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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
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;27:1341-1381.
PerindoprilPerindopril 8mg8mg
12
4
01 3 40
Placebo
Years
8
52
RRR -20%P = 0.0003
CV death, MI, cardiac arrest%
PerindoprilPerindopril 8mg8mg
12
4
01 3 40
Placebo
Years
8
52
RRR -20%P = 0.0003
CV death, MI, cardiac arrest%12
4
01 3 40
Placebo
Years
8
52
RRR -20%P = 0.0003
CV death, MI, cardiac arrest%
Cardio/ cerebrovascular
death
End-stagerenal
disease
Nephroticproteinuria
Macro-proteinuria
Micro-albuminuria
Endothelialdysfunction
Hypertension risk factorsdiabetes, obesity, elderly
Atherosclerosisand LVH
Myocardialinfarction &
stroke
RemodellingVentricular dilation/
cognitive dysfunction
Congestive heart failure/secondary stroke
End-stageheart disease,brain damageand dementia
Cardio/ cerebrovascular
death
End-stagerenal
disease
Nephroticproteinuria
Macro-proteinuria
Micro-albuminuria
Endothelialdysfunction
Hypertension risk factorsdiabetes, obesity, elderly
Atherosclerosisand LVH
Myocardialinfarction &
stroke
RemodellingVentricular dilation/
cognitive dysfunction
Congestive heart failure/secondary stroke
End-stageheart disease,brain damageand dementia
Circulation coronaire
Athérosclérose
Remodelageventriculaire
Quelles sont les cibles ?
Ischémie myocardique
TASC
68%41%
39%Arteriopathy
30% 50%
StrokeCoronary
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 Pathophysiological continuum underlying the cardiovascular continuumcardiovascular continuum
From From J Am Coll Cardiol J Am Coll Cardiol 2001;37:975-84.2001;37:975-84.
Endothelial damageEndothelial damage
Mechanical fatigueMechanical fatigue
AtherosclerosisAtherosclerosis
Central aortic pressuresCentral aortic pressures
Pulse pressurePulse pressure
Central wave Central wave
reflectionreflection
Large arteries Large arteries
stiffening stiffening
Pathophysiological Pathophysiological continuumcontinuum
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 To test the hypothesis that the degree of calcification in plaques affects the outcome of longitudinal ICUS driven progression-regression studies.the outcome of longitudinal ICUS driven progression-regression studies.
Bruining N et al. Coron Artery Dis. 2009; 20: 409-414.
PERSPECTIVE
ICUS Sub-Segmentation
and Calcium Detection
Normal coronaryartery (distal reference)
Atheroscleroticplaque in coronaryartery
Normal coronaryartery (distal reference)
Atheroscleroticplaque in coronaryartery
ICUS Sub-Segmentation and Calcium Detection
The amount of calcium per segment The amount of calcium per segment ((Calcium content levelCalcium content level):):
Total framesTotal frames
Positive Calcium framesPositive Calcium framesCCL = X 100%
PERSPECTIVE
3 cohorts detected:
CCL N segments (%)
0-25% 540 (76%)
25-50% 73 (10%)
50-100% 98 (13%)
Bruining N et al. Coron Artery Dis. 2009; 20: 409-414.
Reduction of noncalcified coronary Reduction of noncalcified coronary plaques’ size with perindoprilplaques’ size with perindopril
Change in plaque area (mm2)
* P=0.04 for perindopril vs placebo
-0,35
-0,3
-0,25
-0,2
-0,15
-0,1
-0,05
0
Perindopril placebo
*-0.33
-0.03
PERSPECTIVE
Segments with CCL 0-25%
N=242 N=298
Bruining N et al. Coron Artery Dis. 2009; 20: 409-414.
New insights from PERSPECTIVE
Non-calcified plaques are amenable Non-calcified plaques are amenable
to regression, with treatment of the to regression, with treatment of the
ACE inhibitor Perindopril, while ACE inhibitor Perindopril, while
heavily calcified plaques are subject heavily calcified plaques are subject
to progression. to progression.
PERSPECTIVE
Bruining N et al. Coron Artery Dis. 2009; 20: 409-414.
Baseline 7 months
Carotid distensibility (kPa.10-3)
ANOVA:Interaction P=0.014
Carotid PP (mmHg)
ANOVA: Interaction P<0.05
0
5
10
15
20
4 mg 8 mg
*NS
55
65
75
85
4 mg 8 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
Mechanisms of coronary event prevention with perindopril
TissueACE
Angiotensin II mediated effects
Bradykinin mediated effects
Remodellingimpact
Antiinflammatory effect
Vasodilation
Restoration of fibrinolytic balance
Reduction in coronary eventsReduction in coronary events
Plaque stabilization
Antiapoptoticeffect
Restoration of endothelial function
Circulation coronaire
Athérosclérose
Remodelageventriculaire
Quelles sont les cibles ?
Ischémie et fonction
myocardique
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
DT150 vs <150 ms
Vena contracta0.4 vs 0.4 cm
Fraction d’éjectionAmélioration du pronostic sous traitement
Cintrom, Circulation 1993
Age (ans)55 60 70
FEVG (%)
30
40
50
60
SOLVD
AIRESAVE
GISSI 3
CONSENSUS 1
PEACE
EUROPA
HOPE
QUIET
CONSENSUS 2
CAPTIN
FAMIS
CAST
Mdie coronaireMdie coronaire.
IDMIDM
Ins CardIns Card
Effet du blocage du SRA sur le remodelage VG
CritèreCritère primaire
0,0 1,0 2,0
RRRRRR(%)(%)
Mortalité totaleMortalité totale 00 0,900,90
Hospitalisation pour ICHospitalisation pour IC 2727 0,240,24
RemodelageRemodelage 4646 <0,001<0,001
Décès, IC ou RemodelageDécès, IC ou Remodelage 3838 <0,001<0,001
PPEn faveur En faveur
de Perindoprilde PerindoprilEn faveurEn faveur du placebodu placebo
PREAMI : Effet sur le remodelage VG
In the PERSPECTIVE substudy of In the PERSPECTIVE substudy of EUROPA, ACE inhibition with high EUROPA, ACE inhibition with high dose of perindopril promoted dose of perindopril promoted regression of non-calcified plaquesregression of non-calcified plaques
Together with previously shown Together with previously shown vascular properties of perindopril, vascular properties of perindopril, these effects may underpin the these effects may underpin the differential results of ACE inhibitor differential results of ACE inhibitor trials in CADtrials in CAD
““The earlier, the better” initiation of The earlier, the better” initiation of therapy should be considered in therapy should be considered in hypertension and CAD patients for hypertension and CAD patients for the prevention of CV events.the prevention of CV events.
ConclusionFrom vulnerable plaque to vulnerable patient…