Download Angiotensin-converting enzyme inhibitors and atherosclerotic plaque

European Heart Journal Supplements (2009) 11 (Supplement E), E9–E16
doi:10.1093/eurheartj/sup022
Angiotensin-converting enzyme inhibitors and
atherosclerotic plaque: a key role in the
cardiovascular protection of patients with
coronary artery disease
Jean-Claude Tardif*
Department of Medicine, Montreal Heart Institute, Université de Montréal, 5000 Belanger Street, Montreal, Canada,
H1T 1C8
KEYWORDS
Atherosclerosis;
Angiotensin-converting
enzyme inhibitors;
Coronary artery disease;
Coronary remodelling;
Endothelial dysfunction;
Perindopril
In EUROPA, the angiotensin-converting enzyme inhibitor (ACEI) perindopril on top of
other preventative therapies reduced the risk of major coronary events (cardiovascular death, myocardial infarction, resuscitated cardiac arrest) by 20% when compared
with placebo (P ¼ 0.0003) in patients with stable coronary artery disease (CAD). These
cardiovascular benefits may be attributable not only to the blood pressure-lowering
effect of the drug, but also potentially to a direct cardioprotective vascular effect
as determined in two substudies of EUROPA. Analysis of intravascular ultrasound
data from the PERSPECTIVE substudy indicated that perindopril treatment may be
associated with favourable patterns of coronary remodelling that are associated
with plaque stabilization and may induce regression of non-calcified lesions. In the
PERTINENT substudy, there were reductions in markers of coronary vascular endothelial cell dysfunction and the rate of endothelial cell apoptosis in perindopril recipients. Experimental data suggest an advantage of perindopril over other ACEIs at
the level of tissue ACE inhibition and relative selectivity for bradykinin, which may
explain the mechanism of the beneficial effect of perindopril on the endothelium.
These differences may underpin the differential results in large clinical trials of
ACEIs in patients with stable CAD.
Introduction
Coronary artery disease (CAD) is a manifestation of atherosclerosis, an inflammatory process characterized by the
formation of lipid-rich atheromatous plaques in the arterial wall.1 Atherosclerotic plaques in the aorta and
femoral arteries are strong predictors of coronary heart
disease (CHD).2 Without detection and treatment, the
formation of coronary plaques inevitably progresses,
and is clinically manifested in stable angina, unstable
angina, myocardial infarction (MI), cardiovascular
* Corresponding author. Tel: þ1 514 376 3330, Fax:
E-mail address: [email protected]
þ1 514 593 2500,
complications, and death. Ischaemic heart disease
remains the leading cause of death worldwide,3 which
suggests that this condition remains undertreated.
Angiotensin-converting enzyme inhibitors (ACEIs)
target abnormal ACE activation of the renin–angiotensin–aldosterone system and could theoretically therefore
offer cardioprotection (i.e. reduce the risk of cardiovascular events, including MI, cardiac arrest, stroke, death
from cardiovascular causes) because of direct vascular
effects.4 ACEIs are recommended in current clinical practice guidelines for secondary prevention in patients with
cardiovascular disease.5,6 Much research has focused on
the mechanisms by which ACEIs are cardioprotective.
This review briefly summarizes the role of ACEIs in CAD
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2009.
For permissions please email: [email protected].
E10
J.-C. Tardif
and how imaging is used to assess the effect of treatment
on atherosclerosis, and discusses the cardioprotective
effects of ACEIs via their action on atherosclerotic
plaque and vascular endothelium, with particular emphasis on perindopril.
The use of angiotensin-converting enzyme
inhibitors in coronary artery disease
In general, ACEIs have been shown to be effective in secondary prevention in patients with vascular disease but
without heart failure or left ventricular systolic dysfunction (Table 1),7 despite early investigations that were not
able to show prevention of cardiovascular events with the
ACEI quinapril [the QUinapril Ischemic Event Trial
(QUIET)8]. Dagenais et al.7 conducted a systematic
review of three large clinical trials in patients with
stable CAD: the Heart Outcomes Prevention Evaluation
(HOPE) trial,9 the EUropean trial on Reduction Of
cardiac events with Perindopril among patients with
stable coronary Artery disease (EUROPA),10 and the Prevention of Events with Angiotensin Converting Enzyme
inhibition trial (PEACE).11 Patients received standard
therapy plus placebo or ramipril (HOPE),9 perindopril
(EUROPA),10 or trandolapril (PEACE).11 Overall, 29 805
patients were followed up for a median of 4.8 years.7
There was an 18% reduction in the risk of the composite
endpoint of cardiovascular mortality, non-fatal MI, and
stroke associated with ACEI treatment when compared
with placebo (odds ratio 0.82; 95% CI 0.76–0.88; P ,
0.0001).7
Evidence for the efficacy of perindopril in reducing the
incidence of cardiovascular events is well established.10
In the EUROPA trial, perindopril given at a dose that
reduces high blood pressure (8 mg/day) resulted in a
20% reduction in the primary cardiovascular endpoint
when compared with placebo, and this benefit was
observed across low-, medium-, and high-risk patients
(Table 1), and in a population treated with concomitant
lipid-lowering therapy (given to 69% of patients).10
Additionally, perindopril reduced cardiovascular events
in normotensive and hypertensive patients, and overall,
this reduction was potentially greater than would be
expected from the observed decrease from baseline in
blood pressure (mean reduction of 5/2 mmHg),10
suggesting a direct vascular and anti-atherosclerotic
effect of perindopril. Well-known beneficial actions of
perindopril on vascular structure include reductions in
arterial wall hypertrophy and arterial stiffness, and
improvements in arterial elasticity.12
In contrast to EUROPA, the HOPE study focused on
patients at high CV risk and demonstrated the cardioprotective effects of ramipril 10 mg/day in this population.9
The PEACE study11 was conducted after both the EUROPA
and HOPE trials, and did not demonstrate a beneficial
effect of trandolapril 4 mg/day in reducing the risk of
cardiovascular events (Table 1). The authors suggested
that this could be attributed in part to a low-risk
patient population and to concomitant intensive current
standard therapy, resulting overall in a low cardiovascular event rate,9 although others have disagreed with
this interpretation.7 It is possible that the choice of
ACEI may have influenced these results,12 and as discussed later in this review, there are differences in pharmacodynamic properties between ACEIs which might
have contributed to the different results observed in
these large secondary prevention trials.
Imaging of coronary atherosclerotic plaques
Numerous modern imaging techniques are available to
detect and diagnose atherosclerosis and assess
treatment-induced changes in atherosclerotic lesions
include quantitative coronary angiography (QCA), coronary intravascular ultrasound (IVUS), B-mode ultrasonography, multidetector computed tomography, magnetic
resonance coronary angiography, transoesophageal echocardiography, and positron emission tomography. Only a
Table 1 Primary results of angiotensin-converting enzyme inhibitor trials in patients with stable coronary artery disease
Study
Primary outcome
HOPE9
CV mortality, MI or stroke
EUROPA10
CV mortality, MI or resuscitated cardiac arrest
PEACE11
Death from CV causes, nonfatal MI, CABG or PCI
QUIET8
Cardiac death, nonfatal MI, resuscitated cardiac
arrest, CABG, coronary angioplasty,
hospitalization for angina pectoris
Treatment on top
of standard
therapy
%
Patients
Statistical
comparison
95% CI
P-value
Ramipril
Placebo
Perindopril
Placebo
Trandolapril
Placebo
Quinapril
Placebo
14.0
17.8
8.0
9.9
21.9
22.5
38.5
37.7
RR 0.78
0.70–0.86
,0.001
RRR 20%
9–29
,0.001
HR 0.96
0.88–1.06
0.43
RR 1.04
0.89–1.22
0.60
CABG, coronary-artery bypass grafting; CV, cardiovascular, EUROPA, EUropean trial on Reduction Of cardiac events with Perindopril among patients
with stable coronary Artery disease; HOPE, Heart Outcomes Prevention Evaluation; HR, hazard ratio; MI, myocardial infarction; PCI, percutaneous
coronary intervention; PEACE, Prevention of Events with Angiotensin Converting Enzyme inhibition trial; QUIET, QUinapril Ischemic Event Trial;
RR, risk reduction; RRR relative risk reduction.
Cardiovascular protection of patients with CAD
brief overview of two of the most widely used techniques
(QCA and IVUS) is provided since an in-depth discussion of
each technique is beyond the scope of this review.
Quantitative coronary angiography is the standard/
reference imaging method and has been used extensively
in clinical trials.13,14 Quantitative coronary angiographydetermined stenosis and coronary lesion progression
were predictive of cardiovascular events15 and stenosis
regression after lipid-lowering treatment corresponded
to a decrease in the rate of cardiovascular events.16
Intravascular ultrasound offers several advantages over
coronary angiography (reviewed extensively elsewhere).17,18 Briefly, IVUS accurately measures the coronary lumen dimensions and allows for the assessment of
eccentric lesions, coronary remodelling, atherosclerotic
plaque deposition, and the progression or regression of
atherosclerotic plaque.5 Several large clinical trials in
patients with angiographically demonstrated CAD used
IVUS to demonstrate reduction of plaque progression or
plaque regression associated with lipid-lowering19,20 or
antihypertensive21 therapy, although IVUS parameters
have yet to be established as surrogate endpoints for
the prediction of the risk of cardiovascular events in CAD.
Nevertheless, percent atheroma volume on IVUS may
be a useful cardiovascular biomarker, considering that it
was correlated with coronary angiography parameters
in a study comparing QCA and IVUS for the assessment
of CAD progression in 525 patients.22 Per cent atheroma
volume change over time using IVUS was significantly
but weakly correlated with change in cumulative coronary stenosis score on QCA, probably because per cent
atheroma volume takes into account plaque burden as
well as vascular coronary remodelling.
Coronary remodelling begins as a compensatory
process whereby arteries enlarge (i.e. ‘positive’ remodelling) when plaques first develop to prevent the atheroma from impeding the lumen, and as a result a vessel
can contain extensive plaque but show little evidence
of luminal obstruction.17,23 Intravascular ultrasound
studies have shown that positive remodelling is associated with an unstable clinical phenotype; patients with
acute coronary syndromes more frequently exhibit positive remodelling.24,25 Paradoxically, constrictive coronary remodelling (‘negative’ remodelling) where vessel
size decreases is associated with a more stable clinical
phenotype,25 and as recently shown in another IVUS
study,26 with plaque regression. Serial IVUS of 432
patients with coronary disease receiving lipid-lowering
therapy demonstrated that plaque regression induced
by LDL-cholesterol level reductions was associated with
a decrease in total vessel size but without an increase
in lumen size.26 Therefore, plaque regression does not
necessarily lead to an increase in lumen size and would
therefore not be detected by QCA. The mechanisms
linking pharmacological treatment, plaque regression,
coronary remodelling, and plaque stabilization are not
completely understood.27
Current evidence, from a retrospective serial IVUS
virtual histology study in 41 patients with angiographically confirmed non-obstructive stenoses (less than 50%
diameter), suggests that the plaque composition of
E11
Figure 1 Frequency of lesion types in plaques with (A) negative remodelling (n ¼ 9) and (B) positive remodelling (n ¼ 29) in a retrospective
intravascular ultrasound study.28 The remodelling index was 0.95 in
negatively and 1.05 in positively remodelled lesions, where the remodelling index was defined as the external elastic membrane crosssectional area (EEM CSA) at the site of the minimum lumen area
divided by the EEM CSA of the reference site. Figure adapted with permission (Figure 4 on page 390 of Rodriguez-Granillo et al.28).
negatively remodelled lesions is more stable (i.e. less
likely to rupture).28 Coronary lesions displaying positive
remodelling had a significantly larger lipid core (P ,
0.0001), and more frequently had a phenotype associated
with greater risk of rupture (i.e. thin cap fibroatheroma),
when compared with negatively remodelled vessels
(Figure 1). Conversely, negatively remodelled lesions
were more likely to have a stable phenotype (pathological intimal thickening and no evidence of a thin cap
fibroatheroma) and only one-third were of the unstable
plaque phenotype.28 Thus, the state of remodelling
appears to be related to plaque composition and consequently to plaque stability.
Effect of angiotensin-converting enzyme
inhibitors and perindopril on atherosclerotic
plaque
Several studies using IVUS techniques have assessed the
effect of ACEIs on changes in atherosclerotic lesions in
patients with CAD or risk factors for CAD.21,29–33 The
PERindopril’s proSPective Effect on Coronary aTherosclerosis by Intra Vascular ultrasound Evaluation (PERSPECTIVE) substudy of EUROPA used serial coronary
angiographic and IVUS measurements to assess the
effects of perindopril vs. placebo on coronary atherosclerosis progression in 244 patients.34 After 3 years of
treatment, no progression of atherosclerosis was
observed either in placebo or in perindopril-treated
patients, and thus, differences between groups in the
change from baseline in lumen dimensions (primary endpoint) were not significant.34 How then could the cardioprotective effects of perindopril as observed in the
EUROPA study be explained? The primary endpoint of
the PERSPECTIVE study was lumen size, and as discussed
previously, this measurement does not give an indication
of plaque regression, changes in plaque stability, or coronary remodelling.
Thus, PERSPECTIVE investigators turned their attention
to the effect of perindopril vs. placebo on patterns of
E12
Figure 2 Proportion of coronary segments displaying negative, positive,
or neutral remodelling in patients with coronary artery disease after 3
years of treatment with perindopril or placebo. Data from a post hoc
analysis of the PERindopril’s proSPective Effect on Coronary aTherosclerosis by Intra Vascular ultrasound Evaluation serial intravascular ultrasound
study.31 The remodelling index was defined as the external elastic membrane (EEM)area at follow-up divided by the EEMarea at baseline. Positive
remodelling was defined as a relative increase and negative remodelling
as a relative decrease in the vessel cross-sectional area of more than two
standard deviations from the mean relative intra-observer difference.
coronary remodelling and plaque composition in further
post hoc analyses (n ¼ 118).31 The remodelling pattern
was assessed by measuring lumen and vessel crosssectional area (CSA) by IVUS. The number of segments
in coronary arteries presenting with positive remodelling
[defined as a relative increase in vessel CSA .2 standard
deviations (SDs) from the mean relative intra-observer
difference) and negative remodelling (defined as the
relative temporal decrease in vessel CSA.2 SD] was evaluated.31 Figure 2 shows that after 3 years of treatment,
perindopril was associated with a greater proportion of
segments
with
negative
remodelling.31
Other
between-group differences were not statistically significant, except for the change from baseline in mean
(+SD) vessel CSA (20.18 + 2.4 mm2 perindopril vs.
þ0.19 + 2.4 mm2 placebo; P ¼ 0.04).31 Taken together,
these data suggest that perindopril treatment induces
negative remodelling of coronary atherosclerotic
lesions, whereby a significant decrease in vessel size is
not associated with any change in lumen size.31 In
addition, although there were no significant changes
from baseline for vessel, lumen, or plaque CSA, or
plaque burden or remodelling index (RI) in either
group, hypoechogenicity, a study-defined indirect
measure of plaque composition, was significantly
decreased from baseline in the perindopril group (P ¼
0.001), which suggested a beneficial stabilizing effect.31
In another post hoc analysis of PERSPECTIVE,35 noncalcified plaque showed regression, as indicated by a significant reduction in mean plaque area (measured by
IVUS) in patients receiving perindopril, when compared
with those receiving placebo (Figure 3). Plaques containing moderate calcifications did not change from baseline,
regardless of treatment. Heavily calcified plaques in
perindopril and placebo groups showed atherosclerotic
progression (increase from baseline in mean plaque
area).35 Indeed, these findings allow us to postulate
that the effects of pharmacological therapy would
J.-C. Tardif
Figure 3 In a post hoc analysis of non-calcified plaques, change from
baseline in mean atherosclerotic plaque area determined by quantitative
IVUS in patients with stable coronary artery disease after treatment for 3
years with perindopril or placebo. *P ¼ 0.04 vs. placebo. Figure adapted
with permission (from Bruining et al.35).
differ at different stages of coronary atherosclerosis.
Advanced atherosclerotic disease with greater plaque
calcification36 may be less likely to regress when
treated, while early intervention with perindopril may
induce atherosclerotic regression. Atherosclerosis
regression as assessed by IVUS has not yet been demonstrated to be directly associated with a reduction in
the risk of CV events. Nevertheless, the observations of
a reduction in CV events in EUROPA after treatment
with perindopril and beneficial effects on early atherosclerotic plaque as observed in various post hoc analyses
of the PERSPECTIVE substudy seem to support the possibility that pharmacological intervention as soon as
CAD is diagnosed would give improved long-term clinical
outcomes.
Other evidence for the influence of perindopril on
atherosclerosis as mediated via its effects on plaque is
available from experimental studies. In rabbit models
of atherosclerosis, perindopril treatment reduced lesion
size, induced plaque stabilization, and reduced atherosclerotic disease progression when compared with
untreated controls (reviewed extensively previously37).
In a mouse model of advanced coronary atherosclerosis,
perindopril attenuated ACE expression and activity in
the aorta vessel wall independent of its blood pressurelowering effect or any lipid-mediated effect (serum
lipid levels were unchanged vs. untreated controls).38
Effect of angiotensin-converting enzyme
inhibitors and perindopril on endothelial
function
Coronary endothelial dysfunction predicts the risk of cardiovascular events in patients with CAD39–41 or at risk of
CAD.41 Endothelial dysfunction, defined as adverse
alterations to endothelial physiology, is important not
only in the early stages of development of atherosclerotic
lesions,42 but also in the progression of plaques to
advanced stages.43 Additionally, vascular endothelial
cell apoptosis occurs in early atherosclerotic lesions,
and as the disease progresses, the rate of apoptosis
increases (reviewed previously).44 Injury to the vascular
endothelium, whether by physical or biochemical
Cardiovascular protection of patients with CAD
means, impairs the functioning of the endothelium and
affects nitric oxide (NO) bioavailability. Nitric oxide is a
key mediator of endothelial functions such as regulation
of vascular tone and vasomotor function, regulation of
inflammation, thrombosis, and platelet activation.45
The ACEIs improve endothelium-dependent vasodilation in patients with hypertension46–50 or CAD.51,52
There is currently no direct evidence that
treatment-induced improvement in endothelial function
has a causal role in the reduction of cardiovascular
events.43 However, the effect of perindopril on markers
of endothelial function in the PERindopril-Thrombosis,
InflammatioN Endothelial dysfunction and Neurohormonal activation Trial (PERTINENT) substudy of
EUROPA53 suggests that the improvement of endothelial
function contributed to perindopril’s cardioprotective
effects (see EUROPA study, Table 1). After 1 year of treatment, perindopril (n ¼ 44) induced significantly (P , 0.05
vs. placebo) greater increases from baseline in plasma
levels of bradykinin (14.8–17.7 pg/mL) and reductions
in angiotensin II levels (17.1–12.5 pg/mL).53 The
reduction in production of the vasoconstrictor angiotensin II and increase in bradykinin levels, the latter in
turn stimulates the endothelium to release vasodilators
such as NO and prostacyclin, and enhance endotheliumdependent vasodilation.4 Additionally, the serum level
of tumour necrosis factor (TNF)-a, which is known to
induce apoptosis and inhibit endothelial nitric oxide
synthase (eNOS) activity, decreased from baseline after
treatment with perindopril vs. placebo (P , 0.05).53
Baseline serum levels of von Willebrand factor (a
marker of endothelial cell damage), which were found
to be predictive of cardiovascular events (P , 0.01),
were also significantly reduced by perindopril treatment
(P , 0.001).
Perindopril has a significantly beneficial effect on the
NO pathway, and thus on the endothelium.53,54 In a
small in vivo study of 14 patients with ischaemic heart
disease, 5 weeks of treatment with perindopril increased
eNOS expression in endothelial cells and increased inducible NOS (iNOS) expression in the medial vascular
smooth muscle, via inhibition of circulating and tissue
ACE.54 In PERTINENT, perindopril improved the serum
nitrite/nitrate ratio (NOx) (from 22.0 to 26.5 vs. 21.7 to
22.4 mmol/L with placebo; P , 0.01), which mirrored
the changes in NO metabolism observed in the ex vivo
experiments in this study.53 Human umbilical vein endothelial cells (HUVECs) were isolated and incubated for
72 h with serum from healthy volunteers (n ¼ 45) and
from patients with CAD at both baseline, and again following 1 year of treatment with either perindopril or
placebo.53 Endothelial nitric oxide synthase protein
expression was upregulated by 19% (albeit nonsignificantly) and eNOS activity by 27% with perindopril
(P , 0.05) vs. placebo. Effects on NO were mediated by
bradykinin, as bradykinin levels were significantly correlated with eNOS activity and expression (P , 0.05), and
an antagonist of bradykinin B2 receptors counteracted
the improvement induced by perindopril.53
It is proposed that the clinical benefit of perindopril
treatment in patients with stable CAD is attributable in
E13
part to a reduction in the rate of endothelial cell apoptosis, which is elevated in patients with atherosclerosis
when compared with healthy controls.53 In the ex vivo
part of the PERTINENT study, there was a 31% reduction
in the rate of apoptosis when cells were exposed to the
serum from perindopril-treated patients, which was significantly better than the 10% reduction observed in the
placebo group (P , 0.05).53 This result was proposed to
have occurred via an ACEI-induced increase in bradykinin
levels, which in turn mediated an increase in eNOS
protein expression; certainly the observed correlation
between bradykinin levels and eNOS seems to support
this hypothesis.53
Clinical evidence for the beneficial effect of perindopril on endothelial dysfunction is supported by experimental data.55–57 Perindopril treatment resulted in a
lower rate of apoptosis of aortic endothelial cells
in vivo that was significant vs. control (P , 0.001),
whereas reductions observed with other ACEIs (ramipril,
quinapril, trandolapril, and enalapril) were nonsignificant vs. control (Figure 4).55 Between-group comparisons indicated the superior effect of perindopril
(Figure 4). In an in vivo rat study, enalapril, perindopril,
quinapril, ramipril, and trandolapril given at equihypotensive doses increased eNOS expression and activity
vs. control in the aorta and cardiac myocytes. In
cardiac myocytes, perindopril was associated with significantly greater eNOS expression and activity than trandolapril and ramipril (P , 0.05) and enalapril (P , 0.01),
resulting in increased levels of circulating nitrite/
nitrate (the end-metabolites of NO).56 Indeed, these
studies have highlighted that ACEIs are not equal in
terms of direct vascular activity, and it has been
suggested that the anti-atherosclerotic activities of
ACEIs such as perindopril may vary and might not only
represent a class effect.58
Indeed, there are differences between ACEIs in ACE
binding affinity and selectivity, as shown in in vitro
studies. Perindoprilat, the active drug of the prodrug
ester perindopril, had greater affinity for bradykinin
than for angiotensin I binding sites of ACE, and although
other ACEIs also showed a greater affinity for bradykinin
Figure 4 Rate of apoptosis in rats treated for 7 days with angiotensinconverting enzyme inhibitor or vehicle only (control) expressed as the
percentage of annexin V-positive rat aortic endothelial cells following
lipopolysaccharide-induced apoptosis.55 *P , 0.001 vs. control.
E14
J.-C. Tardif
Conflict of interest: J.-C.T. has received honoraria from Servier.
References
Figure 5 Relative tissue potency of angiotensin converting-enzyme
inhibitors. Adapted with permission from Ferrari60 .
than angiotensin I sites, the bradykinin/angiotensin I
selectivity ratio was the highest with perindoprilat
(1.44 + 0.12), followed by ramiprilat (1.16 + 0.16), quinaprilat (1.09 + 0.15), and trandolaprilat (1.08 + 0.16),
with enalaprilat (1.00 + 0.14) being the least selective.59
Perindoprilat, quinaprilat, and ramiprilat also had higher
tissue ACE potency than enalaprilat and fosinoprilat
(Figure 5).60 The relative ability to bind tissue ACE is
potentially important in CAD because there is a marked
ACE accumulation in human atherosclerotic plaque and
in endothelial cells.61 Studies in human subjects have
also shown that myocardial uptake of perindoprilat following single dose administration of i.v. perindopril was
faster than enalaprilat (P ¼ 0.04).62
These studies provide a possible mechanism explaining
the difference in cardiovascular outcomes between the
PEACE study with trandolapril11 and the EUROPA study
with perindopril.10 Trandolapril and perindopril have different vascular effects at the endothelial level via effects on
NO bioavailability and apoptosis, possibly because of difference in tissue ACE potency and differential selectivity for
bradykinin and angiotensin I-binding sites of ACE.59
Conclusion
Differences exist between ACEIs in terms of duration of
action and level of tissue ACE inhibition. Perindopril is
more selective for tissue ACE and appears to have
higher bradykinin vs. angiotensin I selectivity for
binding sites of ACE. These effects may explain the
benefits of perindopril in reducing the rate of endothelial
cell apoptosis and improving endothelial dysfunction,
mediated via downstream improvements in NO bioavailability. Perindopril is known to reduce arterial hypertrophy, arterial stiffness and improve arterial elasticity. At
the atherosclerotic plaque level, perindopril treatment
in patients with CAD appears to be associated with
favourable patterns of coronary remodelling and possibly
regression of non-calcified plaque. These effects,
together with blood pressure control, contribute to the
protection of endothelial function and reversal of vascular remodelling associated with an unstable plaque phenotype. Such effects may also explain the benefit of
secondary prevention of cardiovascular events with perindopril in patients with stable CAD, regardless of baseline
cardiovascular risk or blood pressure or concomitant
lipid-lowering therapy, as observed in the EUROPA study.
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