Small dense LDL and VLDL predict common carotid artery IMT and elicit an inflammatory response in peripheral blood mononuclear and endothelial cells.

OBJECTIVE: The presence of small dense LDL has been associated with increased cardiovascular risk and with the progression of coronary and carotid atherosclerosis in case-control and prospective studies. The aim of this study was to investigate the relation between different lipoprotein subfractions with intima-media thickness of the common carotid artery in a free-living, healthy population, and to evaluate whether in patients with comparable LDL-C, the different lipoprotein subclasses differently affected the expression of chemokines, cytokines and adhesion molecules in peripheral blood mononuclear and endothelial cells. METHODS AND RESULTS: The lipoprotein cholesterol profile and the LDL buoyancy (LDL-RF) were evaluated in a cohort of 156 healthy subjects randomly selected from the PLIC (Progressione Lesione Intimale Carotidea) study. The LDL-RF was directly and significantly correlated to weight, body mass index, waist, hip, waist/hip ratio, triglycerides, fasting glycemia and intima media thickness (IMT) of the common carotid artery and inversely related to HDL-C. After multivariate statistical analysis, IMT was independently associated with age, LDL-RF and HDL-C and among the lipoprotein subclasses, only those corresponding to triglyceride-rich lipoproteins (TGRL) and small dense LDL (sdLDL) independently predicted IMT variance. Peripheral blood mononuclear cells (PBMC) isolated from patients with the predominance of sdLDL (pattern B) had an increased mRNA expression of pro-inflammatory molecules compared to PBMC from patients with the predominance of large LDL (pattern A); in endothelial cells TGRL from pattern B subjects and much less those from pattern A induced the expression of pro-inflammatory genes while sdLDL from either pattern A or B subjects were less effective and showed comparable effects. CONCLUSION: LDL-relative flotation rate significantly correlates with several cardiometabolic parameters. Furthermore cholesterol levels lipoprotein subfractions within the TGRL and sdLDL density range are independent predictors of IMT variance and are associated with a pro-inflammatory activation of PBMC and endothelial cells.

Common hepatic lipase gene promoter variant predicts the degree of neointima formation after carotid endarterectomy: impact of plaque composition and lipoprotein phenotype.

BACKGROUND: The common -514 C-T promoter polymorphism of the hepatic lipase gene (LIPC) and the cholesteryl ester transfer protein (CETP) gene TaqIB polymorphism affect atherogenesis. We investigated the potential relationship between these polymorphisms and the maximum-intima-media thickness (M-IMT) after carotid endarterectomy. METHODS: The LIPC and CETP genotypes were determined by PCR in 68 patients undergoing endarterectomy. Plaque specimens were analysed for cell composition by immunocytochemistry. Six month after surgery the M-IMT of the revascularized vessel was assessed by B-mode ultrasonography. RESULTS: The CC carriers had denser LDL particles (p<0.0005), an abundance of macrophages (p<0.0005), fewer SMCs in the carotid plaque (p<0.0005), and higher prevalence of cerebrovascular events (72% versus 28%, p=0.002) compared to CT/TT carriers. After endarterectomy, CC carriers showed a lower M-IMT than the CT/TT group (1.36 mm versus 1.76 mm, p=0.04). No association between the CETP polymorphism and either carotid plaque cellular composition or M-IMT was observed. In a multivariate analysis, M-IMT was associated with plaque cell composition (macrophages, r=-0.39; SMC, r=0.44; p<0.005 for both) but not with pre-operative LDL-C, HDL-C, triglycerides, or LDL density. CONCLUSIONS: The LIPC promoter -514 C-T polymorphism is associated with a significantly reduced development of neointima after surgery. This effect seems to be mediated by scarcity of SMC in the plaque of CC carriers who display an excess prevalence of cerebrovascular events prior endarterectomy but are at low risk for restenosis. The pre-operative lipid phenotype plays a marginal role in the neointima formation.

Association between the --514 C-->T polymorphism of the hepatic lipase gene promoter and unstable carotid plaque in patients with severe carotid artery stenosis.

OBJECTIVE: We investigated the potential association between -514 C-->T polymorphism in the promoter of the hepatic lipase gene (LIPC) and the prevalence of inflammatory cells in the plaque of patients with severe carotid artery stenosis. BACKGROUND: This common LIPC polymorphism has been related to the presence of an atherogenic lipoprotein pattern. METHODS: We studied 68 consecutive patients undergoing carotid endarterectomy. The LIPC genotype was determined by polymerase chain reaction. Endarterectomy specimens were examined by immunocytochemistry using monoclonal antibodies for smooth muscle cells, macrophages, or lymphocytes. RESULTS: In 50 of 68 patients who had evidence of previous ipsilateral ischemic events, 36 (72%) were carriers of the CC genotype, whereas only 14 (28%) were carriers of the CT/TT genotype (p = 0.002). Among the 18 patients without evidence of events, the two genotypes were equally distributed (9 vs. 9). The low-density lipoprotein (LDL) particles were denser in CC than in CT/TT genotype carriers (flotation rate: 0.315 +/- 0.025 vs. 0.356 +/- 0.019, p < 0.0005). The CC genotype was associated with an abundance of macrophages (6.7 +/- 3.5 vs. 2.1 +/- 2.1 cells/area unit in the CT/TT group, p < 0.0005) and a reduced number of smooth muscle cells (6.9 +/- 6.2 vs. 14.5 +/- 6.4 in the CT/TT group, p < 0.0005) in the plaque. An inverse relationship was found between LDL buoyancy and the number of macrophages in the plaque (r = -0.639, p < 0.0005). CONCLUSION: We provide evidence, for the first time, that LIPC promoter -514 C-->T polymorphism, by modulating LDL density, significantly affects the number of macrophages in the plaque and possibly affects the occurrence of cerebrovascular events in patients with carotid artery stenosis.