Davos Mechanisms of ACS: the clinical perspective. Filippo Crea Institute of Cardiology Catholic University of the Sacred Heart Rome, Italy

Transcription

1 Davos 2015 Mechanisms of ACS: the clinical perspective Filippo Crea Institute of Cardiology Catholic University of the Sacred Heart Rome, Italy

2 No conflict of interest to declare

3 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

4 Dysregulation of T cell subsets in ACS (Liuzzo et al, IJC 2013)

5 CD31 signaling in immunomodulation CREB Treg (Flego et al, Basic Res Cardiol 2014)

6 Auto-antigens Obstructive ATS with adaptive immunity activation Plaque fissure White/red thrombus Infectious agents

7 Association between inflammation and CV events CRP < 2mg/dl in 41% of patients! (Cianflone et al, JACC 2012)

8 Cluster analysis according to T cell subsets and their ratio 100% 80% Cluster analysis 60% 40% 20% 0% CD4 + CD28 null T-cells > 4% Tregs < 5% Ratio > 2 ACS SA Controls Present (Liuzzo et al, IJC 2013)

9

10 Mechanical triggers of plaque fissure: stress Mechanisms of stress-induced ACS associated Hypertension Plaque fissure rate (%) to plaque fissure Constriction of epicardial coronary arteries Increase of coronary microvascular resistance Platelet activation and hypercoagulability Stress (Burke et al, JAMA 1999) Rest

11 Mechanical triggers of plaque fissure: cholesterol crystals Factors affecting cholesterol crystallization Cholesterol saturation Hydration Temperature ph (Abela et al, Clin Cardiol 2005, AJC 2009)

12 Auto-antigens Systemic stress Obstructive ATS with adaptive immunity activation Plaque fissure White/red thrombus Plaque fissure Obstructive ATS without systemic inflammation Infectious agents Local stress

13 Plaque erosion (Fog Bentzon et al, Circ Res 2014)

14 Myeloperoxidase is Associated with Coronary Plaque Erosion (Ferrante et al, Circulation 2010)

15 Differential accumulation of hyaluronan expressing CD44 in culprit lesions (Kolodgie et al, ATVB 2002)

16 Auto-antigens Systemic stress Obstructive ATS with adaptive immunity activation Plaque fissure White/red thrombus Plaque fissure Obstructive ATS without systemic inflammation Infectious agents Plaque erosion Local stress Strong local thrombogenic stimuli Obstructive ATS with innate immunity activation Neutrophil recruitment

17 Mortality of patients with NSTE-MI and nonobstructive CAD in ACUITY (n=2442; 8.8% MINOCA) (Planer et al, Circ Cardiovasc Interv 2014))

18

19 Coronary microvascular dysfunction in Tako-tsubo syndrome Contrast score index End-sistolic volume Ejection fraction (Galiuto et al, EHJ 2010) (De Caterina AR et al, EHJ 2010)

20 Vasoconstrictor stimuli No obstructive ATS Dysfunctional endothelial and/or SMC Auto-antigens Proximal or distal spasm Systemic stress Obstructive ATS with adaptive immunity activation Plaque fissure White/red thrombus Plaque fissure Obstructive ATS without systemic inflammation Infectious agents Plaque erosion Local stress Strong local thrombogenic stimuli Obstructive ATS with innate immunity activation Neutrophil recruitment

21 Plaque rupture and erosion assessed by OCT portend a different outome in ACS (n=139) (Niccoli et al, EHJ 2015)

22 Rupture Erosion Smooth plaque

23 Morpho-functional correlations in NSTE-ACS (Niccoli et al, IJC 2014)

24 Targeting the mechanisms of ACS Plaque fissure with inflammation Plaque fissure without inflammation Methotrexate, IL-1b antagonists, Treg expansion, Vaccines Colchicine Plaque erosion Antithrombotics SMC hyperreactivity Vasodilators

25 It is complex I am sorry, it is not my fault!

26 SMC function assessment No obstructive ATS Cystatin C Rho kinase Molecular imaging for T-cells Proximal or distal spasm Anatomical imaging Obstructive ATS with adaptive immunity activation Plaque fissure White/red thrombus Plaque fissure Obstructive ATS without systemic inflammation CRP T-cell perturbation Plaque erosion Markers of cholesterol crystallization Molecular imaging for MPO Obstructive ATS with innate immunity activation MPO

27 Cholesterol crystals and plaque fissure (Fog Bentzon et al, Circ Res 2014)