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…