Remodelage et plaque dathérome: intérêt des IEC à forte dose G. Derumeaux Lyon Conflit d'intérêt : Servier, Actelion, Sanofi-Aventis

In CAD patients with co-existing indications for ACE inhibitors: hypertension, heart failure, left ventricular dysfunction, prior MI, or diabetes (class I, level of evidence A) In all patients with angina and proven coronary disease based on benefits weighted against costs and risks for side effects (class IIa, level of evidence B) Agents and doses of proven efficacy for secondary prevention should be employed ACE inhibitors are recommended for secondary prevention in CAD Guidelines on the management of stable angina. Eur Heart J 2006;27:

Circulation coronaire Athérosclérose Remodelage ventriculaire Quelles sont les cibles ? Ischémie myocardique

TASC 68% 41% 39% Arteriopathy 30% 50% Stroke Coronary Events Major underlying lesion of atherosclerosis : plaque Atherosclerosis = inflammatory process characterized by the formation of lipid-rich atheromatous plaques in the arterial wall

Pathophysiological continuum underlying the cardiovascular continuum From J Am Coll Cardiol 2001;37: Endothelial damage Mechanical fatigue Atherosclerosis Central aortic pressures Central aortic pressures Pulse pressure Central wave Central wavereflection Large arteries Large arteriesstiffening Pathophysiologicalcontinuum

Remodelage vasculaire König A et al ; Heart 2007 IVUS accurately measures the coronary lumen dimension IVUS allows for assessment of eccentric lesions, coronary remodelling, and progression or regression of atherosclerotic plaque With IVUS, more detailed plaque characterization with differentiation of fibrocellular, lipid-rich, and calcified regions is feasible

New insights from PERSPECTIVE To test the hypothesis that the degree of calcification in plaques affects the outcome of longitudinal ICUS driven progression-regression studies. Bruining N et al. Coron Artery Dis. 2009; 20: PERSPECTIVE ICUS Sub-Segmentation and Calcium Detection

ICUS Sub-Segmentation and Calcium Detection The amount of calcium per segment (Calcium content level): Total frames Positive Calcium frames CCL = X 100% PERSPECTIVE 3 cohorts detected: CCLN segments (%) 0-25%540 (76%) 25-50%73 (10%) %98 (13%) Bruining N et al. Coron Artery Dis. 2009; 20:

Reduction of noncalcified coronary plaques size with perindopril Change in plaque area (mm 2 ) * P=0.04 for perindopril vs placebo Perindopril placebo * PERSPECTIVE Segments with CCL 0-25% N=242N=298 Bruining N et al. Coron Artery Dis. 2009; 20:

New insights from PERSPECTIVE Non-calcified plaques are amenable to regression, with treatment of the ACE inhibitor Perindopril, while heavily calcified plaques are subject to progression. PERSPECTIVE Bruining N et al. Coron Artery Dis. 2009; 20:

Baseline 7 months Carotid distensibility (kPa ) ANOVA: Interaction P=0.014 Carotid PP (mmHg) ANOVA: Interaction P< mg8 mg * NS mg8 mg * NS DAPHNET: dose-dependent effects of perindopril on carotid artery function in diabetic patients Tropeano AI et al. Hypertension 2006 …for a similar reduction in MBP (office and ABPM)

Mechanisms of coronary event prevention with perindopril Tissue ACE Angiotensin II mediated effects Bradykinin mediated effects Remodelling impact Antiinflammatory effect Vasodilation Restoration of fibrinolytic balance Reduction in coronary events Plaque stabilization Antiapoptotic effect Restoration of endothelial function

Circulation coronaire Athérosclérose Remodelage ventriculaire Quelles sont les cibles ? Ischémie et fonction myocardique

La taille dIDM est un puissant marqueur de risque CV Solomon SD, Circulation 2005

Orn S, AJC 2007

Le remodelage ventriculaire gauche

Physiopathologie du remodelage myocardique

Remodelage VG : facteurs pronostiques LVEDVI 120 vs >120 ml/m 2 DT 150 vs <150 ms Vena contracta 0.4 vs 0.4 cm

Fraction déjection Amélioration du pronostic sous traitement Cintrom, Circulation 1993

Age (ans) FEVG (%) SOLVDAIRESAVEGISSI 3CONSENSUS 1PEACEEUROPAHOPEQUIETCONSENSUS 2CAPTINFAMISCAST Mdie coronaire Mdie coronaire. IDM Ins Card Effet du blocage du SRA sur le remodelage VG

Critère Critère primaire 0,01,02,0 RRR (%) Mortalité totale 0 0,90 Hospitalisation pour IC 27 0,24 Remodelage 46 <0,001 Décès, IC ou Remodelage 38 <0,001 P En faveur de Perindopril En faveur du placebo du placebo

PREAMI : Effet sur le remodelage VG

In the PERSPECTIVE substudy of EUROPA, ACE inhibition with high dose of perindopril promoted regression of non-calcified plaques In the PERSPECTIVE substudy of EUROPA, ACE inhibition with high dose of perindopril promoted regression of non-calcified plaques Together with previously shown vascular properties of perindopril, these effects may underpin the differential results of ACE inhibitor trials in CAD Together with previously shown vascular properties of perindopril, these effects may underpin the differential results of ACE inhibitor trials in CAD The earlier, the better initiation of therapy should be considered in hypertension and CAD patients for the prevention of CV events. The earlier, the better initiation of therapy should be considered in hypertension and CAD patients for the prevention of CV events. Conclusion From vulnerable plaque to vulnerable patient…