C.M. Barbagallo

Increased thromboxane biosynthesis in type IIa hypercholesterolemia.

BackgroundIncreased platelet thromboxane (TX)A2 production has been described in type IIa hypercholesterolemia. To verify the relevance of these capacity-related measurements to the actual rate of TXA2 biosynthesis in vivo, we studied the urinary excretion of its major enzymatic metabolites in 46 patients with type hIa hypercholesterolemia and 20 age-matched controls. Methods and ResultsUrinary 11-dehydro-TXB2 and 2,3-dinor-TXB2 were measured by previously validated radioimmunoassays. The excretion rate of 11-dehydro-TXB2 was significantly (p < 0.001) higher in patients (68.7±35.1 ng/hr, mean±SD) than in controls (22.4±9.4 ng/hr), with metabolite excretion >2 SD of the normal mean in 74% of the patients. Urinary 11-dehydro-TXB2 was significantly (p < 0.01) correlated with the threshold aggregating concentration of collagen (r = −0.641) and arachidonate (r = −0.734) and with agonist-induced platelet TXB2 production in vitro (r = 0.647 and 0.748, respectively). Moreover, a statistically significant correlation (r = 0.673, p < 0.001, n = 66) was found between 11-dehydro-TXB2 excretion and total plasma cholesterol. The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin (20 mg/day for 6 months) significantly reduced cholesterol levels by 22–28% and urinary 11-dehydro-TXB2 excretion by 32–42% in 10 patients. However, the reduction in the latter did not correlate with the reduction in the former and may have resulted from a nonspecific effect of simvastatin. Moreover, selective inhibition of platelet cyclooxygenase activity by low-dose aspirin (50 mg/day for 7 days) was associated with cumulative inhibition of 11-dehydro-TXB2 excretion by approximately 70% in six patients. ConclusionsTXA2 biosynthesis is enhanced in the majority of patients with type lla hypercholesterolemia; this is, at least in part, a consequence of abnormal cholesterol levels, as suggested by the correlation between the two. Low-dose aspirin can largely suppress increased metabolite excretion, thus suggesting that it reflects TXA2-dependent platelet activation in vivo.

Prevalence of overweight and obesity in a rural southern Italy population and relationships with total and cardiovascular mortality: the Ventimiglia di Sicilia project

OBJECTIVE: We investigated the prevalence of overweight and obesity and their relationships with the main cardiovascular risk factors in the population of Ventimiglia di Sicilia, a rural village in Southern Italy characterized by low cholesterol levels and by a low incidence of early coronary heart disease mortality. We related all deaths to body weight and fat distribution during an 8u2005y follow-up.DESIGN: Cross-sectional and prospective observational study.SUBJECTS: A total of 835 free-living individuals, 363 males and 472 females, of age between 20 and 69u2005y.MEASUREMENTS: In all participants body weight, waist-to-hip ratio (WHR), cardiovascular risk factors and plasma lipids were measured. During the follow-up, total and cardiovascular deaths were registered.RESULTS: We found a high overall prevalence of subjects with overweight or obesity (respectively 45.0% and 27.7%), with great differences among classes of age. As expected, body weight and fat distribution were associated with diabetes, hypertension, dyslipidemia and with a worsening of lipid profile. During the follow-up we registered 37 total and 11 cardiovascular deaths. All-cause and cardiovascular mortality risks were, respectively, 1.64 (95% CI 0.65–4.15) and 2.71 (95% CI 0.29–25.26) in subjects with a body mass index (BMI) of 27–29.99u2005kg/m2 and 2.45 (95% CI 1.03–5.87) and 5.36 (95% CI 1.41–62.01) in subjects with a BMI of≥30u2005kg/m2 in comparison with participants with a BMI of <27u2005kg/m2, and 3.48 (95% CI 1.46–8.30) and 4.55 (95% CI 1.12–18.40) in subjects with a WHR higher than the median in comparison with individuals with a WHR lower than the median.CONCLUSION: The Ventimiglia di Sicilia Study highlights the great importance of overweight and obesity as a public health issue in a rural population and indicates that it is necessary to consider the impact of body weight and fat distribution on both total and CHD mortality.

Low‐density‐lipoprotein peak particle size in a Mediterranean population

Background The predominance of small, dense low‐density lipoprotein (LDL) particles (‘LDL phenotype B’) has been associated with a three‐fold increased risk of myocardial infarction, but the feasibility of the identification of small, dense LDL as independent predictors of coronary artery disease risk in population studies remains questioned.

Effects of synvinolin on platelet aggregation and thromboxane B2 synthesis in type IIa hypercholesterolemic patients

An increased susceptibility of platelets to aggregation induced by various agents and a higher production of active arachidonate metabolism have been described in type IIa hypercholesterolemia. This study was designed to evaluate whether changes in platelet function could be observed in hypercholesterolemic patients after synvinolin therapy. Administration of synvinolin to 12 type IIa hypercholesterolemic patients for 24 weeks had a lipid lowering effect and resulted in a marked reduction of platelet aggregation and thromboxane formation induced by collagen and arachidonate. Maximum response was achieved at 4-8 weeks and lipid lowering effects at 2 weeks. This finding indicates that platelet changes cannot be explained by a direct effect of synvinolin on platelets, and the antiplatelet response may therefore depend on platelet membrane lipid composition changes, particularly in the platelet cholesterol content of platelet membranes, following substantial reductions of total plasma cholesterol and LDL-cholesterol.

Lipoprotein (a) Levels in End-Stage Renal Failure and Renal Transplantation

Some previous studies have documented an increase in lipoprotein (a) [Lp(a)] levels in renal diseases. Here, we report data in subjects with end-stage renal failure treated with hemodialysis (HD) or with continuous ambulatory peritoneal dialysis (CAPD) and in renal transplant recipients (RTR), compared with a group of normolipidemic controls (C). Lp(a) levels were significantly increased in HD and CAPD patients in comparison with C, while they were only slightly increased in RTR. Both HD and CAPD patients showed Lp(a) levels higher than in RTR, but no difference was found between the subjects of the two dialysis procedures. The prevalence of Lp(a) levels > 25 mg/dl was significantly higher in HD and CAPD patients, but not in RTR, in comparison with C. Moreover, Lp(a) levels did not change after HD. When patients were divided according to their fasting lipid levels in normolipidemics and hyperlipoproteinemics, no difference was found for Lp(a) levels in any group. Mechanisms underlying the increase in Lp(a) levels in these patients are not known. It is possible to suggest an active role of the kidney in the Lp(a) metabolism or that uremic plasma contains some factors affecting Lp(a) metabolism.

Effects of Mediterranean Diet on Lipid Levels and Cardiovascular Risk in Renal Transplant Recipients

Background: Renal transplant recipients have an increased incidence of cardiovascular disease. These patients present abnormalities of lipoprotein profile which are persistent and involve an increasing number of individuals, suggesting the opportunity of an early therapeutic intervention. Methods: We evaluated the effects of a 10- to 12-week diet based on the American Heart Association step-one diet criteria, modified with an increased intake of monounsaturated fats and alimentary fibers, on lipid profile and lipid-related cardiovascular risk in 78 normolipidemic and hyperlipidemic renal transplant recipients. Results: Diet led to a significant reduction in total cholesterol levels by 10%, triglycerides by 6.5%, low-density lipoprotein (LDL)-cholesterol by 10.4% and LDL-cholesterol/high-density lipoprotein (HDL)-cholesterol ratio by 10%, whereas HDL-cholesterol levels remained unchanged. Dividing renal transplant recipients into risk classes according to the National Cholesterol Expert Program guidelines and LDL-cholesterol levels, we observed a progressively increasing reduction in total cholesterol and LDL-cholesterol levels among ‘desirable LDL-cholesterol’, ‘borderline high-risk LDL-cholesterol’ and ‘high-risk LDL-cholesterol’ patients, while HDL-cholesterol levels did not change in any group and the LDL-cholesterol/HDL-cholesterol ratio significantly decreased in ‘borderline high-risk LDL-cholesterol’ and in ‘high-risk LDL-cholesterol’ patients (respectively by 6.8%, p < 0.05, and by 21.1%, p < 0.0001). Reduction in triglyceride levels was statistically significant only in subjects with ‘desirable LDL-cholesterol’ (by 12.3%, p < 0.01). Patients in the ‘desirable LDL-cholesterol’ class increased from 28 (35.9% of total patients) before diet to 45 (57.7% of total patients, p < 0.01), while subjects in the ‘high-risk LDL-cholesterol’ class reduced from 24 (30.8% of total patients) to 8 (10.2% of total patients, p < 0.005). Conclusion: These data suggest the possibility of a nutritional hypolipidemic approach in renal transplant recipients, even if normolipidemic. Dietetic treatment determined an inversion in the typical trend of renal transplant recipients, reducing instead of increasing the number of subjects with hypercholesterolemia, permitting the selection of individual candidates for further pharmacological treatment by carefully evaluating risk/benefit costs.

Autosomal recessive hypercholesterolemia in a Sicilian kindred harboring the 432insA mutation of the ARH gene

We describe a Sicilian family presenting a recessive form of hypercholesterolemia harboring a mutation of the autosomal recessive hypercholesterolemia (ARH) gene. In two of the three sibs, a 26-year-old male and a 22-year-old female, a severe hypercholesterolemia was diagnosed with very high levels of plasma cholesterol (15.9 and 12.2 mmol/l, respectively); tendon xanthomatas and xanthelasms were present and in the male proband was documented a diffuse coronary atherosclerotic disease with a rapid and fatal progression. Both the parents had normal or slightly increased levels of plasma cholesterol. All causes of secondary hypercholesterolemia were ruled out as well as an involvement of the LDL receptor or apoB genes. Beta-Sitosterol plasma levels were in the normal range. Cultured fibroblasts from skin biopsy from parents and the two probands displayed a normal ability to bind and degrade 125I-LDL. Direct sequencing of ARH gene demonstrated the presence of a 432insA mutation in homozygosis in the two probands; parents were heterozygotes for the same mutation. This mutation is the first report of a mutation of the ARH gene responsible for recessive forms of hypercholesterolemia in Sicily.

ApoE polymorphism in a small Mediterranean island: Relationships with plasma lipids, lipoproteins and LDL particle size

Polymorphisms of apoE gene are able to modulate lipoprotein metabolism at different steps and to influence LDL-cholesterol (LDL-C) levels and also other lipoproteins features. Population studies documented large differences in the frequency of apoE alleles which could be even related to the prevalence of cardiovascular disease. In this study we evaluated the apoE genotypes and allele frequency in 576 subjects living in a small island in the Tyrrhenian Sea and the relative contribution of apoE polymorphism on plasma lipid and lipoprotein profile, including LDL particle size. We found a cumulative frequency of 0.073, 0.866 and 0.061 for ε2, ε3 and ε4 alleles respectively. Moreover ε3 subjects had only triglyceride levels significantly lower and LDL-C and lipoprotein (a) (Lp(a)) levels higher than ε2 carriers. LDL-particle size was significant smaller in ε2 subjects than both ε3 and ε4 carriers, but the difference disappeared when data were adjusted for triglycerides. In conclusion we have provided further evidence of a low prevalence of ε4 allele in a Mediterranean population which may represent a genetic protective factor of these populations. Environmental factors, such as diet, occurring in this area may have attenuated the influence of this gene on plasma lipoproteins.

Increased Lipoprotein (a) Levels in Subjects with Chronic Renal Failure on Hemodialysis

Dr. Carlo M. Barbagallo, Viale Francesco Scaduto 6/C, I-90144 Palermo (Italy) Dear Sir, It is already known that chronic renal failure on hemodialytic treatment is associated with an elevated incidence of premature atherosclerosis [1]. A close relationship between the lipid abnormalities documented in uremia [2] and the increased cardiovascular mortality of these patients has been suggested [3]. Recently, the role of Lp(a), lipoprotein discovered by Berg [4] in 1963, in the development of atherosclerosis has been revalued [5]. The structure of Lp(a) is very similar to that of low-density lipoproteins (LDL): both contain apo B-100 as major protein, but only Lp(a) contains apo(a), a protein structurally very close to plasminogen [6]. Although the metabolic function of Lp(a) is still unknown, it seems to be linked to lipoprotein metabolism as well as to the fibrinolytic system [7]. Plasma levels are strongly regulated by a genetic trait [8] but renal diseases seem to be associated with increased levels of Lp(a) [9, 10]. We have evaluated the apolipoprotein profile [total cholesterol (TC), triglycerides (TG), HDL-cholesterol (HDL-C), apo A-I and B] and Lp(a) levels, after an overnight fast, in a group of 45 subjects with chronic renal failure on hemodialytic treatment (26 males, 19 females, aged 55.6+12.9 years, BMI 25.2 ± 2.2, age of dialysis 4.1 ± 2.7 years) and in a group of normal subjects matched for age, gender, body weight and fasting TC and TG levels as controls. None of them, patients or controls, was affected by diseases (diabetes, obesity, liver diseases) or used drugs affecting the lipid metabolism. TC and TG were quantified by enzymatic methods, HDL-C after precipitation of apo-B-con-taining lipoproteins by PTA/magnesium chloride, apo A-I and apo B by the nephelometric method and Lp(a) levels by RIA. Because the Lp(a) distribution is highly skewed, statistical analysis for this parameter was performed by both the Mann-Whitney U test and by Student’s t test after log transformation of values. We have observed that patients with chronic renal failure on hemodialytic therapy showed levels of HDL-C and apo A-I lower and levels of Lp(a) always significantly higher than controls, even if they were matched for fasting lipid levels (table 1). Therefore, the prevalence of subjects with Lp(a) levels above 25 mg/dl was significantly higher in patients with chronic renal failure (53% vs. 18%; p < O.01; data not shown). These data agree with the report of Parra et al. [9] who found, in subjects

The C(-260)>T gene polymorphism in the promoter of the CD14 monocyte receptor gene is not associated with acute myocardial infarction.

Abstract.CD surface molecules mediates cell activation andnsignaling. In particular, CD14 on blood monocytes mediatenmonocyte/macrophage activation by lipopolysaccharide.Lipopolysaccharide and its receptor, CD14, have beennimplicated in atherogenesis. It has been recently shown that anC(-260)T polymorphism in the promoter of the CD14 receptor maynbe a risk factor for coronary artery disease. Recently thisnassociation has been questioned because no increased risk wasnfound with the T allele, even in the homozygous state. In thenpresent study we investigated a possible association between thenC(-260)T polymorphism in the CD14 promoter and acute myocardialninfarction. Two hundred and thrteen patients with and acutenmyocardial infarction 213 healthy controls were included in thenstudy. Genotype frequencies of the C(-260)T polymorphism in thenCD14 promoter were determined by polimerase chain reaction andnthe amplified product was cleaved with HaeIII. The frequency of the T allelenwas not significantly different in patients compared withncontrols. In this study we were not able to detect differencesnof frequency of the allele T (-260) in the promoter of the CD14nreceptor gene in survivors of myocardial infarction andncontrols.