Milan lecture kounis syndrome

Kounis Syndrome
From Bedside to Bench!
“A hypersensitivity blow up inside the coronaries”

Hypersensitivity inflammation
Acute coronary syndrome
+

Hypersensitivity inflammation
Acute coronary syndrome
Hypersensitivity coronary syndrome
(Kounis syndrome)
+

“ ……even ordinary allergic reactions could promote plaque disruption………”
Circulation 1995; 92: 1083

Mast cells*
From bone marrow enter the circulation as mononuclear cell
precursors that express messenger ribonucleic acid (mRNA) for
stem cell factor and have KIT receptors for the SCF. They migrate
into all the tissues, including the brain which does not suffer from
allergic reactions because IgE does not cross the blood-brain barrier
and they differentiate and mature there.
This takes several days to weeks.
Basophils develop in bone marrow from granulocyte
precursors and entering the circulation only when
fully mature.. They are not normally found in extravascular
tissues compartments, only migrating there during late-phase
allergic responses
*Named by Paul Erlich in 1887 (German=mastzellen=well fed)

Kounis syndrome: the
hypersensitivity coronary syndrome
What is?
“The concurrence of acute coronary syndromes with conditions
associated with mast cell activation, involving interrelated and
interacting inflammatory cells, and including allergic or
hypersensitivity and anaphylactic or anaphylactoid insults”. “It is
caused by inflammatory mediators such as histamine, neutral
proteases, arachidonic acid products, platelet activating factor
and a variety of cytokines and chemokines released during the
activation process.” “A subset of platelets bearing FCεRI and
FCεRII receptors are also involved in the activation cascade”
Mast cells
Macrophages T-cells
Mast cells

.
The cytokine network. Image of the global network of cytokine interactions between the
4 immune cells (red nodes) and the 15 non-immune body cells (blue nodes). The black edges represent mutual connections; the grey edges represent one-way connections.

The vicious cycle of
inflammatory cells
Macrophages
Mast cells
Macrophages
T-cells
Macrophages
All these inflammatory cells participate in a
vicious inflammatory cycle and via
multidirectional signals:
1. Mast cells can enhance T cell activation1
2. T cells can mediate mast cell activation
and proliferation2
3. Inducible macrophage protein-1α can
activate mast cells3
4. mast cells can activate macrophages4
5. T cells can regulate macrophage
activity5
1. Nakae S, et al. J Immunol 2006; 176: 2238
2. Mecori YA, et al. Clin Immunol 1999; 104: 517
3. Miyazaki D, et al. J Clin Invest 2005; 115: 434
4. Salari H, et al. J Immunol 1989; 142: 2821
5. Doherty TM. Curr Opin Immunol 1995; 7: 400

Mast cell: the pleiotropocyte and
its Inflammatory mediators• PREFORMED MEDIATORS
• Biogenic amines
• -histamine
• -Renin
• -angiotensin II
• -serotonin
• Chemokines
• -IL-8, MCP-1, MCP-3,
MCP-4, RANTES
• Enzymes
• -arysulfatases
• -carbopeptidase A
• -Chymase
• -kinogenases
• -phospholipases
• -tryptase, Cathepsin G
•
• Peptides
• -bradykinin
• -corticotropin-releasing
hormone
• -endorphins
• -endothelin
• -somatostatin
• -substance B
• -vasoactive intestinal
peptide
• -urocortin
• -vascular endothelial
growth factor
• -vascular factor
• Proteoglycans
• NEWLY SYNTHESIZED MEDIATORS
• Cytokines
• -interleukins (IL)-
1,2,3,4,5,6,9,10,13,16
• -interferon-γ
• -macrophage
• activating factor
•
•
• -tumor necrosis factor-α
• Growth factors
• -granulocyte
monocyte-colony stimulating factor
• -fibroblast growth
factor
• -nerve growth factor
• -stem cell factor
• -vascular endothelial growth
factor
•
• Arachidonic acid products
• -leukotrienes
• -platelet activating factor
• -prostaglandins
(thromboxane)
Theoharides TC. J Clin Psychopharmacol 2002;22:103

Kounis syndrome:
main actions of main mediators
Cardiac effects of histamine
1.Coronary vasoconstriction (histamine test)
2. Induces tissue factor expression and activity
3. Activates platelets and potentiates the
aggregatory response of agonists e.g.
adrenaline, 5-hydroxytryptamine, and thrombin
4. Intimal thickening
5. Inflammatory cell modulation
6. Modulates the activity of neutrophils,
monocytes, and eosinophils
7. Proinflammatory cytokine production
8. P-selectine upregulation
9. Sensitizites nerve endings in coronary plaques

Kounis syndrome: cardiac actions of
main mediators: Proteases
Tryptase
1. Activates the zymogen forms of
metalloproteinases such as
interstitial collagenase, gelatinase,
and stromelysin and can promote
plaque disruption or rupture.
2. Degrates the pericellular matrix
components fibronectin and
vitronectin and neuropeptides,
such as vasoactive intestinal
peptide (VIP) and calcitonin gene
related peptide (CGRP)
3. Tryptase can degrade HDL
4. Activates neighboring cells by
cleaving and activating protease-
activated receptor (PAR)-2, and
thrombin receptors
Chymase
1. Converts angiotensin I to angiotensin
II and angiotensin II receptors are
found in the medial muscle cells of
human coronary arteries. Thus,
angiotensin II generated by
chymase could act synergistically
with histamine and aggravate the
local spasm of the infarcted
coronary artery. Chymase also can
remove cholesterol from HDL
2. Activates MMP-1,-2,-9 and plays a
major role in the physiologic
degradation of fibronectin and
thrombin
Cathepsin D
1. Angiotensin II-forming protease
2.Degrates both fibronectin and VE-cadherin which are necessary for

Leukotrienes: Powerful arterial vasoconstrictors
and their biosynthesis is enhanced in the acute phase of
unstable angina
Thromboxane: A potent mediator of platelet
aggregation with vasoconstricting properties
Platelet activating factor: In myocardial
ischemia acts as proadhesive signalling molecule or via
activation of leucocytes and platelets to release other
mediators. It can act either through the release of
leukotrienes or as a direct vasoconstrictor
Kounis syndrome: cardiac actions
of the main mediators

Kounis syndrome variants
Type I variant: includes patients with normal
coronary arteries without predisposing factors for coronary artery
disease in whom the acute release of inflammatory mediators can
induce either coronary artery spasm without increase of cardiac
enzymes and troponins or coronary artery spasm progressing to
acute myocardial infarction with raised cardiac enzymes and
troponin Nikolaidis LA, et al. Can J Cardiol 2002; 18: 508Nikolaidis LA, et al. Can J Cardiol 2002; 18: 508
Type II variant: includes patients with culprit but
quiescent pre-existing atheromatous disease in whom the acute
release of inflammatory mediators can induce either coronary artery
spasm with normal cardiac enzymes and troponins or plaque
erosion or rupture manifesting as acute myocardial infarction
Type III variant: includes patients with coronary
artery stent thrombosis in whom aspirated thrombus specimens
stained with hematoxylin-eosin and Giemsa demonstrate the
presence of eosinophils and mast cells respectively
Biteker M. Expert Rev Clin Immunol 2010; 6: 777-88
Nikolaidis LA, et al. Can J Cardiol 2002; 18: 508Nikolaidis LA, et al. Can J Cardiol 2002; 18: 508

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 (e.g., allopurinol, enalapril,, esmolol, dextran,
bupropion, fructose, insulin, iodine,
protamine,tetanus antitoxin, glaphenine and
mesalamine, Losartan, gelofusin)
2. Conditions
Angioedema
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
Poison ivy
Shellfish eating (kiss of death)
Viper venom
Causes capable of inducing Kounis
syndrome
1. Drugs

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 (e.g. allopurinol, enalapril,, esmolol, dextran,
bupropion, fructose, insulin, iodine,
protamine,tetanus antitoxin, glaphenine and
mesalamine, Losartan, gelofusin)
2. Conditions
Angioedema
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
Poison ivy
Shellfish eating (kiss of death)
Viper venom
Causes capable of inducing Kounis
syndrome
1. Drugs

Clinical and Electrocardiographic
Features of Kounis Syndrome
Clinical Symptoms
• Chest discomfort
• Acute chest pain
• Dyspnea
• Faintness
• Nausea
• Vomiting
• Syncope
• Pruritus
• Urticaria
Clinical sings
• Hypotention
• Diaphoresis
• Pallor
• Palpitations
• Bradycardia
• Tachycardia
Electrocardiographic sings
T-wave flattering
T-wave inversion
ST segment elevation (STEMI)
ST segment depression (non-STEMI)
QRS complex prolongation
QT segment prolongation
Sinus tachycardia
Sinus bradycardia
Nodal rhythm
Atrial fibrillation
Ventricular ectopics
Bigeminal rhythm
Kounis NG, Zavras GM. Br J Clin Pract 1991; 45: 121

The challenging treatment of
Kounis syndrome
• Τype I: Treatment of the allergic event alone can
abolish it, so give corticosteroids, H1 and H2
blockers, Ca-blockers, nitrates
• Τype ΙΙ: The acute coronary event protocol plus
the type I treatment
• Τype ΙΙΙ: The type I and type II treatment plus
thrombus aspiration. Histological examination of
thrombus and staining for eosinophils
(hematoxylin-eosin) and mast cells (Giemsa).
Allergic symptoms following stent implantation
need anti allergic treatment, if they insist
desensitization for the guilty component and
finally ? Stent extraction!

One shoud bear in mind:
-Nitroglycerin: can cause hypotension and tachycardia
-B-blockers: can exaggerate coronary spasm due to unopposed
a- adrenergic receptors action
-Epinephrine: can aggravate ischemia and worsen coronary
spasm in Kounis syndrome. In severe cases sulfide free
epinephrine is preferable (0.2-0.5mg 1:1000 aqueous solution). In
patients on b-blockers may be ineffective. Glucagon may be
considered
-Opiates: such as morphine, codeine and meperidine should be
given with extreme caution because can induce massive mast cell
degranulation and aggravate allergic reaction. Fentanyl and its
derivatives show slight mast cell activation and should be
preferable

Kounis Syndrome
………………. “Allergic angina and allergic
myocardial infarction represent a
magnificent natural paradigm that might
have profound clinical and therapeutic
implications. This is based on clinical and
laboratory findings”……………..
Kounis NG, et al. Circulation 1999; 10: e156

Τhree important questions
concerning Kounis syndrome
(“Τhere are more more questions than answers,” top 20 song of 70nties, perfomed by Jony Nash)
1. Does inflammatory
cell activation
precede acute
coronary events?
Are the released
inflammatory
mediators the cause
or are the result of the
acute coronary
syndrome?
2. Is ischemic
myocardial damage a
primary event during
hypersensitivity
insults? (It is believed that systemic
vasodilatation, reduced venous return, leakage
of plasma and volume loss due to increase
vascular perneability, and the ensuing
depression of cardiac output contribute to
coronary hypoperfusion with subsequent
myocardial damage)
3. Why Kounis
syndrome occurs less
often while allergic
reactions are so
common?

cell activation
precede acute
coronary events?
Are the released
inflammatory
mediators the cause
acute coronary
syndrome? I believe
2. Is ischemic
myocardial damage a
hypersensitivity
insults? (It is believed that systemic
vasodilatation, reduced venous return, leakage of
plasma and volume loss due to increase vascular
perneability, and the ensuing depression of cardiac
output contribute to coronary hypoperfusion with
subsequent myocardial damage)
3. Why Kounis
reactions are so
common?

Sakata Y, et al. Am J Cardiol 1996; 77: 1121-1126
P<0.001
First question: Are the released inflammatory mediators the cause or
are the result of the acute coronary syndrome? I believe YES
Plasma histamine in the great cardiac vein in 11 patients
with variant angina (group A) and in 8 with normal
angiogram or with fixed coronary stenosis (group B)

Overnight histamine levels in the
same patient in two different dates
with and without anginal attack
Sakata Y, et al. Am J Cardiol 1996; 77: 1121-1126

Plasma histamine did not raise during or
after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y, et al. Am J Cardiol 1996;77: 1121-1126

Kovanen PT, et al. Circulation 1995;92:1084
First question: Are the released inflammatory mediators the cause or are the
result of the acute coronary syndrome? I believe YES
Densities of activated mast cells in 20 patients
died from acute myocardial infarction in the previous
24 hours
Circulating blood contains
only mast cell precursors
and these take several
days or weeks to mature
and filled with cytoplasmic
secretory granules
Therefore,the mast cells
must have been present at
the site of rupture before
the acute event

cell activation
precede acute
coronary events?
Are the released
inflammatory
mediators the cause
acute coronary
syndrome? I believe
2. Is ischemic
myocardial damage a
anaphylactic insults?
I THINK YES (It is believed that systemic
vasodilatation, reduced venous return, leakage of
plasma and volume loss due to increase vascular
perneability, and the ensuing depression of cardiac
output contribute to coronary hypoperfusion with
subsequent myocardial damage)
3. Why Kounis
reactions are so
common?

Question 2: Is ischemic myocardial damage a
primary event during anaphylactic insults?
I think yes
Before infusion
Felix SB, et al. Exper Med 1990; 190: 2439Felix SB, et al. Exper Med 1990; 190: 2439
2 min after ovalbumin infusion was started (guinea pigs)

Question 2
Anaphylaxis affects the heart directly
a. LVSP c. LVdP/dt d. mean BP (rapid increase in contractile
papameters) b.LVEDP(cardiac pump failure) e. cardiac output f.stroke
volume

Question 2
Anaphylaxis affects the heart directly
a. LVSP c. LVdP/dt d. mean BP (rapid increase in contractile
papameters) b.LVEDP(cardiac pump failure) e. cardiac output f.stroke
volume
“The present data
showed a significant rise
in BP, concurrent
myocardial ischemia , and
incipient LV pump failure
during the early stages of
anaphylaxis. Thus the
idea that the
registered
anaphylactic
cardiac damage
might be due to
peripheral
vasodilation can
be definitely
excluded”.

“Takotsubo and Kounis syndrome following
intravenous adrenaline injections for
anaphylactic reaction” Kajander OA , et al . Int J Cardiol 2012, in press
Intravenous fluids
administration and
corticosteroids did not revert
anaphylactic shock but the
patient recovered with the
current myocardial infarction
therapy protocol (ACE-
inhibitor, ASA, thrombolysis
etc.)

cell activation
precede acute
coronary events?
Are the released
inflammatory
mediators the cause
acute coronary
syndrome? I believe
2. Is ischemic
myocardial damage a
hypersensitivity
insults? I THINK YES (It is
believed that systemic vasodilatation, reduced
venous return, leakage of plasma and volume loss
due to increase vascular perneability, and the
ensuing depression of cardiac output contribute to
coronary hypoperfusion with subsequent
myocardial damage)
3. Why Kounis
reactions are so
common? Let’s see!

Question 3
Why Kounis syndrome occurs less often while allergic
reactions are so common?
-A threshold level of mast cell content
(histamine,tryptase,chymase, leukotriene,
thromboxane, PAF and chemokines) exists, above
which it can provoke coronary artery spasm and/or
plaque erosion or rupture Kounis NG, et al, Int J Cardiol 2006; 110: 7-
14

Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common?
-A threshold level of mast cell content (histamine,tryptase,chymase, leukotriene,
thromboxane, PAF and chemokines) exists, above which it can provoke coronary
artery spasm and/or plaque erosion or rupture Kounis NG, et al, Int J Cardiol 2006; 110: 7-14
-Patients with increased baseline tryptase are prone to develop immediate and
severe allergic reaction to hymenoptera sting. Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activation
Akin C, et al. Blood 2007; 110: 2331-3
Are there any KIT
mutations that lower the stimulus threshold
for anaphylaxis, and “these patients have hyper-responsive mast
cell phenotype resulting in the development of severe allergic reactions”
Metcalfe DD, et al. J Allergy Clin Immunol 2009; 123: 687-688
and why not
of Kounis syndrome?
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)
that is essential for mast cell growth, differentiation, development,
proliferation,
survival, adhesion and homing.

“Kounis syndrome, a cause of chest pain
to keep in mind, may be associated with
E148Q mutation” Saylan b et al. Hong Kong J Emerg Med 2012; 19: 278-282
Coincidence?
Let’s see……..

Clinical implications of Kounis syndrome
Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis

Frequency of stent thrombosis
up to 3.5%, Death 20% to 40%)
-“Of 5842 STEMI
patients treated
with primary PCI
201 (3.5%)
presented with
definite early ST. 97
(1.7%) were acute
and 104(1.8%)
were subacute ST”
Heestermans AA, et al. J Thromb Haemost 2010 ; 8:
2385-93
-Thereafter 0.5% to 1%
Holmes DR, et al. JACC White Paper 2010; 56: 1357
The incidence of
stroke in
untreated atrial
fibrillation is
approximately
2-10% per year
and 2.6-2.9% in
treated
Friberg L, et al. Eur Heart J. 2010; 31: 967-75

Clinical implications of Kounis syndrome
Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Less restenosis but more thrombosis
Contrasting mechanisms of
obstruction of bare-metal
and drug-eluting stents

THE FACTS: First generation Drug
Eluting Stents (are still used)
components:
1.The metal itself is made from
stainless steel which contains:
nickel, chromium, titanium, manganese, and molybdenum
2.The polymer coating
3.The antineoplastic Paclitaxel or
3.The antiproliferative Rapamycin
Kounis NG, et al.Kounis NG, et al. J Am Coll Cardiol 2006; 48: 592
33

THE FACTS: First generation Drug
Eluting Stents (are still used)
components:
1.The metal itself is made from
stainless steel which contains:
nickel, chromium, titanium, manganese, and molybdenum
2.The polymer coating
3.The antineoplastic Paclitaxel or
3.The antiproliferative Rapamycin
All these are strong allergens and
constitute the “stent antigenic complex”
Kounis NG, et al.Kounis NG, et al. J Am Coll Cardiol 2006; 48: 592
33

Hypersensitivity to Drug Eluting
Stents components and Kounis
syndrome
Hypersensitivity reactions to nickel
allergic contact dermatitis
baboon syndrome
bronchial asthma
dependent edema
diffuse exanthema
fever
flexural dermatitis
itching erythema
pericarditis
pompholyx formation
rosacea
sarcoid granuloma (delayed hypersensitivity)
Kounis NG. Hahalis G, Theoharides TC. J Interven Cardiol 2007; 20: 314-323

stents components and Kounis
syndrome
Hypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis
-allergic rhinitis
-allergic allergic stomatitis
-facial angioedema
-generalized anaphylactic reaction
-generalized urticaria
-interstitial asthma
-neurodermatitis
-stomatitis venenada

syndrome
Hypersensitivity reactions with the use of paclitaxel
-angioedema
-atrioventricular block
-bronchospasm
-cutaneous flushing
-diaphoresis
-Kounis syndrome
-left bundle branch block
-ventricular tachycardia
-urticaria
Kounis NG. Hahalis G, Theoharides TC. J Interven Cardiol 2007; 20: 314

syndrome
Kounis NG. Hahalis G, Theoharides TC. J Interven Cardiol 2007; 20: 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis
-angioedema
-flushing
-pruritus
-interstitial pneumonitis
-Schonlein-Henoch purpura
-localized eczematiform eruption
-palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction

SECOND GENERATION DES: they are
named cobalt-chromium or platinum
chromium stents (misleading term?)
1.Xience
(everolimus) stent
The information we have obtained from
the manufacturer indicates that the alloy
composition of the Xience stent is 55%
cobalt 20% chromium, 15% tungsten,
10% nickel
Min. Max
Carbon 0.05 0.15
Manganese 1.00 2.00
Silicon -- 0.40
Phosphorus -- 0.040
Sulfur -- 0.030
Chromium 19.00 21.00
Nickel 9.00 11.00
Tungsten 14.00 16.00
ron -- 3.00
Cobalt* Balance Balance
•
2.Endeavor
(zotarolimus) stent
3.The PROMUS platinum-
chromium everolimus-eluting stent
PROMUS (another misleading term?)
Contains also nickel

Nickel sensitization (patch test)in North-Eastern Italy
(Belluno, Bolzano, Padova, Pordedone,
Rovereto,Rovigo, Trento, Trieste)
31.6% in women (9771)
10.0% in men (4693)
The overall prevalence 24.6%

4. Clopidogrel-induced allergic
skin rash

5. Kounis NG, et al. “Myocardial
infarction after aspirin treatment,
and the Kounis syndrome”. J R Soc
Med 2005; 98: 296

The 6th
inadvertent antigen!
6. Atopic stented individuals are
under the risk of any additional
drug or environmental
exposure which may “join
forces” with the previous 5
agents and trigger the cascade
of intrastent thrombosis

More than 5 antigens are irreversibly implanted
and some of them apply continuous, persistent,
chronic and repetitive allergic irritation!
A total of 1000 bridges are
necessary to trigger the cell out of
maximal number of some 500 000 -1
000 000 IgE molecules on the cell
surface. It might be possible to
accumulate the critical number of
bridges by more than one noncross-
reactive allergen and its
corresponding IgE antibody”
“ IgE antibodies with different
specificities can have an
additive effect i.e. if mast
cells are sensitized with small,
even subthreshold numbers of
IgE antibodies of different
specificities they can “join
forces” and trigger the cells
to release its mediators,if the
patient is simultaneously
exposed to corresponding
allergens”
Nopp A, et al. Allergy 2006; 61: 1336

Do Stents, like magnet, attract
inflammatory cells?
1. Stent thrombosis associated with allergic symptoms such as glottis
edema, cold sweat, and tongue enlargement followed a flavonate-
propyphenasone administration a week after stent implantation. Int J Cardiol.
2009; 134: e45-6
2. Acute myocardial infarction, in the stented area, coincided with allergic
reaction following intravenous administration of the non-anionic contrast
material iopromide during a routine excretory urography. Int J Cardiol 2010; 139:
206-9
3. Intrastent thromboses have also been reported following insect and larvae
sting allergic reactions. Cases J. 2009; 2: 7800
4. Late drug eluting stent thrombosis due to acemetacine: Type III
Kounis syndrome - Kounis syndrome due to Acemetacine
Int J Cardiol 2012; 155: 461-2

Do Stents, like magnet, attract
inflammatory cells?
1. Stent thrombosis associated with allergic symptoms such as glottis
edema, cold sweat, and tongue enlargement followed a flavonate-
propyphenasone administration a week after stent implantation. Int J Cardiol.
2009; 134: e45-6
2. Acute myocardial infarction, in the stented area, coincided with allergic
reaction following intravenous administration of the non-anionic contrast
material iopromide during a routine excretory urography. Int J Cardiol 2010; 139:
206-9
3. Intrastent thromboses have also been reported following insect and larvae
sting allergic reactions. Cases J. 2009; 2: 7800
4. Late drug eluting stent thrombosis due to acemetacine: Type III
Kounis syndrome - Kounis syndrome due to Acemetacine
Int J Cardiol 2012; 155: 461-2
5 . Recurrent acute stent thrombosis due to allergic reaction secondary to
clopidogrel
Am J Therapeutics 2011; 18: e119-e122
But clopidogrel is given to prevent stent thrombosis!

-Localized Hypersensitivity and Late Coronary
Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious?-
Virmani et al. Circulation 2004; 109: 701
Focal strut malapposition
with aneurysmal dilatation
(double arrows in D and F)
and occlusive luminal
thrombosis
E Extensive inflammation
consisting primarily of
eosinophils and
lymphocytes, with a focal
giant cell reaction around
stent strut (*) and
surrounding polymer.
Marked inflammation is
similarly present in intima,
media, and adventitia in J
(left box in E). K and L
(Luna stains) show giant
cells (arrowheads) around
a polymer remnant that
has separated from stent
strut and numerous
eosinophils
within arterial

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

It has been stated that
“eosinophilic infiltration
of intrastent thrombus
seems to be a common
finding in stented
patients and is not a
peculiarity”Zavalloni D, et al. J Cardiovasc Med 2009;10: 942 “Humanitas Clinical Institute” Milan

Atherosclerosis 2011; 215: 166–169
Eosinophil cationic protein and clinical outcome
after bare metal stent implantation
Giampaolo Niccoli, Gregory A. Sguegliaa, Micaela Contea, Nicola Cosentinoa,
Silvia Minellia, Flavia Bellonia, Carlo Trania, Vito Sabatob, Francesco Burzottaa,
Italo Portoa, Antonio Maria Leonea, Domenico Schiavinob, Filippo Creaa
-
-Which means that allergic predisposition
may help in prediction of the risk for stent
thrombosis, therefore measuring of eosinophil
cationic protein should be added in our work
up-
Kounis NG, et al. Atherosclerosis 2011; 217: 67-69

Atherosclerosis 2011; 215: 166–169
Eosinophil cationic protein and clinical outcome
after bare metal stent implantation
Giampaolo Niccoli, Gregory A. Sguegliaa, Micaela Contea, Nicola Cosentinoa,
Silvia Minellia, Flavia Bellonia, Carlo Trania, Vito Sabatob, Francesco Burzottaa,
Italo Portoa, Antonio Maria Leonea, Domenico Schiavinob, Filippo Creaa
-
“History of allergy is a predictor of adverse
events in unstable angina treated with
coronary angioplasty” Brunneti et al Allergol
Immunopathol 2012, in press
-Which means that allergic predisposition
may help in prediction of the risk for stent
thrombosis, therefore measuring of eosinophil
cationic protein should be added in our work
up-
Kounis NG, et al. Atherosclerosis 2011; 217: 67-69

Platelets play an important role in
pathogenesis of Thrombosis
1. Platelet adhesion
2. Platelet activation
3. Platellet aggregation

serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
AD
P
Fibrinogen
GP IIb/ IIIa inhibitors
2. ACTIVATION
Mediators
Adhesive (vWF, fibrinogen))
Prothrombotic (V,XI, PAI-1)
Proinflammatory (PDGF, PF4)
Aggregatory (ADP, ATP, Ca, Mg)
Mast cell
ME
DA
TO
RS
Eosinophil
Aspirin
Mast cell
serotonin
Pl changes from discoid
to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
Clopidogrel
Prasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb/ IIIa receptors
Ticlopidin

serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
AD
P
Fibrinogen
2. ACTIVATION
Mediators
Adhesive (vWF, fibrinogen)
Mast cell
ME
DA
TO
RS
Eosinophil
Aspirin
Mast cell
serotonin
to spiculated form
Degranulation
Clopidogrel
Prasugrell
(P2Y12)
Ticagrelor
Triflusal
PAF
Ticlopidin

serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
AD
P
Fibrinogen
2. ACTIVATION
Mediators
Mast cell
ME
DA
TO
RS
Eosinophil
Aspirin
Mast cell
serotonin
to spiculated form
Degranulation
Clopidogrel
Prasugrell
(P2Y12)
Ticagrelor
Triflusal
PAF histamine
Ticlopidin

serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
AD
P
Fibrinogen
2. ACTIVATION
Mediators
Mast cell
ME
DA
TO
RS
Eosinophil
Aspirin
Mast cell
serotonin
to spiculated form
Degranulation
Clopidogrel
Prasugrell
(P2Y12)
Ticagrelor
Triflusal
PAF histamine
FCεRI-FCεRII
Ticlopidin
“allergic unit”

serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
AD
P
Fibrinogen
2. ACTIVATION
Mediators
Mast cell
ME
DA
TO
RS
Eosinophil
Aspirin
Mast cell
serotonin
to spiculated form
Degranulation
Clopidogrel
Prasugrell
(P2Y12)
Ticagrelor
Triflusal
PAF histamine
FCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
“allergic unit”

Nemmar et al,
have managed to
abrogate late
thrombotic events,
experimentally, by
stabilizing mast cell
membrane with
sodium
cromoclycate and
reducing
inflammation with
dexamethasone
Nemmar A, et al. Circulation
2004; 110: 1670-1677

H1- antihistamines and activated blood platelets
M. Petríková1
, V. Janˇc inová1
, R. Nosál1
, M. Májeková1
and D. Holomáˇn ová2
1
Institute of Experimental Pharmacology SAS, Dúbravská 9, 841 04 Bratislava, Slovak Republic,
2
National Transfusion Service, Bratislava, Slovak Republic
Inflammation Res 2006; 55 Suppl 1: S51-S52.
a. Whole human blood from healthy male donors
b. Platelets in plasma
c. Isolated platelets
Antihistamines Dithiaden, Loratadine and Bromadyl
inhibited platelet activation-aggregation in all 3
experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at
specific histamine receptors (!)
Platelets were stimulated with adenosine-5
diphosphate (ADP) in:

Fighting against device thrombosis
1.Taking careful history of adverse
drug reactions and allergies
2. Performing antibody and skin
testing when and where
appropriate
3. Measuring eosinophilic kationic
protein
4 .Monitoring of inflammatory
mediators after stent or device
insertion
5. Performing macrophage and T-cell
activation studies
6. Considering desensitization
strategies
7. Considering the use of mast cell
stabilizers and steroids
Kounis NG, et al. J Am Coll Cardiol 2006; 48: 592
Kounis NG, et al N Engl J Med 2006; 354: 2076
7. Measuring of acute phase reactans
8. Periprocedural antiinflammatory therapy
Gaspardone A, Versaci F. Am J Med 2005; 96: 65L
“ In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent components….”
Nebeker JR, et al. JACC 2006;48: 593

1.Nickel free stainless steel with number
of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for
25 min and 3 hours
Yang K, Ren Y. Sci Technol Adv Mater
2010; 11: 1-13

2. Bioabsorbable Stents: A
self expanding drug-eluting non allergic
poly-lactic acid stent

Kounis Syndrome:
Therapeutic
implications
• So far, attempts have been made to
counteract the actions of inflammatory
mediators by using, experimentally:
• Mediator antagonists
• Mediator receptor blockers
• Inhibitors of mediator biosynthesis

“The same mediators from the same cells are present
in both acute allergic and in acute non allergic
coronary events”
• Histamine concentration is double
than normal in ACS (Clejan S, et
al. J Cell Mol Med 2002; 6: 583)
• Histamine is elevated in attacks
of variant angina (Sakata V, et al.
Am J Cardiol 1996; 77:1121)
• Tryptase is elevated especially in
the ST depression group and is
potentially a new marker for the
unstable plaque (Filipiak KJ, et al.
Clin Cardiol 2003; 26: 366)
• Tryptase elevation could be a
novel biomarker identifying
asymptomatic patients and for the
treatment efficacy (Deliargyris EN,
et al. Atherosclerosis 2005; 178:
381)
• Tryptase is elevated in unstable
angina (Cuculo A, et al.
Cardiologia 1998; 43: 189)
• Arachidonic acid metabolites
Thromboxane and leukotrienes
are significantly increased than
normal in ACS (Takase B, et al.
Angiology 1996;47: 649)
• Arachidonic acid metabolites
Thromboxane and leukotrienes are
elevated in unstable angina.
Stress test is not accompanied by
elevation (Cipollone F, et al.
Circulation 2003; 107: 55)
• IL-6 is elevated in ACS
(Deliargyris EN, et al. Am J
Cardiol 2000; 86: 913)
• Infiltrates of activated mast cells
are in ratio 200:1 in the erosion or
ruptured plaque areas in patients
died within 2 days after acute MI
than in nearby healthy areas
(Kovanen PT, et al. Circulation
1995; 92: 1083)

Xiang M, Sun J, Lin Y et al. Usefulness of
serum tryptase level as an independent
biomarker for coronary plaque instability in a
Chinese population. Atherosclerosis 2011; 215,
494–499
Zdravkovic V, Pantovic S, Rosic G et al.
Histamine blood concentration in ischemic
heart disease patients. J Biomed Biotechnol
2011; 2011: 315709

common pathway
for acute allergic and
non allergic coronary
syndromes?
If it is so, then

A new possibility emerges
for the prevention of
coronary plaques to
become unstable lesions
prone to induce acute
myocardial infarction and
that is:

“inhibition of
mast cell
degranulation”
• Kaartinen M, et al. Circulation 1994; 90: 1669
• Kounis NG. Int J Cardiol 2006; 110; 7
• Lindstedt KA, et al. J Cell Mol Med 2007; 11: 739
• Kounis et al. Future Cardiology 2011; 7: 805-824

In medical armamentarium: Drugs
and natural molecules capable to
stabilize mast cells
• Sodium nedocromil (intal)
• Sodium cromoglycate (lomuntal)
• Lodoxamide
• Ketotifen-H1-blocker (Zaditen)
• Flavonoid quercetin ( intacellular Ca)
• Flavone luteolin inhibits T-cells, mast cells and mast cell-dependent T-cell activation
• Relaxin (hormone from corpus luteus and prostate, generates NO)
• NO inhibits IL-6 production through TNF-α inhibition
• Peptides from C3α, C3α+, C3α9+, inhibit FcεRI-induced degranulation and TNF-α
release
• Simultaneous inhibition of H1 and H2
• Zaprinast (phosphodiesterase inhibitor)
• Stem cell factor (SCF) targeting drugs, since SCF is essential for mast cell
development, proliferation, survival, adhesion, and homing (Jensen, et al. Inflamm Allergy Drug
Targets 2007; 6: 57)
• IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in
mast cell membrane (Leung DYM, et al. N Engl J Med 2003; 348: 986)

Is therefore Kounis syndrome a
magnificent natural paradigm
and nature’s own experiment in
a final trigger pathway
implicated for coronary spasm
and plaque erosion or rupture
namely acute myocardial
infarction ?

““Imagination is more important thanImagination is more important than
knowledge”knowledge”

“This is not the end, it is not
even the beginning of the end,
but perhaps it is the end of the
beginning”

Grazie Tante!Grazie Tante!
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis, IatrosNicholas Kounis, Iatros

Clinical implications
2. MENTAL
STRESS AND
THE KOUNIS
SYNDROME

syndrome
Impulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus
chemical mediator release
-norepinephrine
-serotonin
-acetylcholine
activate cells of paraventricular
nucleus of hypothalamus
production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain)
to secrete norepinephrine at the sympathetic nerve endings
activation of corticotrophs of the anterior pituitary gland
production of propiomelanocortin adrenal medulla to produce kidney to activate the
large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces:
-a heightened cardiovascular activity -cytokine IL-1, IL-6, TNF-α production
-endothelial injury resulting in: -macrophage activation
-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION
-recruiting inflammatory cells to arterial wall
-Acute phase response with protein production such as in inflammation
Kounis NG, et al. Eur Heart J 2006; 27: 757; Kounis NG, Filippatos GS. Circulation J 2007; 71: 170
TheThe brainbrain,, thethe heartheart and theand the KounisKounis

Fighting against device thrombosis
1.Taking careful history of
adverse drug reactions and
allergies
2.Performing antibody and skin
testing when and where
appropriate
3.Monitoring of inflammatory
mediators after stent or
device insertion
4.Performing macrophage and
T-cell activation studies
5.Considering the use of mast
cell stabilizers and steroids
6.Considering desensitization
strategies
Kounis NG, et al. J Am Coll Cardiol 2006; 48: 592
Kounis NG, et al N Engl J Med 2006; 354: 2076
7.Measuring of acute phase reactans
8.Periprocedural antiinflammatory therapy
Gaspardone A, Versaci F. Am J Med 2005; 96: 65L
-

syndrome
Impulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus
chemical mediator release
-norepinephrine
-serotonin
-acetylcholine
activate cells of paraventricular
nucleus of hypothalamus
production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain)
to secrete norepinephrine at the sympathetic nerve endings
activation of corticotrophs of the anterior pituitary gland
production of propiomelanocortin adrenal medulla to produce kidney to activate the
large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces:
-a heightened cardiovascular activity -cytokine IL-1, IL-6, TNF-α production
-endothelial injury resulting in: -macrophage activation
-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION
-recruiting inflammatory cells to arterial wall
-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROME
Kounis NG, et al. Eur Heart J 2006; 27: 757; Kounis NG, Filippatos GS. Circulation J 2007; 71: 170
TheThe brainbrain,, thethe heartheart and theand the KounisKounis

Acute stress and mast cell
activation
• Light photomicrographs of
heart sections from
C57BL mice stained with
toluidine blue to show
cardiac mast cells (A) in
control (unstressed) (B, C
and D) stressed mice.
Empty granules stain pink
(arrowhead) as compared
to the dark blue color of
intact granules (solid
arrows); note almost
totally activated mast cell
in (D). Bar=10 μm.
Huang M, et al. Cardiovascular Research

3
Kounis syndrome and sudden death

Schwartz HJ, et al. Is
unrecognized anaphylaxis a
cause of sudden unexpected
death? Clin Exper Allergy 1995;
25: 866
“ We conclude that mast cell
activation may accompany up to
13% of sudden unexpected deaths
in adults. Measurement of both
tryptase and specific IgE antibody
levels in post mortem sera from
patients experiencing sudden,
unexpected death may identify a
small subset of cases due to
clinically unrecognized fatal
anaphylaxis, including those due
to insect stings”.
Zinka B, et al Unexplained
cases of sudden infant death
shortly after hexavalent
vaccination. Vaccine 2006;
31: 5781
SIDS cases in Austria and general vaccination
with HIB, HBV and hexavalent vaccines in the
vaccination schedule of the first 2 years of life
Unusual causes of sudden
death

ECG of a 13 year old girl with fatal
allergic reaction following rubella
vaccination-Colombo, Sri Lanka
III
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6

“Elevated serum concentrations of beta-
tryptase, but not alpha-tryptase, in Sudden
Infant Death Syndrome (SIDS). An investigation
of anaphylactic mechanisms”
Buckley MG, Variend S, Walls AF. Clin Exp Allergy. 2001; 31: 1696-704
.
“Anaphylactic deaths in Auckland, New
Zealand: a review of coronial autopsies
from 1985 to 2005”
CONCLUSION: Anaphylactic reaction is an uncommon cause of
sudden death. In many cases, no specific macroscopic or microscopic
findings were detected at autopsy. In the presence of a typical clinical
history, postmortem measurement of serum tryptase levels can be a
useful diagnostic aid
Low I, Stables S. Pathology 2006; 38: 328-332

Kounis syndrome
• Therapeutic implications

TREATMENT OF KOUNIS SYNDROME
1. Treatment of type I variant:
Treatment of allergic event alone can abolish type I variant! .Give
vasodilators e. g. nitrates and Ca-blockers
2. Treatment of type II variant:
a. Apply acute coronary event protocol + corticosteroids and antihistamines
b. Give vasodilators e. g. nitrates and Ca-blockers when appropriate
One should bear in mind that:
•Epinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate
ischemia and induce coronary vasospasm. Sulfite free epinephrine is
recommended I.M. 0.2-0.5 mg (1:1000) of aqueous solution is preferable.
•In patients on b-blockers epinephrine may be ineffective. It may also promote
more vasospasm due to unopposed alpha adrenergic effect. Glucagon may be
considered.
•Avoid opiates such as morphine, codeine and meperidine since they can induce
massive mast cell degranulation and aggravate allergic reaction.
•Fentanyl and its derivatives show a slight mast cell activation and should be the
drugs of choice when narcotic analgesia is necessary

Mast cell activation precedes acute
coronary event
• Shoulder: the vulnerable part
of atheroma
Shoulder: the vulnerable part of coronaryShoulder: the vulnerable part of coronary
atheromaatheroma
(In carotids the cap,(In carotids the cap, Karapanayiotides T. CirculationKarapanayiotides T. Circulation

Mast cell activation precedes acute
coronary event“Mast cells, macrophages, and
T-cells infiltrate not only the
sites of coronary arteries at
which plaque rupture or
erosion has occurred but also
the sites of coronary
plaques susceptible to
erosion or rupture
(shoulders, autopsy
findings) which means they
invade before an actual
coronary event”
Therefore they infiltrate the
lesions and release their
mediators before erosion or
rupture and they are not part of
inflammatory response to
rupture initiated by other
processes
Kaartinen M,et al. Circulation 1994;
• Shoulder: the vulnerable part
of atheroma
Shoulder: the vulnerable part of coronaryShoulder: the vulnerable part of coronary
atheromaatheroma
(In carotids the cap,(In carotids the cap, Karapanayiotides T. CirculationKarapanayiotides T. Circulation
90: 1669

Arachidonic acid products such as
leukotrienes and thromboxane were
significantly raised in patients with
unstable angina than with stable angina
and with nonischemic chest pain
• Eicosanoid metabolites did
not increase as a result of
effort-induced ischemia in
stable angina up to 6 days
after positive exercise test
• “This can rule out a role of
ischemia per se in the
induction of eicosanoid
increase”
• Circulation 2003; 107: 55Cipollone F, et al.

Acute stress and mast cell
activation
• Transmission electron
micrographs of cardiac
mast cells from (A)
control, unstressed and
(B) stressed C57BL
mice showing
numerous secretory
granules that have
released their contents
(arrowheads); note
tissue from both control
and stressed mice
have numerous intact
granules (solid arrow).
Bar=1 μm.

The Brain and the Heart: the twain
have met
«Εχε τους πόδας σου
ζεστούς, την κεφαλήν σου
κρύα, τον στόμαχόν σου
αδειανό (ελαφρύ) γιατρό
δεν έχεις χρεία»
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm,
your brain cool and your
stomach (nearly) empty
takes the doctor away)
“Sleep a lot, Eat a
little and walk a
lot”
Paul Dudley White

-Occlusion of metallic biliary stent
related to nickel allergy-
Khan SF, et al. Gastrointestinal Endosc 2007; 66: 413

Milan lecture kounis syndrome

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