Davos 2015

Filippo Crea Institute of Cardiology

Catholic University of the Sacred Heart

Rome, Italy

Mechanisms of ACS:

the clinical perspective

No conflict of interest to declare

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

Dysregulation of T cell subsets in

ACS

(Liuzzo et al, IJC 2013)

(Flego et al, Basic Res Cardiol 2014)

CD31 signaling in immunomodulation

CREB

Treg

White/red thrombus

Plaque fissure

Obstructive ATS with adaptive

immunity activation

Infectious agents

Auto-antigens

Association between inflammation and CV

events

(Cianflone et al, JACC 2012)

CRP < 2mg/dl in 41% of

patients!

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)

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

Mechanical triggers of plaque fissure:

cholesterol crystals

(Abela et al, Clin Cardiol 2005, AJC 2009)

Factors affecting

cholesterol crystallization

•Cholesterol saturation

•Hydration

•Temperature

•pH

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

Plaque erosion

(Fog Bentzon et al, Circ Res 2014)

Myeloperoxidase is Associated

with Coronary Plaque Erosion

(Ferrante et al, Circulation 2010)

Differential accumulation of hyaluronan

expressing CD44 in culprit lesions

(Kolodgie et al, ATVB 2002)

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

Mortality of patients with NSTE-MI and non-

obstructive CAD in ACUITY (n=2442; 8.8% MINOCA)

(Planer et al, Circ Cardiovasc Interv 2014))

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)

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

Plaque rupture and erosion assessed by OCT

portend a different outome in ACS (n=139)

(Niccoli et al, EHJ 2015)

Rupture Smooth plaque Erosion

Morpho-functional correlations in NSTE-ACS

(Niccoli et al, IJC 2014)

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

It is complex

I am sorry,

it is not my fault!

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

Cholesterol crystals and plaque fissure

(Fog Bentzon et al, Circ Res 2014)