Nicholas G Kounis MDConflict of interest related to this lecture: Fees for: reviewing papers, writing papers,

reviewing applications for grants

Kounis syndromeThe history

From Bedside to Bench

A Hypersensitivity Blow up inside the arteries

April 23rd 1981

Medical wards

Department of Internal Medicine-Cardiology Division

In the year 1983-June 27th

Emergency room a 55 year old woman…

Department of Internal Medicine Cardiology Division

1983-June 27thEmergency room a 55 year old woman…

University of Patras School of Medicine

April 23rd 1981

Medical wards

Department of Internal Medicine-Cardiology Division

In the year 1983-June 27th

Emergency room a 55 year old woman…

Department of Internal Medicine Cardiology Division

1983-June 27thEmergency room a 55 year old woman…

University of Patras School of Medicine

“Histamine induced Coronary spasm: The Syndrome

Allergic Angina”

MEDIGO: Kounis Syndrome Treatment at Clinics

and Hospitals worldwide TEL +44 174 45 82 444

• UNIVERSITY HOSPITAL HEIDELBERG

• PANTAI HOSPITALKUALA LUMPUR

• PRIME HOSPITAL DUBAI

• KLINIK HIRSLANDEN ZURICH

• JSC MEDICINA CLINIC MOSCOW

• HIRSLANDEN CLINIQUE CECILLAUSANNE

• ASAN MEDICAL CENTER SEOUL

• SEVENHILLS HOSPITAL MUMBAI

15 hospitals worldwide

1. Takotsubo

cardiomyopathy

2. Cardiac syndrome X

3. Prinzmetal angina

4. Kawasaki disease

5. Torsades de pointes

6. Tetralogy of Fallot

7. Barlow’s syndrome

8. Ebstein’s anomaly

9. Eisenmenger

syndrome

10. Kounis syndrome

Kounis syndrome

What is

(ACS-Conditions–Inflammatory mediators- Inflammatory cells)

The vicious cycle of inflam

matory cells

All these inflammatory cells participate in a vicious inflammatory cycle and via multidirectional signals

:

1. Mast cells can activate macrophages1

2. Inducible macrophage protein-1α can activate mast cells2

3. Mast cells can enhance T cell activation3

4. T cells can mediate mast cell activation and proliferaration4

5. Mast cell activate eosinophils5

6. Eosinophils activate mast cells6

7.T cells can regulate macrophage activity6

κ.o.κ.

1. Mommert S et al. Br J Pharmacol. 2019 Jul 22. doi: 10.1111/bph.14796

2. Miyazaki D, et al. J Clin Invest 2005; 115: 434

3. Lotfi-Emran S et al. J Allergy Clin Immunol 2018 Jan;141(1):311-321

4. Suurmond J et al. Eur J Immunol. 2016 May;46(5):1132-41

5. Gunawardena MD, et al. BMJ Case Rep. 2015 Jan 21;2015

6. Steinke JW et al. J Immunol. 2014 Jul 1;193(1):41-7

7. Doherty TM. Curr Opin Immunol 1995; 7: 400

The vicious cycle of inflam

matory cells

All these inflammatory cells participate in a vicious inflammatory cycle and via multidirectional signals

:

1. Mast cells can activate macrophages1

2. Inducible macrophage protein-1α can activate mast cells2

3. Mast cells can enhance T cell activation3

4. T cells can mediate mast cell activation and proliferaration4

5. Mast cell activate eosinophils5

6. Eosinophils activate mast cells6

7.T cells can regulate macrophage activity6

κ.o.κ.

1. Mommert S et al. Br J Pharmacol. 2019 Jul 22. doi: 10.1111/bph.14796

2. Miyazaki D, et al. J Clin Invest 2005; 115: 434

3. Lotfi-Emran S et al. J Allergy Clin Immunol 2018 Jan;141(1):311-321

4. Suurmond J et al. Eur J Immunol. 2016 May;46(5):1132-41

5. Gunawardena MD, et al. BMJ Case Rep. 2015 Jan 21;2015

6. Steinke JW et al. J Immunol. 2014 Jul 1;193(1):41-7

7. Doherty TM. Curr Opin Immunol 1995; 7: 400

Mast cell activation-degranulation

-by bridging of two mast cell surface-attached IgE antibodies by

antigen or hapten as rapid and explosive process (1000 bridges)-Mast cells, T-cells, macrophages are interacting and interrelated through

bidirectional signals

• Preformed mediators• Histamine

• Neutral proteases (tryptase chymase, cathepsin D)

• Growth factors

• Proteoglycans, Renin

• Angiotensin,5HT, serotonin

Newly formed mediators-Chemokines,Cytokines

-Arachidonic acid products (by liberation of arachidonic acid(ω6) from cell membrane phospholipids through phospholipase action) corticosteroids

Cyclo-oxygenase ASA Lipoxygenase VitE

Prostaglandines PAF leukotrienes

-thromboxane

-prostacyclin

serotonin

LMW Heparin

HIRUDIN

BIVALIRUDIN

epinephrine

TXA2

thrombin

ADP

Fibrinogen

GP IIb/ IIIa inhibitors

2. ACTIVATION

MediatorsAdhesive (vWF, fibrinogen)

Prothrombotic (V,XI, PAI-1)

Proinflammatory (PDGF, PF4)

Aggregatory (ADP, ATP, Ca, Mg)

Mast cell

MEDATORS

1. ADHESIONVia interaction of

GP IIb/II/a and vWF

EosinophilAspirin

Mast cell

serotonin

Pl changes from discoid

to spiculated form

Degranulation

3. AGGREGATION

PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME

Clopidogrel

Prasugrell

(P2Y12)

Ticagrelor

Triflusal

GP IIb/ IIIa receptors

PAF histamineFCεRI-FCεRII

Ticlopidin

MAST CELL INHIBITORS

Kounis syndrome

Causality

Analgesics (e.g., aspirin and dipyrone)

Anesthetics (e.g., etomidate, isoflurane, midazolam,

propofol, remifentanil, rocuronium bromide,

succinylcholine, suxamethonium and trimethaphan)

Antibiotics (e.g., ampicillin, ampicillin/sulfactam,

amoxicillin, amikacin, cefazolin, cefoxitin,

cefuroxime, cephradine, cinoxacin, lincomycin,

penicillin, sulbactam/cefoperazone,

piperacillin/tazobactam, trimethoprim–

sulfamethoxazole, sulperazon and vancomycin)

Anticoagulants (e.g., heparin and lepirudin)

Antineoplastics (e.g., 5-fluorouracil, capecitabine,

carboplatin, denileukin, interferons, paclitaxel

and vinca alkaloids)

Contrast media (e.g., Iohexone, loxagate, diatrizoate

meglumine and sodium indigotindisulfonate)

Glucocorticoids (e.g., b-methasone and

hydrocortisone)

Nonsteroidal anti-inflammatory drugs (e.g.,

alclofenac, diclofenac and naproxen)

Proton pump inhibitors (e.g, lansoprazole,

pantoprazole)

Skin disinfectants (e.g., chlorhexidine and povidone-

iodine)

Thrombolytics (e.g., streptokinase, tissue

plasminogen activator and urokinase)

Others (allopurinol, enalapril, esmolol, dextran,

bupropion, fructose, insulin, iodine, clopidogrel,

protamine, tetanus antitoxin, glaphenine

mesalamine, Losartan, gelofusin, metals,

gadolinium)

2. ConditionsAngioedema

Bronchial asthma

Churg–Strauss syndrome

Exercise-induced anaphylaxis

Food allergy

Hay fever

Idiopathic anaphylaxis

Intracoronary stenting

Mastocytosis-MMAS

Nicotine

Serum sickness

Urticaria

Scombroid syndrome

3. Environmental exposures

Dog licking

Grass cutting

Hymenoptera stings

Jellyfish stings

Latex contact

Millet allergy

Mushroom poisoning

Poison ivy

Shellfish eating (kiss of death)

Viper venom

Causes capable of inducing Kounis S1. Drugs

Kounis syndrome

Incidence

“Epidemiology of acute coronary syndrome co-existent with allergic/hypersensitivity/anaphylactic reactions (Kounis syndrome) in the United States: A nationwide

• Total of 235,420 hospitalizations (National Inpatient Sample-NIS

databases) occurred with allergic/hypersensitivity/anaphylactic

reactions from 2007-2014

•Prevalence of KS among these patients was 1.1% namely 2616 [0.2%

UA, 0.2% STEMI & 0.7% NSTEMI with in-hospital mortality of 7.0%

vs.o.4% as compared to the non-KS group

•KS patients were older, more often white, male, prolonged

hospitalization, higher hospitalization charges

•Rates of stroke (1.0% vs.0.2%), arrhythmia (30.4% vs. 12.4%) and

VTE-venous thromboembolism (1.6% vs. 1.0%) were significantly

higher in KS group

Int J Cardiol October 2019; 292: 35-38

Kounis syndrome

Clinical pictureVariants-Treatment

Tryptase

VARIANTS

The type I variant (coronary spasm), represent a manifestation of endothelial dysfunction or microvascular angina. Constitutes one of the MINOCA causes (Myocardial Infarction with Non-Obstructive Coronary Arteries. Treatment: antihistamines, corticosteroids, vasodilators Kounis NG, Zavras GM. Br J Clin Pract 1991; 45: 121–8

The type II variant: Acute myocardial infarction. Treatment: Myocardial infarction protocol, antihistamines, corticosteroids Nikolaidis LA, Kounis NG, Grandman AH. Can J Cardiol 2002; 18: 508–11

The type III variant: two subtypes, stent thrombosis (a) and in-stent restenosis (b), thrombus infiltrated by eosinophils and /or mast cells. Treatment: Myocardial infarction protocol, thrombus aspiration, angioplasty, restentingBiteker M. Int J Cardiol 2010;145: 553Itoh T, Nakajima Y, Morino Y. Clin Chem Lab Med 2017; 55 :e107

Kounis syndrome

Stent thrombosis

Figure 1. Aspirated thrombus from patient with type III variant of Kounis syndrome. White

star shows thrombus infiltrated by numerous eosinophils, black star shows fibrin deposition and

black–white star shows red cells mixed with scattered eosinophils. Kounis NG et al. Future Cardiology 2011; 7: 805-824

IMPLICATIONS OF KOUNIS

SYNDROME

“KS unveiled a Common Pathway of allergic and non allergic coronary events”

Densities of activated mast cells in 20 patients (12M, 8F) died 24h after an Acute MI Kovanen PT, et al. Circulation 1995;92:1084

Circulating blood contains only mast cell precursors and these take several days or weeks to mature and filled with cytoplasmic secretory granulesTherefore, the mast cells must have been present at the site of rupture before the acute event

Mast cell activation precedes acute coronary event

• Shoulder: the vulnerable part of atheroma

Shoulder: the vulnerable part of

coronary atheroma

INCREASED TRYPTASE IN ACS OF NON ALLERGIC ETIOLOGY

CONCLUSIONS:

High tryptase levels after PCI were

associated with poor myocardial

reperfusion and poor cardiac function

IMPLICATIONS OF KOUNIS SYNDROME

Kounis syndrome: natural paradigm for preventing ACS and thrombosis

Nemmar et al, have managed to abrogate late thrombotic events (induced by intratracheal instillation of diesel exhaust particles for 24h+femoral vein endothelial injury), by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone

Nemmar A, et al. Circulation 2004; 110: 1670-1677

. Platelets were stimulated with adenosine-5

diphosphate (ADP) in:

- Whole human blood from healthy male donors

- Platelets in plasma

- Isolated platelets

Petrikova M, et al. H1 antihistamines and

activated blood platelets. Inflammation

Res 2006; 55 Suppl 1: S51-S52

serotonin

LMW Heparin

HIRUDIN

BIVALIRUDIN

epinephrine

TXA2

thrombin

ADP

Fibrinogen

GP IIb/ IIIa inhibitors

2. ACTIVATION

MediatorsAdhesive (vWF, fibrinogen)

Prothrombotic (V,XI, PAI-1)

Proinflammatory (PDGF, PF4)

Aggregatory (ADP, ATP, Ca, Mg)

Mast cell

MEDATORS

1. ADHESIONVia interaction of

GP IIb/II/a and vWF

EosinophilAspirin

Mast cell

serotonin

Pl changes from discoid

to spiculated form

Degranulation

3. AGGREGATION

PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME

Clopidogrel

Prasugrell

(P2Y12)

Ticagrelor

Triflusal

GP IIb/ IIIa receptors

PAF histamineFCεRI-FCεRII

Ticlopidin

MAST CELL INHIBITORS

. Platelets were stimulated with adenosine-5

diphosphate (ADP) in:

- Whole human blood from healthy male donors

- Platelets in plasma

- Isolated platelets

Antihistamines Dithiaden, Loratadine and Bromadyl inhibited platelet

activation-aggregation in the above 3 experimental systems

Petrikova M, et al. H1 antihistamines and

activated blood platelets. Inflammation

Res 2006; 55 Suppl 1: S51-S52

. Platelets were stimulated with adenosine-5

diphosphate (ADP) in:

- Whole human blood from healthy male donors

- Platelets in plasma

- Isolated platelets

Antihistamines Dithiaden, Loratadine and Bromadyl inhibited platelet

activation-aggregation in the above 3 experimental systems

Petrikova M, et al. H1 antihistamines and

activated blood platelets. Inflammation

Res 2006; 55 Suppl 1: S51-S52

30,569 aged 5-44Y for 20Y

With mild asthma the danger of

myocardial infarction was 22%

lower with the use of inhaled

corticosteroids

With severe asthma the

danger of myocardial

infarction was 81% lower

with the use of inhaled

corticosteroids

Antileukotriene drug (leukotriene receptor antagonists) administration in patients with recent acute coronary syndrome induces reduction in leukotriene production, resulting in a slowed coronary plaque progression at follow-up in comparison with placebo”

Treatment With 5-Lipoxygenase Inhibitor VIA-2291 (Atreleuton) in Patients

With Recent Acute Coronary Syndrom . Circulation: Cardiovascular Imaging 2010; 3: 298–307

that is:

That’s why we believe:a new possibility emerges for prevention of coronary

plaques to become unstable lesions prone to thrombosis

and that is:

“Inhibition of mast cell degranulation”

((((((

Kaartinen M, et al. Circulation 1994; 90: 1669-78

Kounis NG. Int J Cardiol 2006; 110; 7-14

Lindstedt KA, et al. J Cell Mol Med 2007; 11: 739-58

Kounis et al. Future Cardiology 2011; 7: 805-824

Kounis NG. Clin Chem Lab Med 2016; 54: 1545–1559

Kounis NG. Balkan Med J 2019 ; 36: 212-221

Drugs and natural molecules capable to stabilize mast cells

A. IgG1 humanized monoclonal antibodies (omalizumab) recognizing and masking corresponding IgE receptors in mast cell membrane (Allergy 2017 Apr; 72: 519-533

B. Stem cell factor (SCF) targeting drugs, since SCF is essential for mast cell development, proliferation, survival, adhesion, and homing (Clin Pharmacol 2019 Jul 10; 11: 77-92).

C. Simultaneous inhibition of H1 and H2

Lodoxamide-Ketotifen-H1-blocker (Zaditen) Sodium cromoglycate (lomuntal)

Sodium nedocromil (intal)

D. Flavonoid quercetin

Flavone luteolin inhibits T-cell action,

mast cell-dependent T- cell activation

“Imagination is more important than knowledge”

CURRENT ACTION: Ηδη τρέχει μια

πολυκεντρικη μελέτη, με Αμερικανούς

συνάδελφους, με εκατοντάδες χιλιάδες

αρρώστους από το National Inpatient Sample

(NIS) and medicaid insurance databases που

;exoyn λεπτομερή ιστορικά αρρώστων που

λαμβάνουν αντιαλλεργικά φάρμακα και

άλλων αρρώστων που δεν λαμβάνουν που

μελετά την επίδρασή τους στον κίνδυνο των

στεφανιαίων επεισοδίων.The near future will

show!

EYXAΡΙΣΤΩ-ΠΡΟΕΔΡΟ ΚΑΙ ΤΑ ΜΕΛΗ ΤΟΥ ΔΣ ΤΗΣ ΕΚΕ

-ΣΥΝΑΔΕΛΦΟΥΣ, ΦΟΙΤΗΤΕΣ ΚΑΙ ΠΡΟΣΩΠΙΚΟ ΤΗΣ ΚΑΡΔΙΟΛΟΓΙΚΗΣ ΚΛΙΝΙΚΗΣ ΤΟΥ

ΠΑΝΕΠΙΣΤΗΜΙΟΥ ΠΑΤΡΑΣ

-ΣΥΝΑΔΕΛΦΟΥΣ MOY ΚΑΙ ΙΔΙΑΙΤΕΡΑ ΤΟΥΣ ΝΕΟΥΣ