No abstract

Imbalance on endothelial turnover can predict cardiovascular outcomes. We aimed at evaluating the effects of lipid-modifying therapies on circulating endothelial progenitor cells (EPCs), endothelial microparticles (EMPs), and platelet microparticles (PMPs) in high cardiovascular risk subjects with elevated C-reactive protein (CRP). Sixty-three individuals with coronary heart disease (CHD) or CHD risk equivalent on stable statin therapy, with LDL-cholesterol <100 mg/dL and CRP ≥ 2.0 mg/L were selected. After a 4-week run-in period with atorvastatin 10 mg, those with persistent CRP ≥ 2.0 mg/L were randomized to another 4-week treatment period with atorvastatin 40 mg, ezetimibe 10 mg or atorvastatin 40 mg/ezetimibe 10 mg. EPC (CD34(+)/CD133(+)/KDR(+)), EMP (CD51(+)), and PMP (CD42(+)/CD31(+)) were quantified by flow cytometry. Atorvastatin 40 mg and atorvastatin 40 mg/ezetimibe 10 mg reduced LDL-cholesterol (P < 0.001, paired T test, vs. baseline). Combined therapy, but not ezetimibe reduced CRP. CD34(+)/KDR(+) EPC were reduced after ezetimibe alone (P = 0.011 vs. baseline, Wilcoxon test) or combined with atorvastatin (P = 0.016 vs. baseline, Wilcoxon test). In addition, ezetimibe increased CD51(+) EMP (P = 0.017 vs. baseline, Wilcoxon test). No correlations between these markers and LDL-cholesterol or CRP were observed. These results contribute to understand the link between inflammation and vascular homeostasis and highlight the broader benefit of statins decreasing inflammation and preventing microparticles release, an effect not observed with ezetimibe alone.

High-risk subjects with elevated C-reactive protein (CRP) are at high risk for cardiovascular events and frequently require potent statins or combined lipid-lowering therapy to achieve lipid targets and decrease inflammation. Our study aimed at evaluating the effects of three lipid-modifying therapies on LDL-cholesterol, CRP levels and markers of cholesterol absorption and synthesis. Main methods: A prospective intervention study was performed in high cardiovascular risk individuals receiving atorvastatin 10 mg daily for four weeks. Those with CRP ≥ 2.0 mg/L were randomized to another four-week treatment period with atorvastatin 40 mg, ezetimibe 10 mg or the combination of atorvastatin 40 mg / ezetimibe 10 mg. Lipids, markers of cholesterol absorption (campesterol and β-sitosterol), and synthesis (desmosterol), as well as CRP were quantified at baseline and end of study. Key findings: One hundred and twenty two individuals were included. Atorvastatin alone or combined with ezetimibe reduced both LDL-cholesterol and CRP (P b 0.002 vs. baseline; Wilcoxon); ezetimibe did not modify CRP. Ezetimibe-based therapies reduced absorption markers and their ratios to cholesterol (P b 0.0001 vs. baseline, for all; Wilcoxon), whereas atorvastatin alone increased campesterol/cholesterol and β-sitosterol/ cholesterol ratios (P b 0.05 vs. baseline; Wilcoxon). In addition, ezetimibe also increased desmosterol and desmosterol/cholesterol ratio (P b 0.0001 vs. baseline; Wilcoxon). Significance: These results contribute to understanding the link between cellular cholesterol homeostasis, inflammation and lipid-modifying therapies. Our findings highlight the broader benefit of combined therapy with a potent statin and ezetimibe decreasing inflammation, and preventing increase in cholesterol biosynthesis, an effect not observed with ezetimibe alone.