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Remodelage et plaque d’athérome: intérêt des IEC à forte dose G. Derumeaux Lyon Conflit d'intérêt : Servier, Actelion, Sanofi-Aventis ACE inhibitors are recommended for secondary prevention in CAD 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) Remodelling Ventricular dilation/ cognitive dysfunction Myocardial infarction & stroke Congestive heart failure/ secondary stroke Microalbuminuria Atherosclerosis and LVH Endothelial dysfunction Macroproteinuria End-stage heart disease, Nephrotic brain damage proteinuria and dementia Cardio/ End-stage renal cerebrovascular death disease Hypertension risk factors diabetes, obesity, elderly 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) CV death, MI, cardiac arrest % 12 Placebo 8 Agents and doses of proven efficacy for secondary prevention should be employed Perindopril 8mg RRR -20% P = 0.0003 4 0 0 1 2 Guidelines on the management of stable angina. Eur Heart J 2006;27:1341-1381. 3 4 5 Years Quelles sont les cibles ? Circulation coronaire Athérosclérose Ischémie myocardique Remodelage ventriculaire Major underlyingTASC lesion of atherosclerosis : plaque Stroke 41% 50% 30% Atherosclerosis = inflammatory process characterized by the formation of lipid-rich atheromatous plaques in the arterial wall Arteriopathy 39% Coronary Events 68% Pathophysiological continuum underlying the cardiovascular continuum Central wave reflection Large arteries stiffening Central aortic pressures Pathophysiological continuum Pulse pressure Endothelial damage Mechanical fatigue Atherosclerosis From J Am Coll Cardiol 2001;37:975-84. Remodelage vasculaire 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 König A et al ; Heart 2007 PERSPECTIVE 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. ICUS Sub-Segmentation and Calcium Detection Normal coronary artery (distal reference) Bruining N et al. Coron Artery Dis. 2009; 20: 409-414. Atherosclerotic plaque in coronary artery PERSPECTIVE ICUS Sub-Segmentation and Calcium Detection The amount of calcium per segment (Calcium content level): Positive Calcium frames X 100% CCL = Total frames 3 cohorts detected: Bruining N et al. Coron Artery Dis. 2009; 20: 409-414. CCL N segments (%) 0-25% 540 (76%) 25-50% 73 (10%) 50-100% 98 (13%) Reduction of noncalcified coronary plaques’ size with perindopril PERSPECTIVE Change in plaque area (mm2) Perindopril placebo 0 -0.03 -0,05 * P=0.04 for perindopril vs placebo -0,1 -0,15 -0,2 -0,25 -0,3 -0,35 Segments with CCL 0-25% -0.33 * N=242 Bruining N et al. Coron Artery Dis. 2009; 20: 409-414. N=298 PERSPECTIVE 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. Bruining N et al. Coron Artery Dis. 2009; 20: 409-414. DAPHNET: dose-dependent effects of perindopril on carotid artery function in diabetic patients Carotid distensibility Carotid PP (kPa.10-3) (mmHg) 20 NS * 85 NS * 15 75 10 65 5 55 0 4 mg 8 mg ANOVA: Interaction P=0.014 4 mg 8 mg ANOVA: Interaction P<0.05 …for a similar reduction in MBP (office and ABPM) Tropeano AI et al. Hypertension 2006 Baseline 7 months Mechanisms of coronary event prevention with perindopril Bradykinin mediated effects Vasodilation Remodelling impact Antiinflammatory effect Tissue ACE Angiotensin II mediated effects Restoration of endothelial function Restoration of fibrinolytic balance Reduction in coronary events Antiapoptotic effect Plaque stabilization Quelles sont les cibles ? Circulation coronaire Athérosclérose Ischémie et fonction myocardique Remodelage ventriculaire La taille d’IDM 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/m2 DT 150 vs <150 ms Vena contracta 0.4 vs 0.4 cm Fraction d’éjection Amélioration du pronostic sous traitement Cintrom, Circulation 1993 Effet du blocage du SRA sur le remodelage VG FEVG (%) 60 PEACE QUIET EUROPA CAPTIN 50 CAST GISSI 3 HOPE FAMIS CONSENSUS 2 40 Mdie coronaire. Ins Card SAVE 30 SOLVD 55 60 IDM AIRE CONSENSUS 1 70 Age (ans) Critère primaire En faveur En faveur RRR de Perindopril du placebo (%) P 38 <0,001 0 0,90 Hospitalisation pour IC 27 0,24 Remodelage 46 <0,001 Décès, IC ou Remodelage Mortalité totale 0,0 1,0 2,0 PREAMI : Effet sur le remodelage VG Conclusion From vulnerable plaque to vulnerable patient… 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 “The earlier, the better” initiation of therapy should be considered in hypertension and CAD patients for the prevention of CV events.