Transcript
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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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