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PERTINENT Endothelial Function

 The background hypothesis for EUROPA was a possible vascular and antiatherosclerotic effect of perindopril (8 mg/day)  The PERindopril - Thrombosis, InflammatioN, Endothelial Dysfunction and Neurohormonal Activation Trial (PERTINENT) was a sub-study of EUROPA designed to test this hypothesis.

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PERTINENT Endothelial Function

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  1. The background hypothesis for EUROPA was a possible vascular and antiatherosclerotic effect of perindopril (8 mg/day) The PERindopril - Thrombosis, InflammatioN, Endothelial Dysfunction and Neurohormonal Activation Trial (PERTINENT) was a sub-study of EUROPA designed to test this hypothesis

  2. PERTINENTEndothelial Function METHODOLOGY 1.Human umbilical vein endothelial cells (HUVECs) were isolated from human umbilical cords 2.CulturedHUVECs were incubated for 72 h with serum from either healthy volunteers (n=45) or patients from EUROPA at baseline and after 1 year of treatment with either perindopril (n=43) or placebo (n=44) 3.End-points: - protein expression and activity of endothelial nitric oxide synthase (eNOS) - rate of apoptosis - protein expression of Bcl-2 associated protein X (Bax) - B cell lymphoma/leukemia 2 (Bcl-2)

  3. PERTINENTNeurohumoral Activation METHODOLOGY To draw further insights on the possible vascular and antiatherosclerotic effect of perindopril, in the plasma from the same population as above, we have also measured: - angiotensin II (Ang II) by radioimmunoassay after HPLC separation - bradykinin (BK) by radioimmunoassay after HPLC separation - tumor necrosis factor (TNF)-a by ELISA - soluble FAS (sFAS) by ELISA

  4. eNOS activity Apoptosis Bax/Bcl-2 eNOS expr (ab/mg prot) (ab/mg prot) (%) p=ns p<0.05 p<0.05 p<0.01 8 6 4 2 % changes vs. baseline 0 -2 -4 Placebo n=44 Treated n=43 -6 PERTINENTAnalysis in cultured HUVECs Percent changes from baseline between perindopril and placebo groups

  5. Angiotensin II Bradykinin sFAS TNF-a (pg/mL) (pg/mL) (pg/mL) (ng/mL) p<0.05 p<0.05 p<0.05 p=ns 10 8 6 4 2 0 % changes vs. baseline -2 -4 -6 -8 -10 -12 -14 Placebo n=44 Treated n=43 PERTINENT Neurohumoral Activity Percent changes from baseline between perindopril and placebo groups

  6. PERTINENT Significant Prognostic Role for vWf 1.0 Low (median value) High (>median value) 09 Survival Probability p<0.01 0.8 0.7 450 570 690 810 930 1080 1230 1380 1530 0 90 210 330 Days median value = 142 %/Unit

  7. PERTINENT CONCLUSIONS CAD progression correlates with endothelial dysfunction and biological abnormalities Perindopril improves endothelial function (up-regulates eNOS and reduces apoptosis) through mechanisms partially dependent on preserved BK levels and reduced TNF-activation Perindopril reduces vWf levels that are positively correlated with incidence of end-points occurrence

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