Download - Allergic Myocardial Infarction
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HYPERSENSITIVITY CORONARY SYNDROME (KOUNIS SYNDROME)
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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)
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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)
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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)
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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)
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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
Kounis NG;J ajem 2009
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ACS with allergic etiologyKounis syndrome 2 type 1. Type I2. Type II
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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)
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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
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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
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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
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EKG revealed 1 mm ST depression in leads II, III, AVF, V4–V6 , inferolateral MI
George Almpanis, International Journal of Cardiology 2009
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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
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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)
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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)
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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)
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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)
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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)
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Dogu Kılıc; International Journal of Cardiology 135 (2009)
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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)
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ST segment elevations in leads II, III, aVF, V4, V5 and V6
Murat Biteker; International Journal of Cardiology 136 (2009)
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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)
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Biteker et al; Kounis syndrome: first series in Turkish patients
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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)
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Causes capable of inducing Kounis syndromeConditions Drugs Environmental
exposures
Angio-edema Antibiotics Ant stings
Bronchial asthma Analgesics Bee stings
Exercise inducedanaphylaxis
Thrombolytics Anticoagulants
Wasp stings
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
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Mechanism
Mast cell activation and degranulation1. IgE mediated cross linking of Fcε receptor2. Histamine releasing factor secret by Macrophage
or T lymphocyte3. 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
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Preformed mediators (from
granules)• Histamine• TNF-α• proteoglycans,
mainly heparin (active as anticoagulant)
• serine proteases, such as tryptase, chymase
Lipid mediators (eicosanoids)
• Prostaglandin D2
• Leukotriene B4• Platate-
activating factor
Cytokine
• Eosinophil chemotactic factor
Rapid process of anaphylactic degranulation
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Type Mediator Major functionsBiogenic 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
Preformed mediators of mast cells
F Ida Hsu ; Middleton
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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
Preformed mediators of mast cells
F Ida Hsu ; Middleton
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Mast cell in MIAdventitia
Lipid accumulation
Proximal Coronary segment
Middle Coronary segment
Distal Coronary segment
Petri Laine ; Circulation. 1999
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Petri Laine ; Circulation. 1999
Hematoxylin counterstaining,light blue; magnification x100
Mast cell
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Petri Laine ; Circulation. 1999
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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)
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Platelet and Histamine
Masini E, Infamm Res 1997
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Tissue factor and histamine
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plasma histamine levels in the great cardiac vein
Yasuhiko Sakata, Am J Cardior 1997
Variant angina
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Steffel et al; Circulation. 2005
Tissue factor and histamine
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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
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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)
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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)
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TNF-α
Strong pro-inflemmatory cytokins
Activated inflammation
Tranfroms stable plaque to vulnerable plaque
Władysław Sinkiewicz et al ; Caridol J 2008
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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)
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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)
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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
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Beta-blockerMeta-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
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Beta-blocker
Post MI Model
Variable b-blocker N0 b-blocker
Lifetime risk of Moderate to severe anaphylaxis
25% 24%
Anaphylaxis mortality 6% 0.6%
Cardiac mortality 63% 72%
Life expectancy, y 11.1 10.3
Trenbrook et al:J Allergy Clin Immunol 2004
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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
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“Kounis syndrome not rare diseases,
are very rarely diagnosed and differentiated diseases” Nicholas G.
Kounis
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