ACE inhibition with perindopril and endothelial function. Results of a substudy of the EUROPA study: PERTINENT.
OBJECTIVE
EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease [EUROPA] demonstrates reduction in cardiovascular mortality and myocardial infarction for a possible vascular and antiatherosclerotic effect of angiotensin-converting enzyme (ACE) inhibition with perindopril. Our objective was to study the effect of perindopril on endothelial function and to verify its link to risk and occurrence of cardiovascular events.


METHODS
Blood from 1200 EUROPA patients was withdrawn at baseline and after 1 year of treatment with either perindopril or placebo to measure von Willebrand factor and from 45 healthy subjects and 87 EUROPA patients to study endothelial function at the cellular level by cultivating in vitro human umbilical vein endothelial cells. In this setting, we determined protein expression/activity of endothelial nitric oxide synthase and the rate of apoptosis. Plasma levels of angiotensin II, bradykinin, tumor necrosis factor alpha, and nitrite/nitrate were also measured.


RESULTS
The occurrence of cardiovascular events was related to von Willebrand factor at baseline (P = 0.013) that also significantly decreased after 1 year's treatment (P < 0.001). Perindopril upregulated 19% and 27% protein expression/activity of endothelial nitric oxide synthase (P < 0.05) as well as reduced the rate of apoptosis by 31% (P < 0.05). There was also a significant reduction in levels of angiotensin II, increase in bradykinin, reduction in tumor necrosis factor alpha, and increase in nitrite/nitrate (P < 0.05 for all).


CONCLUSIONS
Abnormal endothelial function occurs in patients with coronary artery disease, and this can be counteracted by angiotensin-converting enzyme inhibition with perindopril. These effects could contribute, at least in part, to explaining the results of the main EUROPA Study.
Ceconi
Claudio
C
University of Ferrara and Cardiovascular Pathophysiology Research Centre, Salvatore Maugeri Foundation, IRCCS, Gussago (Brescia), Italy.
Fox
Kim M
KM
Remme
William J
WJ
Simoons
Marteen L
ML
Bertrand
Michael
M
Parrinello
Giovanni
G
Kluft
Cornelius
C
Blann
Andrew
A
Cokkinos
Dennis
D
Ferrari
Roberto
R
D000368:Aged; D000704:Analysis of Variance; D000804:Angiotensin II / Q000097:blood / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000097:blood; D001920:Bradykinin / Q000097:blood; D002478:Cells, Cultured; D003327:Coronary Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009569:Nitric Oxide / Q000097:blood; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D020913:Perindopril / Q000627:therapeutic use*; D016016:Proportional Hazards Models; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000494:pharmacology; D014841:von Willebrand Factor / Q000032:analysis
D000806:Angiotensin-Converting Enzyme Inhibitors; D015415:Biomarkers; D014409:Tumor Necrosis Factor-alpha; D014841:von Willebrand Factor; D000804:Angiotensin II; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D001920:Bradykinin; D020913:Perindopril