Allergic Myocardial Infarction

HYPERSENSITIVITY CORONARY SYNDROME (KOUNIS SYNDROME)

Introduction  Sign and symptom of anaphylaxis , cardiovascular  Tachycardia  Presyncope  Hypotension  Shock  Chest pain  Bradycardia  Orthostasis  Cardiac arrest  Adult 46% (Yocum et al.)  Children 26% (Dibs et al. child 1–19 years of age)

 Younger died of anaphylactic shock tended to vasodilation with hypotension, leading to pulseless electrical activity and death  Older, shock was found to be from arrhythmia, which is more commonly found in older hearts with pre-existing disease (Pumphrey ; Curr Opin Allergy Clin Immunol 4:285–290 2004)

 Myocardial ischemia, in anaphylactic reaction, can result from circulatory system instability (drop in coronary perfusion pressure) and pathophysiologically it does not differ from disturbances shock  Allergic reactions can lead to myocardial ischemia as a result of coronary vessel contraction (Kounis NG ; Int J Cardiol 2006)

 Hypersensitivity coronary syndrome “ concurrence of acute coronary syndromes with condition associated with mast cell activation, involving interrelated and interacting inflammatory cells and including allergic or hypersensitivity and anaphylactic or anaphylactoid insults”  Allergic myocardial infraction and allergic angina (Kounis NG ; Int J Cardiol 2006)

Cardiac features of suspected hypersensitivity myocarditis and hypersensitivity coronary syndrome Hypersensitivity myocarditis Kounis syndrome Cardiac symptoms Acute chest pain − + Chest discomfort + + Dyspnea + + Palpitations + + Sudden death + + Cardiac signs Elevated JVP + + Irregular pulse + + Gallop rhythm + + Electrocardiographic signs Atrioventricular block + + Left bundle-branch block + + Right bundle-branch block + + Sinus tachycardia + + ST-segment elevation + + ST-segment depression + + T-wave inversion + + Ventricular tachycardia + + Laboratory signs Coronary angiography − ± Eosinophilia − ± Increased cardiac enzymes and + + especially CPK-MB Increased troponins + + Cardiomegaly in the chest x-ray + + Dilated cardiac chambers in + + echogram Eosinophils, atypical ± − lymphocytes, and giant cells in biopsy

ACS with allergic etiology Kounis syndrome 2 type 1. Type I 2. Type II

Type I  Normal coronary arteries without predisposing factors for CAD  Acute allergic insult induces coronary artery spasm with normal cardiac enzymes and troponins or coronary artery spasm progressing to acute MI with raised cardiac enzymes and troponins  Positive ergonovine or histamine  Represent a manifestation of endothelial dysfunction or microvascular angina (Kounis NG ; Int J Cardiol 2006)

Case 1  A 57-year old fisherman, heavy smoker 30 yr  Decided to give up smoking and his doctor prescribed nicotine skin patches (nicorette)  PH and FH no CVD and allergy  3 days later he developed itching and hives around the patch area which started progressing to generalized itching George Almpanis, International Journal of Cardiology 2009

 2 days later while cleaning fishes he injured one of his fingers with a fish bone and the following hours hives and itching relapsed in the corresponding hand and arm  Following day the symptoms worsened itching becamewidespread and the rash covered the arms, face, neck and legs George Almpanis, International Journal of Cardiology 2009

 While the patient was in the examination room he developed suddenly severe retrosternal pain radiating to both arms and neck and started vomiting with diaphoresis  pulse increased to 122 bpm regular and the blood pressure also raised to 180/100 mmHg George Almpanis, International Journal of Cardiology 2009

 EKG revealed 1 mm ST depression in leads II, III, AVF, V4–V6 , inferolateral MI George Almpanis, International Journal of Cardiology 2009

 Immediately he was given 5 mg of morphine sulfate, 1 g of hydrocortisone sodium succinate, 50 mg of diphenydramine and 50 mg of ranitidine IV  Admit CCU  Coronary angiography was also normal with ejection fraction 60%.  cardiac enzymes and troponin were within normal limits.  Total IgE was elevated to 203 IU/ml (normal values,  110 IU/ml) and tryptase levels were raised to 25 μg/l and after two hours 20 μm/l (normal 5.6–13.5 μm/l) and eosinophils were also raised to 9% George Almpanis, International Journal of Cardiology 2009

Type II  Pre-existing atheromatous disease  Acute allergic episode can induce plaque erosion or rupture manifesting as an acute MI  Mechanism lead to plaque destabilization (oxidized LDL or allergic process) (Kounis NG ; Int J Cardiol 2006)

Case 2  A 72 year-old man was brought to the ER of after a syncopal attack, which developed 15 min after ingesting a pill  Confused and SBP 80 mm Hg, PR 150/min  Respiratory distress with bronchospasm and rales at the base of both lungs Dogu Kılıc; International Journal of Cardiology 135 (2009)

 EKG : AF and ST segment elevation in leads D2, D3 aVF, and ST segment depression in the leads V1-4, D1, aVL indicating acute inferior injury Dogu Kılıc; International Journal of Cardiology 135 (2009)

 Plan PTCA , bolus dose of heparin (5000 IU), ASA and nebulised mixture of salbutamol and ipratropium  During the preparation ; STsegment elevations resolved, sinus rhythm restored and SBP 115 mm Hg  Elevated cardiac markers were indicative of subsequent myocardial injury Dogu Kılıc; International Journal of Cardiology 135 (2009)

 History could only be taken 8 h after the symptoms to reveal Salbactam ampicillin ingestion 15 min before the syncopal attack  Tryptase level 1.0 mcr/l  Circulating specific IgE levels for the ampicillin was moderately positive (class 2)  Specific IgE levels for the penicilloyl G, penicilloyl V, cefaclor and amoxycillin showing low positive (class 1) values for the former two and negative values for the latter two (class 0). Dogu Kılıc; International Journal of Cardiology 135 (2009)

Dogu Kılıc; International Journal of Cardiology 135 (2009)

Case 3  13-year-old healthy boy admited ER  Severe chest pain and mild pruritic skin rashes  30 min after ingesting an oral dose of 500 mg of amoxicillin/clavulanic acid Murat Biteker; International Journal of Cardiology 136 (2009)

 ST segment elevations in leads II, III, aVF, V4, V5 and V6 Murat Biteker; International Journal of Cardiology 136 (2009)

 Echocardiogram : inferior wall hypokinesia  Troponin-I estimated on arrival was 2.1 ng/ml (reference:0–0.1 ng/ml), creatine kinase-MB fraction (CK-MB) was 30 U/L (reference: 0–25 U/L)  Serum tryptase was 31 μg/L (reference: 5.6– 13.5 μg/L) Murat Biteker; International Journal of Cardiology 136 (2009)

Biteker et al; Kounis syndrome: first series in Turkish patients

Clinical relevance  Incidence and prevacence  Recent study :  9.5% ( Single ant on healthy volunteer, 2/21) S G A Brown ; Emerg Med J 2004  Atopic individual higer risk of ACS, men with high IgE (woman lower IgE low rate) Criqui MH Am J Med 1987 (Kounis NG ; Int J Cardiol 2006)

Causes capable of inducing Kounis syndrome Conditions Drugs Environmental exposures Angio-edema Antibiotics Ant stings Bronchial asthma Analgesics Bee stings Exercise induced Thrombolytics Wasp stings anaphylaxis Anticoagulants Food allergy Contrast media Jellyfish sting Idiopathic anaphylaxis Corticosteroids Grass cutting Mastocytosis Intravenous anaesthetics Poison ivy Serum sickness NSAIDs Latex contact Urticaria Skin disinfectants Limpet ingestion Antineoplasitic Millet allergy Bupropion Shellfish eating Dextran Viper venom poisoning Heparin Protamine Streptokinase Kounis NG ; Int J Cardiol 2006, Władysław Sinkiewicz et al ; Caridol J 2008

Mechanism  Mast cell activation and degranulation 1. IgE mediated cross linking of Fcε receptor 2. Histamine releasing factor secret by Macrophage or T lymphocyte 3. Anaphylatoxin component of complement system C3a, C5a  Neuropeptides and bacterial products through Toll-like receptors 2,4  Drugs such as opioids or analgesics such as high doses of acetylsalicylic acid Endothelin

Preformed Lipid mediators mediators (from Cytokine (eicosanoids) granules) • Histamine • Prostaglandin D2 • Eosinophil • TNF-α • Leukotriene B4 chemotactic factor • proteoglycans, • Platate-activating mainly heparin factor (active as anticoagulant) • serine proteases, such as tryptase, chymase Rapid process of anaphylactic degranulation

Type Mediator Major functions Biogenic amine Histamine Vasopermeability; vasodilation; smooth muscle contraction; secretion of gastric acid; pruritus through actions on endothelial cells, smooth muscle, and nerve endings Neutral proteases Tryptase Degrades fibrinogen; attracts neutrophils through induction of IL-8; stimulates angiogenesis, fibroblast and epithelial proliferation; cleaves complement factors C3 and C3a; degrades VIP and CGRP; kallikrein-like activity Chymase Converts angiotensin to angiotensin II; degrades extracellular matrix; affects endothelin and lipoprotein metabolism; activates matrix metalloproteinases; stimulates angiogenesis; degrades C3a, VIP, substance P, SCF, procollagen, and cytokines including IL-6 and TNF-α; stimulates bronchial mucus secretion; chemoattractant for monocytes, neutrophils Carboxypeptidase Carboxypeptidase-A-like activity, acts in concert with other proteases, may protect against venoms F Ida Hsu ; Middleton

Acid hydrolases β-hexosaminidase Cleavage of β-linked hexosamines from complex carbohydrates and glycoproteins, used experimentally as an easily quantifiable marker of in vitro mast cell activation β-glucuronidase, β-D-galactosidase Removes β-linked glucuronic acid or galactose from complex carbohydrate chains Arylsulfatase Hydrolyzes sulfate esters of aromatic compounds Proteoglycans Heparin Anticoagulant, necessary for granule storage and substrate specificity of proteases and histamine Chondroitin sulfate Unknown – probably protease storage function Preformed cytokine TNF-α Leukocyte recruitment, effects on dendritic cell and lymphocyte functions F Ida Hsu ; Middleton

Mast cell in MI Adventitia Lipid accumulation Proximal Coronary segment Middle Coronary segment Distal Coronary segment Petri Laine ; Circulation. 1999

Mast cell Hematoxylin counterstaining, light blue; magnification x100 Petri Laine ; Circulation. 1999

Petri Laine ; Circulation. 1999

Histamine  Histamine can constrict coronary artery  Histamine can induced platlets and tissue factor  Histamine can induced proinflammatory cytokine production from endothelial cell (Kounis NG ; Int J Cardiol 2006)

Platelet and Histamine Masini E, Infamm Res 1997

Tissue factor and histamine

Variant angina plasma histamine levels in the great cardiac vein Yasuhiko Sakata, Am J Cardior 1997

Tissue factor and histamine Steffel et al; Circulation. 2005

Tryptase and Chymase  Effectively activate the zymogen forms of metalloproteinases such as interstitial collagenase, gelatinase and stromelysin found in atheromatous plaques and important role in atheromatous plaque erosion or rupture Johnson JC, Arterioscler Thromb Vasc Biol 1998

 Found in the medial muscle cells of human coronary arteries  Synergistically with histamine and aggravate the local spasm of the infarcted coronary artery (Kounis NG ; Int J Cardiol 2006)

Platelet activating factor  Proadhesive signaling molecule or through activation of leucocytes and platelets to release other mediator  Thromboxane is a potent mediator of platelet aggregation and has vasoconstricting properties  Directly producing vasoconstriction (Kounis NG ; Int J Cardiol 2006)

TNF-α  Strong pro-inflemmatory cytokins  Activated inflammation  Tranfroms stable plaque to vulnerable plaque Władysław Sinkiewicz et al ; Caridol J 2008

Prognosis  Type I better than Type II  Prognosis depend  Magnitude of the initial allergic respose  Patient sensitivity  Patient comorbidity  Site of Ab-Ag reaction  Allergen concentration  Route of allergen entrance (Kounis NG ; Int J Cardiol 2006)

 Cases of Kounis syndrome are more often encountered in clinical practice than anticipated  Patients with of systemic allergic reactions develop chest pain routine evaluation of EKG ,cardiac enzymes and troponins together with histamine and tryptase levels (Kounis NG ; Int J Cardiol 2006)

Treatment  Corticosteroids  Sodium cromoglicate or ketotifen  H1 and H2 blockers  Anti IgE  Anti-IL4Rα  Severe and persistent cases, the addition of leukotriene antagonists and immunosuppressives may be life saving

Beta-blocker Meta-analysis cohort study 10,000 adult with peanut allergy and heart disease Post MI Model Variable Baseline Range Age 58 30-90 Excess annual cardiac mortality Without b-blocker 7.0% 3.3% to 8.3% Relative risk on b-blocker 0.807 0.74-0.88 Annual rate of anaphylaxis Without b-blocker 2.3% 1% to 30% Relative risk on b-blocker 1.0 0.9-5 Anaphylaxis case fatality rate Without b-blocker 2.5% 1% to 9% Relative risk on b-blocker 10 1-40 Trenbrook et al:J Allergy Clin Immunol 2004

Beta-blocker Post MI Model Variable b-blocker N0 b-blocker Lifetime risk of 25% 24% Moderate to severe anaphylaxis Anaphylaxis mortality 6% 0.6% Cardiac mortality 63% 72% Life expectancy, y 11.1 10.3 Trenbrook et al:J Allergy Clin Immunol 2004

Take home message  Kounis syndrome  Type I – coronary spasm  Type II – plaque rupture  Caused – condition, drugs and environment  Mast cell mediator – histamine, typtase, chymase, PAF, TNFα and eicosanoid

“ Kounis syndrome not rare diseases, are very rarely diagnosed and differentiated diseases” Nicholas G. Kounis

Allergic Myocardial Infarction

by Division of Allergy and Clinical Immunology, Department of Medicine, Faculty of Medicine, Chulalongkorn University

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