M. Fonda

Polymorphism of the Apolipoprotein E Gene and Early Carotid Atherosclerosis Defined by Ultrasonography in Asymptomatic Adults

Clinical and autoptical studies have suggested a predisposing role of the allele E4 of apolipoprotein E (apoE) in the development of atherosclerosis and cardiovascular disease. To investigate the possible contribution of apoE allele polymorphism to the carotid intima-media thickness (IMT) as assessed by ultrasound, we studied 260 asymptomatic nondiabetic subjects (121 men, 139 women; mean +/- SD age, 53 +/- 7 years), randomly selected from the population register of the inhabitants of Trieste, Italy. B-mode ultrasound was used to quantify the maximum IMT at 12 sites on the near and far wall of the common, bifurcation, and internal carotid arteries. ApoE genotypes were determined from amplified apoE sequences by restriction isotyping. The frequencies of E2, E3, and E4 alleles were 0.073, 0.827, and 0.100, respectively. As expected, subjects with E4 allele had the highest levels of total serum cholesterol and LDL cholesterol, subjects with E2 allele had the lowest levels, and those with E3 genotype had intermediate levels. The echographic measurements of carotid IMT showed increasing values from E2 to E4 carriers. After adjustment for total and LDL cholesterol serum levels, triglycerides, ratio of LDL to HDL cholesterol, age, sex, and body mass index, ANCOVA showed that the common carotid IMT was significantly greater (P = .029) in subjects with E4 allele compared with E3 carriers. Our data confirm the influence of apoE4 on cholesterol levels and clearly show that apoE genotype affects carotid atherosclerosis in its early stages in middle-aged asymptomatic subjects.

Factors associated with cognitive impairment among older Italian inpatients

OBJECTIVE: To examine the association of cognitive impairment with educational, demographic, and nutritional variables in older hospitalized people.

Tolerability and efficacy of combination therapy with simvastatin plus gemfibrozil in type IIb refractory familial combined hyperlipidemia

Abstract Type IIb hyperlipidemia due to familial combined hyperlipidemia (FCH) is a common lipid metabolism disorder associated with a high incidence of coronary heart disease. Simvastatin and gemfibrozil are two drugs commonly used to treat this lipid abnormality. However, monotherapy with these drugs often fails to reduce serum cholesterol and triglycerides to optimal levels. In this study the tolerability and efficacy of combined simvastatin plus gemfibrozil therapy was investigated over 18 months in 20 patients (15 men and five women, ages 42 to 71 years) at high risk for atherosclerosis affected by type IIb FCH. Patients were selected because they did not respond satisfactorily to monotherapy with simvastatin or gemfibrozil, taken for at least 6 months with no side effects, namely laboratory test alterations or subjective complaints. The administration protocol was designed as a three-phase open study. In the first phase (8 weeks) patients were assigned to take 10 mg/day simvastatin plus 600 mg/day gemfibrozil; in the second phase (4 months) variable doses of simvastatin [10 to 20 mg/day, depending on the decrease in low-density lipoprotein (LDL) cholesterol] and gemfibrozil (600 to 1200 mg/day, depending on serum triglyceride values) were prescribed. In the follow-up period (phase 3) optimum therapy was maintained. No patient dropped out of the study, and no side effects were recorded. Serum creatine phosphokinase remained within the normal range, as did other hematochemical tolerability parameters. At the end of the follow-up, total (TC) and LDL cholesterol dropped by 35% (from 334 ± 38 mg/dl to 218 ± 27 mg/dl, P P P P P

Low Density Lipoprotein-Apheresis Decreases Oxidized Low Density Lipoproteins and Monocyte Adhesion to Endothelial Cells

The mutual interaction between monocytes and low density lipoprotein (LDL) in atherogenesis prompted a test of the hypothesis that LDL-apheresis could reduce the adhesive properties of monocytes to endothelium; and therefore interfere with a key mechanism in atheroma formation. Five patients affected by heterozygous familial hypercolesterolemia were studied. All patients received LDL-apheresis treatment with selective adsorption of LDL-cholesterol on dextran-sulphate columns. Low density lipoprotein particles were isolated by sequential preparative ultracentrifugation and subfractionated by ion exchange high performance liquid chromatography. Thiobarbituric acid reacting products of lipid peroxidation were measured fluorometrically. Vitamin E was estimated by high performance liquid chromatographic technique. Monocytes were isolated from patients blood before and 1 day after LDL-apheresis by Percoll gradient. The blood samples for monocyte adhesion were drawn from control subjects for 2 consecutive days. The adhesion of monocytes to an endothelial monolayer was evaluated by assaying the peroxidase content of the adherent monocytes. Low density lipoprotein-apheresis reduced total cholesterol (−65%; p < 0.01), LDL-cholesterol (−75%; p < 0.01), triglycerides (−51%; p < 0.05), and fibrinogen (−28%; p < 0.01). With LDL-apheresis treatment, a reduction of 54% in oxidized LDLs was observed; vitamin E concentration significantly increased in LDLs ( + 14.2%; p < 0.05). The monocyte adhesion decreased by approximately 61% after apheresis; the variation became statistically significant (−65%; p < 0.01) when endothelial cells were stimulated by lipopolysaccaride.

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.

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.

Lipoprotein(a) serum concentration in familial combined hyperlipidemia

The lipoprotein(a) (Lp(a) concentrations in serum were measured by an ELISA technique in 53 subjects affected by familial combined hyperlipidemia (FCHL) and in 347 healthy individuals. Lp(a) geometric means did not differ significantly between the two groups despite the different distributions. In hyperlipidemic subjects, the distribution was markedly shifted to the right (median 17 mg/dl) while in controls it was highly skewed to the left (median = 11 mg/dl). In FCHL, Lp(a) serum levels did not differ between patients with or without coronary heart disease (CHD). It was concluded that, differently from familial hypercholesterolemia (FH), in FCHL Lp(a) may not be elevated in comparison with an adequate control population.

Activation of coagulation by a LDL-apheresis device.

LDL-apheresis often induces an almost constant and progressive increase of the differential pressure of plasma flowing through the dextran sulphate cellulose column, reducing the efficacy of the treatment. On two occasions we were able to identify a fibrin plug by immunofluorescence. Our aim was to verify the modification of some coagulation indicators in patients undergoing LDL-apheresis and whether an activation of coagulation occurs in the LDL-apheresis device. Blood samples were obtained from six patients with familial hypercholesterolaemia who were undergoing LDL-apheresis. During the same session further blood/ plasma samples were taken from the LDL-apheresis device at different sites and at different volumes of filtered blood. In patients after LDL-apheresis the following modifications were found: a 25% decrease of fibrinogen and a slight increase in F1 + 2 plasma levels. No relevant changes in thrombin-antithrombin complexes and fibrinopeptide A plasma levels were noted. In the LDL-apheresis device the main results were: (a) fibrinogen was trapped in the dextran sulphate cellulose column in the early phases; (b) activation of coagulation was recognisable in the plasma separator during the procedure and progressively increased with duration of LDL-apheresis; (c) thrombin-antithrombin complexes, formed in the plasma separator, were retained by the dextran sulphate cellulose column. In conclusion, LDL-apheresis activates coagulation in the device. Shortening cycle time or using nafamostat mesilate as an anticoagulant, could be interesting alternatives for improving the procedure.

Efficacy and safety of simvastatin in current clinical practice: the italian family physician simvastatin study

Abstract The availability of modern hypocholesterolemic drugs that are easy to handle may give any physician the ability to treat patients with elevated levels of total serum cholesterol and low-density lipoprotein (LDL)cholesterol. The Italian Family Physician Simvastatin Study was an open-label, noncomparative, diet-controlled, multicenter, post-marketing surveillance study carried out by nonspecialist physicians to evaluate the efficacy and safety of simvastatin in the current clinical practice. The study evaluated 5348 patients (2887 men [mean age, 61 ± 7 years]) and 2461 women [mean age, 55 ± 11 years]) with primary hypercholesterolemia. After a 10-week washout period, the selected patients were actively treated for 24 weeks with simvastatin 10 mg administered once a day in the evening. The dose was increased, if necessary, at the 12-and 18-week visits, to 20 or 40 mg/d. A total of 5081 patients (95%) completed the study; 195 patients (3.6%) were lost at follow-up and the other 72 (1.3%) discontinued the study because of the occurrence of adverse effects. Of the 5081 patients, 3691 (72.6%) received 10 mg/d simvastatin, 1159 (22.8%) 20 mg/d, and 202 (4.0%) 40 mg/d; in the others a personalized dose of the drug (range, 5 to 30 mg/d) was given. Simvastatin produced significant decreases in total serum cholesterol of 30%, LDL cholesterol of 41%, and triglyceride levels of 14%, and significant increases in high-density lipoprotein (HDL) cholesterol of 13%. The efficacy goal of total serum cholesterol level ( 3 times the upper limit of normal) were recorded only in 0.7% of all control visits. Serum creatine kinase (CK) did not significantly change and serum elevations >10 times the upper limit of normal without muscle symptoms was observed in 0.4% of all patients, whereas myalgia without concomitant increase of CK was reported by 0.6% of the 5081 patients. On the whole, 267 clinical adverse effects occurred in 235 patients (4.4%), in a dose-dependent manner. Simvastatin, when studied in the current clinical practice of general practitioners, produced a marked decrease in LDL cholesterol and improved the global lipoprotein profile with infrequent, minor, dose-dependent side effects.

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.