Apolipoprotein A-II Influences Apolipoprotein E-Linked Cardiovascular Disease Risk in Women with High Levels of HDL Cholesterol and C-Reactive Protein

Background: In a previous report by our group, high levels of apolipoprotein E (apoE) were demonstrated to be associated with risk of incident cardiovascular disease in women with high levels of C-reactive protein (CRP) in the setting of both low (designated as HR1 subjects) and high (designated as HR2 subjects) levels of high-density lipoprotein cholesterol (HDL-C). To assess whether apolipoprotein A-II (apoA-II) plays a role in apoE-associated risk in the two female groups. Methodology/Principal: Outcome event mapping, a graphical data exploratory tool; Cox proportional hazards multivariable regression; and curve-fitting modeling were used to examine apoA-II influence on apoE-associated risk focusing on HDL particles with apolipoprotein A-I (apoA-I) without apoA-II (LpA-I) and HDL particles with both apoA-I and apoA-II (LpA-I:A-II). Results of outcome mappings as a function of apoE levels and the ratio of apoA-II to apoA-I revealed within each of the two populations, a high-risk subgroup characterized in each situation by high levels of apoE and additionally: in HR1, by a low value of the apoA-II/apoA-I ratio; and in HR2, by a moderate value of the apoA-II/apoA-I ratio. Furthermore, derived estimates of LpA-I and LpA-I:A-II levels revealed for high-risk versus remaining subjects: in HR1, higher levels of LpA-I and lower levels of LpA-I:A-II; and in HR2 the reverse, lower levels of LpA-I and higher levels of LpA-I:A-II. Results of multivariable risk modeling as a function of LpA-I and LpA-I:A-II (dichotomized as highest quartile versus combined three lower quartiles) revealed association of risk only for high levels of LpA-I:A-II in the HR2 subgroup (hazard ratio 5.31, 95% CI 1.12-25.17, p = 0.036). Furthermore, high LpA-I: A-II levels interacted with high apoE levels in establishing subgroup risk. Conclusions/Significance: We conclude that apoA-II plays a significant role in apoE-associated risk of incident CVD in women with high levels of HDL-C and CRP

Probucol increases cholesteryl ester transfer protein activity in hypercholesterolaemic patients

Probucol, a widely used lipid lowering drug, reduces both low- and high-density (LDL and HDL) lipoprotein levels and can induce a regression of tissue lipid deposits in both animals and man. The suggested mechanism(s) involve the prevention of LDL oxidative modifications and, possibly, an improvement in the reverse cholesteryl ester transport system. Probucol administration to 10 hypercholesterolaemic patients increased the activity of the cholesteryl ester transfer protein (CETP) by 50%. The rise of CETP activity was significantly related with the plasma steady-state drug levels (r = 0.51, P less than 0.005), thus suggesting that probucol may directly stimulate CEPT synthesis and/or release. Furthermore, CETP activity was inversely related with HDL-cholesterol levels, both in the whole series of 10 patients (r = -0.56, P less than 0.001) and, more so, in the single individuals (r between -0.77 and -0.97), thus suggesting that the reduction of plasma HDL-cholesterol levels is a direct consequence of CETP stimulation. These findings support the hypothesis that an improvement in the reverse cholesteryl ester transport is a major mechanism of probucol and that this may explain the drug induced plasma lipoprotein changes