ACE Inhibition and Endothelial Function: Main Findings of PERFECT, a Sub-Study of the EUROPA Trial

Background: ACE inhibition results in secondary prevention of coronary artery disease (CAD) through different mechanisms including improvement of endothelial dysfunction. The Perindopril-Function of the Endothelium in Coronary artery disease Trial (PERFECT) evaluated whether long-term administration of perindopril improves endothelial dysfunction. Methods: PERFECT is a 3-year double blind randomised placebo controlled trial to determine the effect of perindopril 8 mg once daily on brachial artery endothelial function in patients with stable CAD without clinical heart failure. Endothelial function in response to ischaemia was assessed using ultrasound. Primary endpoint was difference in flow-mediated vasodilatation (FMD) assessed at 36 months. Results: In 20 centers, 333 patients randomly received perindopril or matching placebo. Ischemia-induced FMD was 2.7% (SD 2.6). In the perindopril group FMD went from 2.6% at baseline to 3.3% at 36 months and in the placebo group from 2.8 to 3.0%. Change in FMD after 36 month treatment was 0.55% (95% confidence interval −0.36, 1.47; p = 0.23) higher in perindopril than in placebo group. The rate of change in FMD per 6 months was 0.14% (SE 0.05, p = 0.02) in perindopril and 0.02% (SE 0.05, p = 0.74) in placebo group (0.12% difference in rate of change p = 0.07). Conclusion: Perindopril resulted in a modest, albeit not statistically significant, improvement in FMD

Primary and secondary prevention in cardiovascular disease: an old-fashioned concept?

Objective. Is the concept of primary and secondary cardiovascular prevention an old-fashioned concept that needs to be re-defined? Design. Discussion paper. Results. Cardiovascular prevention means reduction of absolute risk for cardiovascular disease (CVD), irrespective of clinical stage. Conclusion. For the calculation of an individual probability to develop CVD all factors that contribute to the risk must be taken into account, including previous CVD events

Aggressive lipid lowering does not improve endothelial function in type 2 diabetes - The Diabetes Atorvastatin Lipid Intervention (DALI) study:A randomized, double-blind, placebo-controlled trial

OBJECTIVE - Endothelial dysfunction is considered an important early marker of atherosclerosis and cardiovascular risk and is currently used as a surrogate end point for cardiovascular at risk in clinical trials. Type 2 diabetic patients show a characteristic dyslipidemia. Aggressive lipid lowering might he an effective method to improve endothelial function in these patients. RESEARCH DESIGN AND METHODS - A randomized, double-blind, placebo-controlled trial was completed to study the effect of 30 weeks' administration of atorvastatin 10 rug and 80 rug on endothelial function, as assessed by B-mode ultrasound of the brachial artery, in 133 patients with type 2 diabetes without a history of cardiovascular disease. RESULTS- patients with diabetes and diabetic dyslipidemia had considerable endothelium-dependent and endothelium-independent dysfunction; mean flow-mediated vasodilation (SD) was 3.16% (3.56), and mean response on sublingual nitroglycerin was 6.58% (6.04). Despite su stantia owering of all atherogenic lipid parameters, no improvement of endotheliumdependent vasodilatation was found (P > 0.8). CONCLUSIONS - We observed considerable baseline endothelium-dependent and endothelium-independent dysfunction in patients with diabetes and diabetic dyslipidemia without a history of cardiovascular disease. Aggressive lipid lowering by administration of atorvastatin, resulting in substantial improvement of the lipid profile, did not reverse endothelial dysfunction

Common cholesteryl ester transfer protein gene polymorphisms and the effect of atorvastatin therapy in type 2 diabetes

OBJECTIVE - The cholesteryl ester transfer protein (CETP) plays a key role in the remodeling of triglyceride (TG)-rich and HDL particles. Sequence variations in the CETP gene may interfere with the effect of lipid-lowering treatment in type 2 diabetes. RESEARCH DESIGN AND METHODS - We performed a 30-week randomized double-blind placebo-controlled trial with atorvastatin 10 mg (A10) and 80 mg (A80) in 217 unrelated patients with diabetes. RESULTS - CETP TaqlB and A-629C polymorphisms were tightly concordant (P <0.001). At baseline, B1B1 carriers had lower plasma HDL cholesterol (0.99 +/- 0.2 vs. 1.11 +/- 0.2 mmol/l,P <0.05), higher CETP mass (2.62 +/- 0.8 vs. 2.05 +/- 0.4 mg/l, P <0.001), and slightly increased, though not significant, plasma TGs (2.7 +/- 1.05 vs. 2.47 +/- 0.86, P = 0.34) compared with B2B2 carriers. Atorvastatin treatment significantly reduced CETP mass dose-dependently by 18% (A10) and 29% (A80; both Vs. placebo P <0.001, A10-A80 P - 0.001). CETP mass and activity were strongly correlated (r = 0.854, P <0.0001). CETP TaqlB polymorphism appeared to modify the effect of atorvastatin on HDL cholesterol elevation (B1B1 7.2%, B1B2 6.1% B2B2 0.5%; P <0.05), TG reduction (B1B1 39.7%, B1B2 38.4%, B1B2 18.4%; P = 0.08), an CETP mass reduction (B1B1 32.1%, B1B2 29.6%, B2B2 21.9%; P = 0.27, NS). Similar results were obtained for the A-629C polymorphism. CONCLUSIONS - in conclusion, the B1B1/CC carriers of the CETP polymorphisms have a more atherogenic lipid profile, including low HDL, and they respond better to statin therapy. These results favor the hypothesis that CETP polymorphisms modify the effect of statin treatment and may help to identify patients who will benefit most from statin therapy