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ESC Congress 2004: PERTINENT - PERindopril - Thrombosis, InflammatioN, Endothelial dysfunction and Neurohormonal activation Trial
August 31, 2004A Sub-Study of the EUROPA Study Evaluation of the Effect of Perindopril on Endothelial Function
The EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) showed a reduction of cardiovascular events (20% relative risk) that was present beyond the effect on blood pressure: in fact, it was greater than the expected for the observed reduction in blood pressure (mean systolic/diastolic blood pressure reduction 5/2 mmHg, respectively). The positive outcome was also observed in patients with normal blood pressure and was not related to the degree of blood pressure reduction.
In order to investigate a possible mechanism for the above-mentioned effects of perindopril, a series of sub-studies have been designed to evaluate alterative - other than the hypotensive one - mechanisms of action. Among them, the PERindopril - Thrombosis, InflammatioN, Endothelial Dysfunction and Neurohormonal Activation Trial (PERTINENT) was aimed at investigating the possible endothelial protection induced by perindopril.
We a priori hypothesised that perindopril - administered to the patients included in the EUROPA study - could render the endothelium more resistant. To this end, we applied an unusual technique based on the cultivation of human umbilical vein endothelial cells with blood from these patients and measured various parameters of endothelial function. The concept behind is that, if the endothelium is normal, atherosclerosis cannot occur. Conversely, when the endothelium in not functioning, atherosclerosis can occur.
The two most important parameters of endothelial function are i) rate of apoptosis (or, in other words, the frequency by which the endothelium suicides) and ii) activity and expression of nitric oxide synthase, the enzyme that produces nitric oxide and which, in turn, maintains vascular homeostasis. Of interest, we found that EUROPA patients have an increased apoptotic rate and a decreased expression and activity of nitric oxide synthase.
This finding is extremely relevant because EUROPA patients were at low risk for complications and yet the endothelium was not functioning well. One year of treatment with perindopril was able to significantly reduce the rate of endothelium suicide and increase the activity and expression of nitric oxide synthase thus maintaining endothelium function and ultimately, impeding the atherosclerosis process to occur. To further understand the mechanism of action of perindopril, we also measured the serum level of angiotensin II, bradykinin and tumour necrosis factor-? before and after 1 year of treatment with perindopril.
The results showed that there was a significant reduction of angiotensin II (-27%) and increase of bradykinin (17%) and a decrease of tumour necrosis factor-?.
Angiotensin II is related to the rate of apoptosis while bradykinin and of tumour necrosis factor-? are related to nitric oxide synthase and it is possible that perindopril induces its positive effects on human endothelium by modifying these parameters.
So, in conclusion, the data of PERTINENT demonstrate, for the first time, that the positive effect of ACE-inhibition with perindopril on prevention of cardiovascular diseases is not only due to its hypotensive action but also to a positive effect on endothelium.
This is also confirmed by other data from PERTINENT in 1200 patients where perindopril reduced a typical marker of endothelial dysfunction, i.e. the von Willebrand factor and this was correlated with the rate of events.
What is the practical meaning of angiotensin II reduction and bradykinin increase?
It means that perindopril restores the altered balance between angiotensin II and bradykinin that is a restoration of the vasodilatation/vasoconstriction balance.
What is the practical meaning of nitric oxide synthase up-regulation?
It means that the endothelium is better functioning thus producing nitric oxide (NO) that promotes vasodilatation and platelets' anti-adhesion.
What is the practical meaning of a reduced rate of apoptosis?
It means that endothelial cells suicide to a lesser extent thus maintaining intact the "floor" of the vessels and counteracting the atherosclerotic process.
What is the practical meaning of reduced levels of tumour necrosis factor-??
It means that perindopril has an anti-inflammatory effect that is useful to stabilise the atherosclerotic plaque.
What is the practical meaning of reduced levels of von Willebrand factor?
It means that perindopril protects the endothelium and this is linked to less coronary events.
R Ferrari (Ferrara, IT)
European Society of Cardiology (ESC)
We a priori hypothesised that perindopril - administered to the patients included in the EUROPA study - could render the endothelium more resistant. To this end, we applied an unusual technique based on the cultivation of human umbilical vein endothelial cells with blood from these patients and measured various parameters of endothelial function. The concept behind is that, if the endothelium is normal, atherosclerosis cannot occur. Conversely, when the endothelium in not functioning, atherosclerosis can occur.
The two most important parameters of endothelial function are i) rate of apoptosis (or, in other words, the frequency by which the endothelium suicides) and ii) activity and expression of nitric oxide synthase, the enzyme that produces nitric oxide and which, in turn, maintains vascular homeostasis. Of interest, we found that EUROPA patients have an increased apoptotic rate and a decreased expression and activity of nitric oxide synthase.
This finding is extremely relevant because EUROPA patients were at low risk for complications and yet the endothelium was not functioning well. One year of treatment with perindopril was able to significantly reduce the rate of endothelium suicide and increase the activity and expression of nitric oxide synthase thus maintaining endothelium function and ultimately, impeding the atherosclerosis process to occur. To further understand the mechanism of action of perindopril, we also measured the serum level of angiotensin II, bradykinin and tumour necrosis factor-? before and after 1 year of treatment with perindopril.
The results showed that there was a significant reduction of angiotensin II (-27%) and increase of bradykinin (17%) and a decrease of tumour necrosis factor-?.
Angiotensin II is related to the rate of apoptosis while bradykinin and of tumour necrosis factor-? are related to nitric oxide synthase and it is possible that perindopril induces its positive effects on human endothelium by modifying these parameters.
So, in conclusion, the data of PERTINENT demonstrate, for the first time, that the positive effect of ACE-inhibition with perindopril on prevention of cardiovascular diseases is not only due to its hypotensive action but also to a positive effect on endothelium.
This is also confirmed by other data from PERTINENT in 1200 patients where perindopril reduced a typical marker of endothelial dysfunction, i.e. the von Willebrand factor and this was correlated with the rate of events.
What is the practical meaning of angiotensin II reduction and bradykinin increase?
It means that perindopril restores the altered balance between angiotensin II and bradykinin that is a restoration of the vasodilatation/vasoconstriction balance.
What is the practical meaning of nitric oxide synthase up-regulation?
It means that the endothelium is better functioning thus producing nitric oxide (NO) that promotes vasodilatation and platelets' anti-adhesion.
What is the practical meaning of a reduced rate of apoptosis?
It means that endothelial cells suicide to a lesser extent thus maintaining intact the "floor" of the vessels and counteracting the atherosclerotic process.
What is the practical meaning of reduced levels of tumour necrosis factor-??
It means that perindopril has an anti-inflammatory effect that is useful to stabilise the atherosclerotic plaque.
What is the practical meaning of reduced levels of von Willebrand factor?
It means that perindopril protects the endothelium and this is linked to less coronary events.
R Ferrari (Ferrara, IT)
European Society of Cardiology (ESC)
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