Objective
To determine the mechanisms by which the ACE inhibitor perindopril significantly improved outcomes
in patients with stable coronary artery disease (as observed in the EUROPA study).
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Rationale
EUROPA showed that treatment with perindopril reduced the primary endpoint, i.e.,
combined risk of cardiovascular death, myocardial infarction and cardiac arrest,
by 20 per cent (p=0.0003). Blood pressure lowering alone cannot be completely responsible
for the observed benefits of perindopril, as a similar result was observed in people with stable
coronary artery disease who had low or high blood pressure at entry into the study,
or whose blood pressure did not fall during the study.
By acting on the angiotensin II / bradykinin balance, ACE inhibitors are thought to have an impact
on endothelial dysfunction. Endothelial dysfunction can be considered as a biomarker of vascular
disease as it predisposes the vascular wall to vasoconstriction, vascular inflammation,
platelet activation, thrombosis, and atherosclerosis.
The PERTINENT study therefore set out to establish if the benefits achieved by perindopril observed in EUROPA
were due to the drug’s effect on endothelial function and markers of inflammation and thrombosis.
Lead Author of Study
Professor Roberto Ferrari, Professor of Cardiology, University of Ferrara, Italy
Methodology
Several parameters were measured:
 Human umbilical
vein endothelial cells (HUVEC) function in terms of (1) endothelial cell nitric
oxide synthase (ecNOS) expression and activity, of (2) rate of endothelial apoptosis
Blood levels of angiotensin II
Blood levels of bradykinin
Blood levels of TNF-α
Blood levels of von Willebrand factor
Study design
Human umbilical vein endothelial cells (HUVECs),
a type of endothelial cell, were incubated with blood taken from either normal matched controls (n=45),
or from EUROPA patients before and after 1 year of treatment with either perindopril (n=43) or placebo (n=44).
Results
Results showed in the treated patients group:
A significant increase in ecNOS activity
A significant reduction in endothelial apoptosis rate
A significant reduction in angiotensin II levels
A significant increase in bradykinin levels
A significant decrease in TNF-α
A significant reduction in von Willebrand factor
A significant correlation was observed between bradykinin and ecNOS activity.
The levels of von Willebrand factor are predictive for cardiovascular outcomes.
Conclusion
These results indicate that coronary artery disease progression correlates with
endothelial dysfunction and biological abnormalities. Perindopril in stable coronary
artery disease modifies the biochemical parameters involved in inflammation and
thrombosis, and improves endothelial dysfunction through mechanisms that are
partially dependent on increased bradykinin.
Perindopril also reduces vWf levels that are predictive for outcomes.
Taken together, these results confirm the vascular and anti-atherosclerotic effects
of the ACE inhibitor perindopril and partly explain the results of EUROPA.
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ESC 2003 Hotline - video
