filippo crea - european society of cardiology · davos 2015 filippo crea institute of cardiology...
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Davos 2015
Filippo Crea Institute of Cardiology
Catholic University of the Sacred Heart
Rome, Italy
Mechanisms of ACS:
the clinical perspective
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No conflict of interest to declare
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Why?
C-reactive protein Berk et al, AJC 1990
Liuzzo et al, NEJM 1994
Neutrophils Dinerman et al, JACC 1990
Biassucci et al, JACC 1994
Monocytes Mazzone et al, Circulation 1993
Lymphocytes Serneri et al, Circulation 1992
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Dysregulation of T cell subsets in
ACS
(Liuzzo et al, IJC 2013)
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(Flego et al, Basic Res Cardiol 2014)
CD31 signaling in immunomodulation
CREB
Treg
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White/red thrombus
Plaque fissure
Obstructive ATS with adaptive
immunity activation
Infectious agents
Auto-antigens
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Association between inflammation and CV
events
(Cianflone et al, JACC 2012)
CRP < 2mg/dl in 41% of
patients!
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Cluster analysis according to
T cell subsets and their ratio
0%
20%
40%
60%
80%
100%
ACS SA Controls
Present
Cluster analysis
CD4+CD28null T-cells > 4%
Tregs < 5%
Ratio > 2
(Liuzzo et al, IJC 2013)
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Mechanical triggers of plaque fissure: stress
(Burke et al, JAMA 1999)
0
10
20
30
40
50
60
70
80
Stress Rest
Plaque fissure rate (%)
Mechanisms of stress-induced ACS associated
to plaque fissure
• Hypertension
• Constriction of epicardial coronary arteries
• Increase of coronary microvascular resistance
• Platelet activation and hypercoagulability
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Mechanical triggers of plaque fissure:
cholesterol crystals
(Abela et al, Clin Cardiol 2005, AJC 2009)
Factors affecting
cholesterol crystallization
•Cholesterol saturation
•Hydration
•Temperature
•pH
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White/red thrombus
Plaque fissure
Obstructive ATS with adaptive
immunity activation
Infectious agents
Auto-antigens
Obstructive ATS without systemic
inflammation
Plaque
fissure
Local stress
Systemic stress
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Plaque erosion
(Fog Bentzon et al, Circ Res 2014)
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Myeloperoxidase is Associated
with Coronary Plaque Erosion
(Ferrante et al, Circulation 2010)
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Differential accumulation of hyaluronan
expressing CD44 in culprit lesions
(Kolodgie et al, ATVB 2002)
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White/red thrombus
Plaque fissure
Obstructive ATS with adaptive
immunity activation
Infectious agents
Auto-antigens
Obstructive ATS without systemic
inflammation
Plaque
fissure
Local stress
Systemic stress
Obstructive ATS with innate immunity
activation
Plaque erosion
Strong local thrombogenic stimuli
Neutrophil recruitment
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Mortality of patients with NSTE-MI and non-
obstructive CAD in ACUITY (n=2442; 8.8% MINOCA)
(Planer et al, Circ Cardiovasc Interv 2014))
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Coronary microvascular dysfunction in
Tako-tsubo syndrome
Contrast score index
End-sistolic volume
(De Caterina AR et al, EHJ 2010)
Ejection fraction
(Galiuto et al, EHJ 2010)
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White/red thrombus
Plaque fissure
Obstructive ATS with adaptive
immunity activation
Infectious agents
Auto-antigens
Obstructive ATS without systemic
inflammation
Plaque
fissure
Local stress
Systemic stress
No obstructive ATS
Proximal or distal
spasm
Dysfunctional endothelial and/or SMC
Vasoconstrictor stimuli
Obstructive ATS with innate immunity
activation
Plaque erosion
Strong local thrombogenic stimuli
Neutrophil recruitment
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Plaque rupture and erosion assessed by OCT
portend a different outome in ACS (n=139)
(Niccoli et al, EHJ 2015)
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Rupture Smooth plaque Erosion
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Morpho-functional correlations in NSTE-ACS
(Niccoli et al, IJC 2014)
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Targeting the mechanisms of ACS
• Methotrexate, IL-1b antagonists, Treg expansion, Vaccines
Plaque fissure with inflammation
• Colchicine Plaque fissure
without inflammation
• Antithrombotics Plaque erosion
• Vasodilators SMC hyperreactivity
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It is complex
I am sorry,
it is not my fault!
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White/red thrombus
Plaque fissure
Obstructive ATS with adaptive
immunity activation
Obstructive ATS without systemic
inflammation
Plaque
fissure
No obstructive ATS
Proximal or distal
spasm
Obstructive ATS with innate immunity
activation
Plaque erosion
Molecular imaging for T-cells
CRP T-cell
perturbation
Cystatin C Rho kinase
SMC function assessment
Anatomical imaging
Markers of cholesterol
crystallization
Molecular imaging for MPO MPO
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Cholesterol crystals and plaque fissure
(Fog Bentzon et al, Circ Res 2014)