Reduced incidence of cardiovascular events in hyper-Lp(a) patients on lipoprotein apheresis. The G.I.L.A. (Gruppo Interdisciplinare Aferesi Lipoproteica) pilot study.

BACKGROUND: Lipoprotein apheresis (LA) is the elective therapy for homozygous and other forms of Familial Hypercholesterolemia, Familial Combined Hypercholesterolemia, resistant/intolerant to lipid lowering drugs, and hyper-lipoproteinemia(a). Lipoprotein(a) [Lp(a)] has been classified as the most prevalent genetic risk factor for coronary artery disease and aortic valve stenosis. AIM: Our multicenter retrospective study has the aim to analyze the incidence of adverse cardiovascular events (ACVE) before and during the LA treatment, in subjects with elevated level of Lp(a) (>60 mg/dL) [hyper-Lp(a)] and chronic ischemic heart disease. METHODS: We collected data of 23 patients (mean age 63 ± 9 years, male 77%; from hospital of Pisa 11/23, Pistoia 7/23, Verona 2/23, Padova 2/23 and Ferrara 1/23), with hyper-Lp(a), pre-apheresis LDL-cholesterol <100 mg/dL, cardiovascular disease, on maximally tolerated lipid lowering therapy and LA treatment (median 7 years, interquartile range 3-9 years). The LA treatment was performed by heparin-induced LDL precipitation apheresis (16/23), dextran-sulphate (4/23), cascade filtration (2/23) and immunoadsorption (1/23). The time lapse between first cardiovascular event and beginning of apheresis was 6 years (interquartile range 1-12 years). RESULTS: The recorded ACVE, before and after the LA treatment inception, were 40 and 10 respectively (p < 0.05), notably, the AVCE rates/year were 0.43 and 0.11 respectively (p < 0.05) with a 74% reduction of event occurrence. CONCLUSIONS: Our data confirm long-term efficacy and positive impact of LA on morbidity in patients with hyper-Lp(a) and chronic ischemic heart disease on maximally tolerated lipid lowering therapy.

[Dyslipidemia: news in diagnosis and drug therapy]. / Dislipidemie: attualita' in diagnosi e terapia farmacologica.

Plasma lipid levels are to a large extent determined by genetic factors. In its more extreme forms this is manifested as familial hyperlipidemias, which are an important cause of premature coronary heart disease. It has been demonstrated that rigorous treatment of familial forms reduces the burden of ischemic heart disease. Statins are among the most studied drugs in cardiovascular prevention; a number of large-scale clinical trials have demonstrated that statins substantially reduce cardiovascular morbidity and mortality in both primary and secondary prevention. The currently available evidence suggests that the clinical benefit is largely independent of the type of statin, but depends on the extent of LDL-C lowering. When the most potent statins are insufficient, LDL-C apheresis should be used.

Relationships between desacylated and acylated ghrelin and insulin sensitivity in the metabolic syndrome.

CONTEXT: Metabolic syndrome shows clustered metabolic abnormalities with major roles for insulin resistance and obesity. Ghrelin is a gastric hormone whose total plasma concentration (T-Ghr) is associated positively with insulin sensitivity and is reduced in obesity. Ghrelin circulates in acylated (A-Ghr) and desacylated (D-Ghr) forms, but their potential differential associations with insulin resistance and whether they are differentially altered in obesity remain undefined. OBJECTIVE: Our objective was to determine potential differential associations of ghrelin forms with insulin resistance [homeostasis model assessment of insulin resistance (HOMA-IR)] and the impact of obesity on their plasma concentrations in metabolic syndrome. DESIGN: This is a cross-sectional study. SETTING: The study was performed in a metabolic outpatient unit. PATIENTS: Patients with metabolic syndrome (National Cholesterol Education Program-Adult Treatment Panel III; n = 45, 23 males/22 females) were included in the study. MAIN OUTCOMES: The main study outcomes were metabolic syndrome criteria, HOMA-IR, and ghrelin forms. RESULTS: Plasma insulin and HOMA-IR were associated negatively with T-Ghr and D-Ghr but positively with A-Ghr and acylated to desacylated ghrelin (A/D-Ghr) ratio (n = 45; P < 0.05). Compared with nonobese [body mass index (BMI) < 27.5 kg/m(2); n = 12, six males/six females], obese metabolic syndrome patients (BMI > 27.5 kg/m(2); n = 33) had lower T-Ghr and D-Ghr but comparable A-Ghr and higher A/D-Ghr ratio (P < 0.05). BMI and waist circumference (WC) were positively related with HOMA-IR (n = 45; P < 0.05). However, opposite associations between A/D-Ghr ratio and HOMA-IR remained significant after adjustment for sex and BMI (or WC). Additional obese individuals without metabolic syndrome (n = 10: age-, sex-, BMI-, and WC-matched to obese metabolic syndrome patients) had lower T-Ghr but higher A-Ghr (P < 0.05) compared with age-, sex-matched healthy nonobese counterparts (n = 15). T-Ghr and A-Ghr were comparable in obese with or without metabolic syndrome. CONCLUSION: Obesity could alter circulating ghrelin profile, and relative A-Ghr excess could contribute to obesity-associated insulin resistance in metabolic syndrome.

Gender-Specific Association of Desacylated Ghrelin with Subclinical Atherosclerosis in the Metabolic Syndrome.

OBJECTIVE: Ghrelin, a gastric hormone with pleiotropic effects modulates vascular function and may influence atherosclerosis. Plasma ghrelin is reduced in the metabolic syndrome (MS), which is also characterized by early atherosclerosis. Ghrelin circulates in acylated (AG) and desacylated (DAG) forms. Their relative impact and that of gender on subclinical atherosclerosis in MS is unknown. AIM OF THE STUDY: To investigate potential associations of total, AG and DAG with carotid atherosclerosis and with gender in the MS. METHODS: Plasma total ghrelin, AG, DAG and carotid artery IMT (cIMT) were measured in 46 MS patients (NCEP-ATP III criteria, 22M/24F). RESULTS: Compared with males, females had higher (p <0.05) total and DAG. In the association analysis, age and plasma glucose were positively (p <0.05) correlated with cIMT in all MS patients. The positive (p <0.05) association between cIMT and age was also confirmed in males, while that between cIMT and glucose was significant in women. In contrast, neither total ghrelin nor AG and DAG were associated with cIMT in all MS patients nor in the male subgroup. In females, a negative (p <0.05) association between carotid artery IMT, DAG and glucose was detected, but not between cIMT, total ghrelin and AG. In multivariate modeling, DAG remained negatively (p <0.05) associated with cIMT after adjusting for plasma glucose and cardiovascular risk factors. CONCLUSIONS: These data indicate a negative independent association between DAG and cIMT in middle-aged women with the MS and suggest a gender-specific modulatory function of DAG in the development of atherosclerosis.

Production of polyacrylamide gradient gel for lipoprotein electrophoretic separation.

BACKGROUND: Small LDL are associated with risk of coronary heart disease. Gradient gel electrophoresis for LDL separation is not a simple method and high-quality non-denaturing gradient gels are lacking. METHODS: In this paper, we describe a method for the preparation of a polyacrylamide gel system that consists of an upper linear gradient gel (1.8-10%) and a lower homogeneous gel (16%) for the determination of LDL size. RESULTS: The linear gradient is highly reproducible. Intra-inter gel coefficients of variation for LDL particle size are lower than 0.6%. CONCLUSION: Effective LDL size measurement from pre-stained serum samples is possible in a stable gel.

HELP LDL apheresis reduces plasma pentraxin 3 in familial hypercholesterolemia.

BACKGROUND: Pentraxin 3 (PTX3), a key component of the humoral arm of innate immunity, is secreted by vascular cells in response to injury, possibly aiming at tuning arterial activation associated with vascular damage. Severe hypercholesterolemia as in familial hypercholesterolemia (FH) promotes vascular inflammation and atherosclerosis; low-density lipoprotein (LDL) apheresis is currently the treatment of choice to reduce plasma lipids in FH. HELP LDL apheresis affects pro- and antiinflammatory biomarkers, however its effects on PTX3 levels are unknown. We assessed the impact of FH and of LDL removal by HELP apheresis on PTX3. METHODS: Plasma lipids, PTX3, and CRP were measured in 19 patients with FH undergoing chronic HELP LDL apheresis before and after treatment and in 20 control subjects. In the patients assessment of inflammation and oxidative stress markers included also plasma TNFα, fibrinogen and TBARS. RESULTS: At baseline, FH patients had higher (p = 0.0002) plasma PTX3 than matched control subjects. In FH PTX3 correlated positively (p≤0.05) with age, gender and CRP and negatively (p = 0.01) with HELP LDL apheresis vintage. The latter association was confirmed after correction for age, gender and CRP. HELP LDL apheresis acutely reduced (p≤0.04) plasma PTX3, CRP, fibrinogen, TBARS and lipids, but not TNFα. No association was observed between mean decrease in PTX3 and in LDL cholesterol. PTX3 paralleled lipids, oxidative stress and inflammation markers in time-course study. CONCLUSION: FH is associated with increased plasma PTX3, which is acutely reduced by HELP LDL apheresis independently of LDL cholesterol, as reflected by the lack of association between change in PTX3 and in LDL levels. These results, together with the finding of a negative relationship between PTX3 and duration of treatment suggest that HELP LDL apheresis may influence both acutely and chronically cardiovascular outcomes in FH by modulating PTX3.

Nonalcoholic fatty liver and metabolic syndrome in Italy: results from a multicentric study of the Italian Arteriosclerosis society.

Nonalcoholic fatty liver disease (NAFLD) is associated with all the components of metabolic syndrome (MS) and might to be considered an additional component of MS itself. The Italian Society for the Study of Atherosclerosis (SISA) in 2005 started a research project aimed to study the NAFLD, using ultrasound (US), in nondiabetic MS subjects matching at least one of the ATP III criteria for HDL-C or triglycerides [TG]. Prevalence of US-NAFLD and its associated risk factors and prevalence of hypertransaminasemia and its possible determinants were evaluated. NAFLD prevalence was 0.78. Men with steatosis compared to men without steatosis were younger (P < 0.05) with higher TG (P < 0.03), homeostasis model assessment insulin resistance (HOMA-R) (P < 0.003), and visceral fat thickness (VFT) (P < 0.0001). Women with steatosis showed higher TG (P < 0.05), HOMA-R (P < 0.04), VFT (P < 0.0001), and lower age (P < 0.05). At multivariate analyses, VFT (P < 0.0001), HOMA-R (P < 0.02), and TG/HDL (P < 0.05) were associated with severity of NAFLD. Age (P < 0.05), LogTG (P < 0.005), and VFT (P < 0.01) were associated with higher ALT. The US prevalence of steatosis in this study (0.78) is the highest reported in patients with MS. Considering the exclusion of severe obese and diabetic patients and the recruitment criteria, this finding highlights the prominent role played by the alterations of lipid metabolism in the pathogenesis of NAFLD.

The plasma concentration of Lpa-I:A-II particles as a predictor of the inflammatory response in patients with ST-elevation myocardial infarction.

OBJECTIVE: To investigate the relationship between plasma HDL at admission and the extent of the inflammatory response during an ST-elevation myocardial infarction (STEMI), and to analyse structural HDL changes during STEMI as related to the extent of inflammation. METHODS AND RESULTS: CRP and IL-6 were monitored for 96h in 45 patients with STEMI. Plasma apoA-II and LpA-I:A-II levels at admission, but not HDL cholesterol or other HDL-related biomarkers, were associated with the extent of the inflammatory response during STEMI, as indicated by the positive correlations with CRP AUC (apoA-II: F=7.44, p=0.009; LpA-I:A-II: F=14.29, p<0.001), and IL-6 AUC (apoA-II: F=6.98, p=0.012; LpA-I:A-II: F=6.67, p=0.013). By multivariate analysis the plasma LpA-I:A-II level at admission was a powerful independent predictor of the inflammatory response, evaluated either as CRP AUC (F=22.30, p<0.001), or IL-6 AUC (F=6.92, p=0.012). During STEMI, the plasma concentration of LpA-I:A-II, but not LpA-I particles decreased, HDL became larger and progressively enriched in serum amyloid A; these changes occurred only in patients with a significant inflammatory response. CONCLUSION: An elevated plasma concentration of LpA-I:A-II particles was an independent predictor of a more severe inflammatory response in patients with STEMI.

Circulating pentraxin 3 levels are higher in metabolic syndrome with subclinical atherosclerosis: evidence for association with atherogenic lipid profile.

Metabolic syndrome is characterized by increased cardiovascular risk. Pentraxin 3 (PTX3), an acute phase protein, is involved in atherosclerosis. No information is available on PTX3 plasma concentrations in metabolic syndrome and on its associations with metabolic alterations and subclinical atherosclerosis. The aim of this study was to assess PTX3 plasma levels in metabolic syndrome patients compared to control subjects and their potential associations with anthropometric and clinical components of the syndrome as well as with carotid artery intima-media thickness (cIMT), a marker of subclinical atherosclerosis. Plasma was obtained from metabolic syndrome patients (NCEP-ATP III criteria n = 41, 20 M/21F) and by age-matched control subjects (n = 32, 16 M/16F). PTX3 was measured using sandwich ELISA and cIMT with ultrasound. Compared to those of the control subjects, plasma levels of PTX3 were higher (? * 100%, P = 0.0009) in metabolic syndrome patients. In univariate analysis, plasma PTX3 was negatively (P = 0.005) associated with high-density lipoprotein (HDL) cholesterol and positively (P = 0.046) with plasma triglycerides and with cIMT (P = 0.045) in the patients (n = 41). In multivariate analysis the direct association between PTX3 and cIMT was no longer significant after correction for HDL. None of these associations were detected in the control patients. These data demonstrate that PTX3, a novel marker of vascular disease, is higher in patients with metabolic syndrome associated with subclinical atherosclerosis. In addition, PTX3 is significantly independently correlated with low HDL cholesterol, but not with cIMT, suggesting a novel association between PTX3 and atherogenic lipid profile.