Circulating oxidized low-density lipoprotein and its association with carotid intima-media thickness in asymptomatic members of familial combined hyperlipidemia families.
ABSTRACT Oxidized low-density lipoprotein (Ox-LDL)is implicated in the pathogenesis of atherosclerosis. Circulating oxidation-specific epitopes on plasma Ox-LDL has been linked with coronary artery disease, but its determinants and its association with early development of atherosclerosis in familial combined hyperlipidemia (FCHL) has not been very well studied. This study aimed to investigate the determinants of the circulating Ox-LDL and the association between Ox-LDL and carotid intima-media thickness (IMT) in asymptomatic members of FCHL families.
Ox-LDL, susceptibility of LDL to oxidation in vitro, plasma 8-isoprostane and antioxidants, lipids and lipoproteins, LDL particle size, and carotid IMT were measured in 150 asymptomatic FCHL family members. Affected FCHL family members had reduced LDL particle size and lag time for LDL oxidation, increased plasma levels of Ox-LDL, increased plasma urate and alpha-tocopherol, and a trend for the increase of 8-isoprostane as compared with nonaffected FCHL. Ox-LDL was independently associated with serum LDL cholesterol, apoB, and 8-isoprostane in multivariate analysis but only univariately correlated with LDL particle size and lag time for LDL oxidation. In addition, Ox-LDL was significantly associated with carotid mean IMT independently of other clinical and biochemical variables in a multivariate model.
Serum LDL cholesterol, apoB levels, and 8-isoprostane were the most important determinants of Ox-LDL. Ox-LDL is independently associated with carotid IMT in asymptomatic FCHL family members and can be used as a marker of early atherosclerosis in FCHL.
Article: Carotid atherosclerosis in familial combined hyperlipidemia associated with the APOB/APOA-I ratio.[show abstract] [hide abstract]
ABSTRACT: The effects of risk factors on carotid atherosclerosis in familial combined hyperlipidemia (FCHL) remain unclear. We assessed carotid intima-media thickness (IMT) and plaque in relation to classical risk factors and apolipoprotein A-I (apoA-I) and B (apoB) levels in patients with FCHL. We included 131 unrelated FCHL patients (27 with prior cardiovascular disease (CVD)) diagnosed by standard criteria and 190 age- and sex-matched control subjects. Cardiovascular risk factors were assessed and IMT in the far wall of all carotid segments and plaque burden were determined in FCHL patients and controls. All carotid measurements were increased in FCHL patients compared to controls (P<0.001), irrespective of CVD status. For asymptomatic FCHL, the adjusted difference in mean common carotid IMT was 0.08 mm, corresponding to approximately 16 years of physiological IMT increase. By multivariate analysis in a model with all risk factors, inclusive of the metabolic syndrome, independent associations of IMT were age, the apoB/apoA-I ratio, systolic blood pressure, fasting glucose, family history of CVD and total/HDL cholesterol ratio (r(2)=0.475, P<0.001). The strongest determinant of IMT was the apoB/apoA-I ratio (beta=0.422, P<0.001). Patients with FCHL have increased carotid IMT that is strongly related to the apoB/apoA-I ratio, a measure of overall lipid abnormalities. The findings support the atherogenicity of the lipid phenotype in FCHL beyond associated risk factors. They also have implications for diagnosis and management of CVD risk in this condition.Atherosclerosis 04/2008; 197(2):740-6. · 3.79 Impact Factor
Article: Microsomal triglyceride transfer protein gene polymorphism strongly influences circulating malondialdehyde-modified low-density lipoprotein.[show abstract] [hide abstract]
ABSTRACT: Microsomal triglyceride transfer protein (MTP) plays a critical role in the assembly of lipoproteins. Therefore, we studied whether MTP gene polymorphisms are associated with atherosclerosis-promoting parameters, especially metabolic profiles and endothelial function, in healthy young men. One hundred one healthy men (mean age, 30.3 years) were studied. We analyzed the 2 promoter polymorphisms (-493G/T and -400A/T) of the MTP gene. Linkage disequilibrium analysis revealed a significant but incomplete linkage disequilibrium between the 2 polymorphisms (D' = 0.74). The -493T allele carriers (n = 26) showed marked increases in their levels of malondialdehyde-modified low-density lipoprotein (mean value, 135 vs 99 U/L in the G/G carriers; P = .003) and triglycerides (2.15 vs 1.16 mmol/L, P = .014), and reduced low-density lipoprotein particle size (259.2 vs 264.3 nm, P = .023), whereas there was no difference in apolipoproteins, insulin, adiponectin, homocysteine, folate, and endothelial function assessed using ultrasound measurement of brachial artery flow-mediated vasodilation. In contrast, the -400T allele carriers (n = 61) showed a reduced endothelial function (P = .044), accompanied by elevated apolipoprotein B levels in subjects with higher triglyceride levels. These results indicate that both promoter polymorphisms may be associated with the development of atherosclerosis and cardiovascular diseases, but that the mechanism responsible may be different.Metabolism: clinical and experimental 07/2009; 58(9):1306-11. · 2.59 Impact Factor
Article: Arterial endothelial function and wall thickness in familial hypercholesterolemia and familial combined hyperlipidemia and the effect of statins. A systematic review and meta-analysis.[show abstract] [hide abstract]
ABSTRACT: To evaluate the impact of familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCH) on arterial properties and the effects of statins. We meta-analyzed 51 studies providing data for 4,057 FH patients and 732 FCH patients with random-effects models, meta-regression analysis and publication bias analysis. The main outcomes of interest were (1) brachial artery flow-mediated dilation (FMD), (2) intima-media thickness (IMT), and (3) change of IMT and FMD after treatment with statins. Compared to normolipidemic controls, FH patients had lower FMD [pooled mean difference (MD): -5.31%, 95% CI -7.09 to -3.53%, P<0.001] and higher carotid IMT (pooled MD: 0.12mm, 95% CI 0.09-0.15mm, P<0.001) and femoral IMT (pooled MD: 0.35mm, 95% CI 0.18-0.51mm, P<0.001). FCH patients had lower FMD and increased IMT (pooled MD: -3.60%, 95% CI -6.69 to -0.50%, P=0.023; and 0.06mm, 95% CI 0.04-0.08mm, P<0.001, respectively). Total and LDL-cholesterol was a significant determinant of FMD and carotid IMT in FCH patients and of FMD and femoral IMT in FH patients. In FH patients, statins improved FMD (pooled MD of change: 5.39%, 95% CI 2.86-7.92%, P<0.001) and decreased carotid IMT (pooled MD of change: -0.025mm, 95% CI -0.042 to -0.009mm, P=0.003). Changes of both FMD and IMT with statins correlated with the duration×treatment intensity product in FH patients (both P<0.01). Additionally, statins improved FMD in FCH patients (pooled MD of change: 2.06%, 95% CI 0.43-3.69%, P=0.013). No significant publication bias was detected. Arterial properties are impaired in subjects with FH or FCH. Statins improve arterial function and structure in FH patients in a treatment intensity-related manner.Atherosclerosis 10/2010; 214(1):129-38. · 3.79 Impact Factor