higher in the acute stage of nonallergic myocardial infarction than in the circulation of normal controls.51
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Interleukin-6 Levels of interleukin-6, derived from inflamed coronary plaques and areas of myocardial necrosis, are reported to have been elevated in patients with nonallergic acute coronary syndromes.52,53
Is the Release of Allergic Inflammatory Mediators the Cause of an Acute Coronary Event, or the Result of Damaged and Inflamed Myocardial Tissue After the Acute Coronary Event? Clinical findings have supported that inflammatory 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 acute coronary event. It has been reported that mast cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred, but also the shoulder sites of coronary plaques susceptible to erosion or rupture, which means they invade before an acute initial event.54 The same applies also for other inflammatory cells, such as macrophages and T lymphocytes, suggesting that inflammatory cells infiltrate the lesions before erosion or rupture and that they are not a part of an inflammatory response to rupture initiated by other processes. In patients who had died within 2 days after an acute coronary event, infiltrates of degranulated mast cells at the site of coronary atheromatous erosion or rupture were found in a ratio of 200:1 compared with the nearby normal endothelial segments.55 Circulating blood contains only mast-cell precursors, which require several days or weeks to differentiate into morphologically identifiable mast cells filled with cytoplasmic secretory granules.56,57 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. In another report,50 concentrations of arachidonic acid products, such as leukotrienes and thromboxane, were significantly greater in patients with unstable angina than in patients with stable angina and in patients with nonischemic chest pain. Stress test–induced myocardial ischemia in the patients with stable angina was not accompanied by any change in leukotriene or thromboxane concentrations up to 6 days after a positive exercise-test result. The investigators in that report concluded that this lack of change in leukotriene and thromboxane concentrations rules out a role of ischemia per se in the induction of increased eicosanoid products.
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Histamine concentration in the great cardiac vein was reported to have been elevated in 8 of 11 patients with variant angina attacks43 and in 0 of 8 control subjects. In the same patients, the investigators did not observe any histamine elevation during or after acetylcholine-induced coronary artery spasm, suggesting that histamine was present in the aforementioned 8 patients to induce the variant angina attacks. In contrast, elevation of plasma histamine levels was antecedent to the angina attacks in 3 patients. In addition, high levels of histamine were observed even in the absence of ST-segment elevation in the same group of patients. Tryptase levels were elevated during spontaneous ischemic episodes in patients with unstable angina,49 but not after ergonovine-induced ischemia in patients with variant angina, suggesting that a primary, yet-unknown stimulus activates mast cells in patients with episodes of unstable angina.
Is the Ischemic Myocardial Damage a Primary Event During Anaphylactic Events? In the author’s view, the heart may be the primary site and target of anaphylaxis resulting in the development of Kounis syndrome.58 So far it is believed that, during anaphylactic episodes, systemic vasodilatation, reduced venous return, leakage of plasma, and volume loss due to increased vascular permeability, and the ensuing depression of cardiac output, contribute to coronary hypoperfusion with subsequent myocardial damage. However, differentiating global myocardial hypoperfusion from a primary cardiac myocardial suppression due to mast-cell mediator activity is clearly challenging. Combined myocardial suppression and peripheral vasodilatation may occur simultaneously. In an experimental model of anaphylaxis in ovalvumin-sensitized guinea pigs,59 it was reported that soon after antigen administration, ECG showed signs of acute myocardial ischemia; the left ventricular enddiastolic pressure was increased significantly, indicating pump failure; the arterial blood pressure was also increased significantly; and cardiac output was decreased by 90%. The blood pressure started declining steadily after 4 minutes. It was concluded that the rapid increase in left ventricular end-diastolic pressure suggested that decreased venous return and volume loss due to an increase in vascular permeability were unlikely to have been the primary causes of the documented depression in cardiac output, and the view that the registered anaphylactic damage might be due to peripheral
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N.G. Kounis vasodilation was definitively excluded. In isolated guinea pig hearts undergoing anaphylaxis after an intra-aortic injection of antigen, a prompt and prolonged decrease in coronary blood flow, an abrupt heart rate increase that peaked within 2 minutes, and a transient increase in ventricular contractile force, followed by a prolonged decrease, were observed.8 These findings are in accordance with those from other reports that anaphylactic cardiac damage may be dissociated temporarily into 2 sets of events: (1) initial primary cardiac reaction caused by the intracardiac release of histamine and (2) a subsequent cardiovascular reaction secondary to the systemic release of mediators.60 In the clinical setting, there are reports according to which patients with anaphylactic cardiac shock did not respond to fluid replacement but recovered with current protocol for myocardial infarction and antiallergy treatment, thus denoting that the heart is primarily affected.32,61
Why Kounis Syndrome Occurs Less Often Than Do Allergic, Hypersensitivity, and Anaphylactic Events The author has suggested that a threshold level of mast-cell content (eg, tryptase, chymase) exists,10 above which coronary artery spasm and/or plaque erosion or rupture is induced. Furthermore, the magnitude of the initial allergic response, the patient‘s sensitivity, the patient‘s comorbidities, the site of antibody–antigen reaction, the allergen concentration, and the route of allergen entrance may represent additional factors. Indeed, recent reports have suggested that patients with increased serum baseline tryptase are at a greater risk for immediate and severe hypersensitivity reaction to hymenoptera sting.62 Such patients were reported to have had underlying clonal mast-cell disorder— either systemic mastocytosis or monoclonal mast-cell activation syndrome.63 In these patients, bone marrow aspiration showed mast-cell aggregates and spindle-shaped mast cells. Flow-cytometric analysis of mast cells revealed mast cells expressing CD2 or CD25 on their surfaces, and on KIT mutation analysis, KIT mutation at codon 816 was found. KIT is the mast receptor for the stem-cell factor that is essential for mast-cell development, proliferation, survival, adhesion, and homing. Therefore, patients with an elevated baseline serum tryptase concentration or KIT mutations may have a lower stimulus threshold for anaphylaxis, as well as a
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hyper-responsive mast-cell phenotype,64 resulting in the development of Kounis syndrome. The following additional findings support the existence of Kounis syndrome. Common allergic symptoms such as allergic rhinoconjunctivitis and wheezing were reported to have been significantly associated with an increased risk for ischemic heart disease (IHD) in the National Health and Nutrition Survey III on noninstitutionalized civilian population in the United States, 1988 –1994.65 In another report, eosinophil counts were significantly increased in patients with vasospastic angina pectoris and might predict the severity of the disease. After medical treatment and relief of chest symptoms, the eosinophil count was decreased significantly to the same level as those in a control group.66 In clinical reports, the absolute number of eosinophils and the eosinophil:leukocyte ratio in the peripheral blood were significantly elevated in patients with coronary artery disease.67 Coronary vasospasm associated with eosinophilia has been reported to respond poorly to conventional vasodilator treatment and, although the risk for recurrence of coronary events is high, the majority of patients responded to treatment that suppressed eosinophilia, such as corticosteroids.68 Subcutaneous allergen-specific immunotherapy for immunoglobulin E–mediated allergic diseases has been associated with lower risks for acute myocardial infarction and autoimmune disease.69 Air pollution has been associated with an increased incidence of deaths from cardiovascular disease70 and Kounis syndrome.71 The use of inhaled corticosteroids has been associated with a reduced risk for myocardial infarction in patients with asthma and in particular in those with more severe disease.72 In reports on several experimental models, diesel exhaust particles triggered mast-cell degranulation and histamine release.73
TREATMENT Treatment of Kounis syndrome is challenging because it needs to address both cardiac and allergic symptoms simultaneously, and the drugs administered may worsen the allergy and aggravate heart function.74 In patients with the type I variant, treatment of the allergic event alone may abolish symptoms. The use of hydrocortisone 1 to 2 mg/kg/d IV and H1 and H2 antihistamines, such as diphenhydramine (1–2 mg/kg) and ranitidine (1 mg/kg), is adequate. The administration of vasodilators such as calcium channel blockers and nitrates may abolish hypersensitivity-induced vasospasm. However, nitroglycerine
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Clinical Therapeutics may cause hypotension and tachycardia, which may further complicate allergic reactions. In patients with the type II variant, treatment should be started with an acute coronary event protocol, together with corticosteroids and antihistamines. Vasodilators such as nitrates and calcium channel blockers are given when appropriate. However, the administration of -blockers may exaggerate coronary spasm due to unopposed activity of ␣-adrenergic receptors. Epinephrine, which is the drug of choice and may save lives in anaphylaxis, may aggravate ischemia and worsen coronary vasospasm in Kounis syndrome. In severe cases, sulfite-free epinephrine given intramuscularly is preferable because it has a faster onset of action and maintains a more stable concentration compared with the subcutaneous route (recommended IM dose, 0.2– 0.5 mg [1:1000]). Aqueous solution is preferable. In patients with a history of IHD who receive -blockers, epinephrine may be ineffective. It may also induce more vasospasm due to an unopposed ␣-adrenergic effect. Glucagon may be considered. Opioids such as morphine, codeine, and meperidine given to relieve acute chest pain should be administered with extreme caution in patients with Kounis syndrome because they may induce massive mast-cell degranulation and aggravate allergic reaction. Acetaminophen (paracetamol) is not recommended, especially by intravenous administration, because it might cause severe hypotension due to a reduction in cardiac output. Fentanyl and its derivatives are weak mast-cell triggers. In patients with the type III variant, the current acute myocardial infarction protocol, together with urgent aspiration of intrastent thrombus, followed by histologic examination of aspirated material and staining for eosinophils (hematoxylin and eosin) and mast cells (Giemsa) should be undertaken. In patients in whom allergic symptoms develop after stent implantation, the administration of antihistamines together with corticosteroids and mast-cell stabilizers may relieve the symptoms. If symptoms persist, the underlying cause should be ascertained and desensitization measures should be applied. If these measures fail, stent extraction seems unavoidable.75 Unfortunately, these are not clinically effective. The medical literature abounds with the earlier-mentioned reports that the same mediators deriving from similar cells and capable of inducing arterial spasm and atheromatous plaque erosion and rupture are found in both allergic and nonallergic acute coronary events. One treatment option might be
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the prevention of the coronary plaque from becoming unstable using inhibition of mast-cell degranulation, which has been already achieved experimentally.73,76 Recently, mast-cell inhibitors—specifically, the mast-cell stabilizer disodium cromoglycate (cromolyn), was reported not to inhibit human mast cells.77,78 However, the flavonoid quercetin was reported to have been more efficacious than cromolyn in blocking mast-cell cytokines in humans.79 This potential option is promising in the effort to prevent Kounis syndrome. A dietary supplement containing a combination of mast-cell inhibitors and natural flavonoids80 may be another option.
CONCLUSIONS The 3 reported variants of Kounis syndrome—vasospastic allergic angina, allergic myocardial infarction, and stent thrombosis with occluding thrombus— are caused by inflammatory mediators. Agents that inhibit mast-cell degranulation may be efficacious in preventing the acute coronary and cerebrovascular events of Kounis syndrome.
ACKNOWLEDGMENTS Dr. Kounis was responsible for the literature search, data interpretation, figure creation, and writing of the manuscript.
CONFLICTS OF INTEREST The author has indicated that he has no conflicts of interest with regard to the content of the article.
REFERENCES 1. Pfister CW, Plice SG. Acute myocardial infarction during a prolonged allergic reaction to penicillin. Am Heart J. 1950; 40:945–947. 2. Czickeli H. Contribution to the problem of the allergic etiology of angina pectoris and myocardial infarct. Klin Med Osterr Z Wiss Prakt Med. 1950;5:364 –367. 3. Schultheiss E. Clinical aspects of allergic heart diseases. Dtsch Med J. 1964;15:15–18. 4. Kounis NG, Zavras GM. Histamine-induced coronary artery spasm: the concept of allergic angina. Br J Clin Pract. 1991;45:121–128. 5. Kounis NG. Kounis syndrome (allergic angina and allergic myocardial infarction): a natural paradigm? Int J Cardiol. 2006;110:7–14. 6. Biteker M. Current understanding of Kounis syndrome. Exp Rev Clin Immunol. 2010;6:777–788.
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Address correspondence to: Nicholas G. Kounis, MD, 7 Aratou Street, Queen Olgas Square, Patras 26221, Greece. E-mail: [email protected]
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