A suggestion for familial hypercholesterolemia (FH) heterozygosity clinical diagnosis based on epidemiological observations in a large Italian population.

We selected 247 subjects from 29 large familial hypercholesterolemia (FH) kindreds from 550 probable FH subjects in Emilia Romagna (Italy) on the basis of LDL-cholesterol plasmatic levels and family trees, in order to define the best diagnostic criteria for heterozygous patients. Familial hypercholesterolemia is a monogenic disease of cholesterol metabolism inherited as an autosomal dominant trait and characterised by early cardiovascular disease. A low xanthomas and xanthelasmas prevalence was found (8.6%); coronary heart disease (CHD) death occurs very frequently in heterozygous males (72% of all deaths; mean age at death 52 years), while in females the primary cause of death was thrombotic stroke (55%; mean age 69 years). Total cholesterol (TC) mean values were 389.8 (m) and 373.3 mg/dl (f) for FH trait carriers, and 223.3 (m) and 228.8 (f) for healthy relatives. No age-related change in TC was found in heterozygotes, while unaffected relatives of FH families showed mean TC and LDL-C values, and a TC frequency distribution and a TC age-related increasing trend similar to the expected values for the Italian population. The TC frequency distribution curve appeared bimodal, with a mid-point between heterozygous and homozygous FH modal values of 280 mg/dl. To identify the FH patients, the final FH heterozygosity risk was evaluated in an unselected free-living population (from 0.07 to 0.8%, respectively, for TC between 265-274 and 295-304 mg/dl) and in hypercholesterolemic families (31 to 83%, and the same TC classes). Our conclusion is that the clinical picture is rarely pathognomonic, while the FH heterozygosity final risk evaluation and the 280 mg/dl cut-off point can be used to guide the practical clinical diagnosis and to select the patients destined for B-E receptor activity evaluation.

Influence of dietary n-3 polyunsaturated fatty acids on plasma lipemic effect of vitamin B6 deficiency.

Since many connections exist between vitamin B6 and lipid metabolism, we aim to investigate the lipemic effect of different dietary intakes of polyunsaturated fatty acids in rats fed a vitamin B6 deficient diet. Diets were either vitamin B6 deficient (-B6) or vitamin B6 sufficient, pair-fed to the deficient group (PF) and ad libitum (N). The diets were combined with normal lipid (LC: soya bean-coconut-palm oils) and fish oil (FO: soya bean-fish oil). The fish oil diet with sufficient vitamin B6 content caused an increase in n-3 long chain polyunsaturated fatty acids and a decrease in arachidonic acid. In the -B6 group fed a normal lipid diet, the arachidonic acid percentage decreased and the linoleic acid percentage increased; in the -B6 group fed fish oil these changes in fatty acid composition, already consequent upon dietary intake of n-3 long chain polyunsaturated fatty acids, did not show further variations. In the dietary condition of vitamin B6 deficiency, plasma cholesterol content increased in rats fed a lipid control diet, whereas no hypocholesterolemic effect was observed in those fed a fish oil diet. Plasma triglyceride contents were not influenced by dietary lipid quality because, in all conditions, the lower food intake of the PF groups caused a decrease and vitamin B6 deficiency caused an elevation in triglyceride contents which reached those of the ad libitum groups. The study highlights the interaction between vitamin B6 and polyunsaturated fatty acids and the opportunity of dietary intake of fish oil to counterbalance some effects of vitamin B6 deficiency.

Solid monounsaturated diet lowers LDL unsaturation trait and oxidisability in hypercholesterolemic (type IIb) patients.

Lowering high cholesterol concentration decreases the probability of atherosclerotic-related pathology onset. MUFA and PUFA decrease total plasma and LDL cholesterol but PUFA may increase the susceptibility of LDL to undergo oxidative modifications thus becoming more atherogenetic. Olive oil, the predominant fat source in Mediterranean diet, may combine the advantages of both lowering cholesterol level and decreasing LDL susceptibility to oxidation. We studied the effects of feeding MUFA vs PUFA enriched diet on LDL composition and feature in hypercholesterolemic (IIb) patients. Antioxidant values remained constant during the study while LDL fatty acids composition reflected the dietary intake: MUFA concentration increased 11% whereas PUFA decreased 10% after olive oil diet (p < 0.05). PUFA/MUFA ratio and the unsaturation index were lower at the end of MUFA-enriched diet. The challenge, in vitro, of oleate-enriched LDL with Cu2- yielded to lower lag-phase (p < 0.05) in diene conjugated production; the same LDL gave lower lipid hydroperoxide contents after exposition to AAPH. We conclude that oleate-enriched LDL and with lower PUFA content were more resistant to oxidative modifications, as measured by different peroxidation indexes. This feature acquired with the diet may be an useful tool for lowering LDL oxidation and indirectly their atherogenicity.

The "Brisighella Terme" Project: effectiveness of preventive medicine in thermal ambient. Hematochemical parameters.

BACKGROUND: The main aims of the Brisighella Terme Project are: 1. evaluation of feasibility and effectiveness of preventive medicine intervention in thermal ambient; 2. identification of subjects with cardiovascular risk factors; 3. to give patients informations on risk factor correction. The data of this work concern the hematochemical parameters: CT, HDL-CT, LDL-CT, TG, ApoA1, ApoB, fibrinogen, GOT, GPT, CPK, glucose, uric acid. METHODS: CT, HDL-CT (after precipitation of the non-HDL fractions), TG, glucose, uric acid are evaluated by enzymatic-colorimetric reactions; GOT, GPT, CK by enzymatic method. ApoA1, ApoB, fibrinogen by immunoturbidimetric methods. LDL-CT is calculated by the Friedewald formula. RESULTS: 390 subjects spontaneously adhered to the Brisighella Terme Project. Of these subjects 38% requested laboratory service and we observed a 47% increment, from 1995 to 1996, with regard to this request. Females showed higher mean values than males of these parameters: CT, LDL-CT, HDL-CT, ApoA1, ApoB, fibrinogen, CPK. 55% of females had LDL-CT > 159 mg/dl, values considered high risk for cardiovascular diseases. 36% of males presented HDL-CT < 40 mg/dl, with 2 cases < 25 mg/dl. TG values > 399 mg/dl were found only in males (2%). We identified new cases of hypertriglyceridaemia, hypercholesterolaemia and hypoHD Laemia; these metabolic pathologies had not yet been diagnosed, whereas the patients already knew they were affected by hyperglicaemia or hyperuricaemia. CONCLUSIONS: People's interest in the Brisighella Terme Project, new case identification, the possibility of providing correct information about risk factors and healthy life style confirm the feasibility and effectiveness of preventive medicine in a thermal ambient.

Cardiovascular disease and Lp(a) in the adult population and in the elderly: the Brisighella study.

OBJECTIVE: The aim of this study was to evaluate the distribution of the concentrations of lipoprotein(a) [Lp(a)] in a free-living population, that of Brisighella, and to study the degree of association with cardiovascular disease (CVD) and other associated risk factors. The Brisighella study is included in the framework of observational and interventional longitudinal studies; it began in 1972 to monitor the spontaneous trend of the risk factors for atherosclerosis and to evaluate the incidence of CVD in a rural population. METHODS: The studies were carried out on 1319 subjects, 627 males and 692 females, aged over 14 years, of which 134 men and 113 women were geriatric (age > 64 years); the data are relative to the control of the population in 1988. The following were evaluated for each subject: (a) weight and height; (b) hematological parameters; (c) clinical events; (d) presence of other concomitant diseases. For the dosage of the hematological parameters, enzymatic-colorimetric parameters were used (total and HDL cholesterol, triglycerides, glycemia and uremia), radial immunodiffusion and immunoturbidimetry (apoAI and B), ELISA-sandwich immunoenzymatic method (Lp(a)). All the methods used are standardized and internal and external laboratory quality control was carried out. The data collected were analyzed with the program STATGRAPHIC VERSION 6.0; the mean, the standard deviation and the median were calculated for all the variables. The frequency tables, distribution curves (approximation estimates with the chi 2 test), and single and multiple regression were also calculated. A value of p < 0.01 was taken as the level of significance. RESULTS: The distribution of Lp(a) in the control population and in subjects with CVD was substantially the same for both sexes; the differences between the mean levels of Lp(a) were not statistically significant (18.5 mg/dl vs 20.09 mg/dl for men and 19.98 mg/dl vs 22.78 mg/dl for women). The same also applies to the elderly population (18.81 mg/dl vs 23.31 in the men and 21.13 mg/dl vs 21.47 mg/dl in the women). No significant variations were observed in the mean values of Lp(a) even when other risk factors were taken into consideration, such as hypertension, obesity and diabetes. Finally, multiple regression analysis did not show any correlation between Lp(a) levels and those of the other hematological parameters. CONCLUSIONS: In this transversal study, we found no evidence to suggest that Lp(a) can be considered and independent and predictive risk factor for CVD. It would therefore seem that in the population of Brisighella the levels of Lp(a) are "causally" distributed, without any correlation with the presence of cardiovascular events or with hypertension, diabetes or obesity in both sexes.

'Normolipidemic' tendinous and tuberous xanthomatosis.

BACKGROUND: Multiple tendinous and tuberous xanthomas are characteristically associated with hyperlipidemic states. However, normolipidemic tendinous and tuberous xanthomas have been reported in the literature, with normal levels of cholesterol, cholestanol and plant sterols. OBJECTIVE AND METHOD: To delineate the disorder and to suggest its likely origin, a case of apparently normolipidemic severe tuberous and tendinous xanthomatosis was studied. Several lipoprotein and lipid analyses, clinical tests and histological studies were performed over a period of 5 years in the propositus and his family. RESULTS: At the first lipid analysis, no quantitative or qualitative alterations of the lipoprotein fractions or of the apoproteins AI, B, CII, CIII, E were detected in the propositus and xanthomatosis was classified as normolipidemic. During the follow-up, the patient showed a nonconstant hypertriglyceridemia and/or hypercholesterolemia associated with the presence of small and dense VLDL and LDL. An increase in apo-B was observed. There was an unusual quantity of conjugated dienes of arachidonic acid in the plasma and in the LDLs of the patient, present only in small traces in the control population. The family study and the long follow-up of the lipid analysis of the propositus were compatible with the diagnosis of familial combined hyperlipidemia. CONCLUSION: Our data highlight the importance of a critical review of studies regarding normolipidemic xanthomatosis, since only after an extensive follow-up and sequential analyses of lipoprotein fractions is it possible to exclude the presence of time variables and complex lipoprotein abnormalities.

[Serum C3 as a screening factor in the primary prevention of myocardial infarct]. / Il C3 sierico come fattore di selezione nella prevenzione primaria dell'infarto miocardico.

This study addresses the possible use of serum C3 (third component of the complement system) to select the subjects to be submitted to diet or drug therapy in the primary prevention of myocardial infarction. C3 is synthesized by macrophages, which are the main cells involved in atheroma formation, and an association between serum C3 and the risk of myocardial infarction has recently been found in the male sex. We have studied 332 men aged 45-75 years, who had no cardiovascular disease at any time before blood sampling. In their sera C3 measurement was performed by nephelometry. The 4 year follow-up was known for all of these subjects: in particular, 11 had a myocardial infarction. The average LDL cholesterol (LDL-C) levels in the whole population were rather high (162.2 +/- 45.8 (1 SD) mg/dl). As standard treatment criteria (A), those suggested for primary prevention by the National Cholesterol Education Program panel of experts were adopted: diet if LDL-C > or = 160 mg/dl, or LDL-C > or = 130 mg/dl + 2 additional risk factors; drugs if, after diet, LDL-C > or = 190 mg/dl, or LDL-C > or = 160 mg/dl + 2 risk factors. This scheme was compared with two models of treatment which included the measurement of serum C3. According to the first of such models (B), diet should be prescribed when C3 levels are within the high third of distribution (> or = 135 mg/dl) with LDL-C > or = 100 mg/dl, and drugs should be given if, after diet, serum C3 is > or = 135 mg/dl with LDL-C > or = 130 mg/dl. The second model based on C3 (C) is of combined type since, in addition to model B criteria, it also suggests to prescribe a diet if LDL-C > or = 190 mg/dl, while drugs should be given if, after diet, LDL-C levels persist > or = 190 mg/dl. The effect of diet has been simulated by assuming a 10% decrease in LDL-C levels. According to all of these criteria, the subjects to treat with diet with the models A, B and C would have been, respectively, 71, 27 (p < 0.0001 vs mod A) and 45% (p < 0.0001 vs mod A) of the whole population, including among them, respectively, 82, 82 and 100% of the future myocardial infarctions. After diet, according to the three models A, B and C -29, 20 (p = 0.0117 vs mod A) and 30% of the whole population should have been treated with drugs, including, respectively, 54, 64 and 82% of the future myocardial infarctions. In conclusion, the use of criteria based on serum C3, with respect to more traditional guidelines, might allow a more precise identification of the subjects to submit to diet and drug treatment in the primary prevention of myocardial infarction.

Association of serum C3 levels with the risk of myocardial infarction.

PURPOSE: Serum complement and IgA levels have been found to be retrospectively associated with the presence of diffuse atherosclerosis. This study was performed to assess whether serum immunoglobulins and complement components are predictive of future ischemic events. PATIENTS AND METHODS: The baseline values of IgG, IgA, IgM, C3, and C4 were measured in the sera from a cohort of 860 inhabitants of the town of Brisighella, Italy. They were 444 men and 416 women, mean age 53.9 years (SD 12.4, range 23 to 84), who had not had any ischemic events (myocardial infarction [MI], angina pectoris, stroke, transient ischemic attack, or intermittent claudication) at the time of blood sampling in 1984. Their baseline values for the main recognized risk factors for atherosclerosis were known at baseline and for 4 years of follow-up. Multiple logistic regression analysis was performed for associations between ischemic events and immunologic variables (including serum IgG, IgA, IgM, C3, and C4) and risk factors for atherosclerosis (including age, sex, diastolic blood pressure, cigarette consumption, Quetelet index, total cholesterol, HDL cholesterol, triglycerides and blood glucose). RESULTS: During follow-up, 57 subjects experienced ischemic events, including 28 cases of coronary heart disease (17 MI and 11 angina pectoris). Of the immunologic variables studied, only serum C3 was found to be independently associated with ischemic events (P < 0.005 for any ischemic events, coronary heart disease, and MI). The population was divided into thirds according to C3 values. The cumulative incidence of MI was 7.1/1,000 in the low third, 10.6/1,000 in the middle third and 40.8/1,000 in the high third (risk ratio for high versus middle plus low = 4.2 after adjustment for age and sex; 95% CI 1.5 to 11.7). A separate analysis for the sexes showed that serum C3 was a particularly powerful predictor of MI in men. Men whose C3 levels were in the top third had a 72.6/1,000 incidence of MI while the incidence in the rest of the male population was 6.2/1,000 (risk ratio 10.7 after adjustment for age; 95% CI 2.3 to 49.0). When similar analyses were performed for angina pectoris, stroke, and intermittent claudication, no significant increase in risk was found to be associated with serum C3. CONCLUSION: C3 levels measured in sera from male subjects without previous ischemic events are independently associated with the risk of MI.

Total cholesterol, high-density lipoprotein cholesterol, and triglycerides in children receiving antiepileptic drugs.

The influence of antiepileptic drug (AED) therapy on total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, and triglycerides was studied in 208 epileptic children compared with 175 normal children. A significant increase in TC plasma levels was observed with carbamazepine (CBZ), phenobarbital (PB), and phenytoin (PHT). The patients receiving valproate (VPA) showed levels very similar to those of the control population. The results may be explainable by the different biotransformation pathway of these drugs. HDL cholesterol and triglycerides were not altered by any of the AEDs. We recommend monitoring TC level in patients receiving CBZ, PB, and PHT and prescription of diet treatment, at least during the time of AED treatment.

Serum IgA antibodies to apoproteins and milk-proteins in severe atherosclerosis.

Total serum IgA and IgA antibodies to some milk antigens are often associated with severe atherosclerosis. In the present study we examined the same serum samples to evaluate the possible involvement of serum IgA antibodies to apoproteins and lipoproteins and their relationship to IgA antibodies to milk antigens. We studied 23 subjects with angiographically assessed atherosclerotic lesions (ATS group) and 20 healthy control subjects with a similar age range (59-69 years) and sex distribution. Anti-ApoB, Apo A-I, Apo A-II and anti-LDL, VLDL and HDL antibodies were measured with the ELISA method. All antibodies tested except those to anti-Apo A-I were significantly higher in the ATS group with respect to controls with a maximum significance for anti-Apo B IgA (p = 0.0018). When, for each antibody, a threshold of positivity was set to the mean + 2 SD of values in the control group, 12 ATS subjects (52%) and 1 control (5%) were found to be positive for either anti-Apo B or anti-Apo A-II IgA. Most of the correlations of anti-apoprotein and anti-lipoprotein IgA with anti-milk protein IgA and total IgA were significant. The association of these antibodies with atherosclerosis might either be specific or represent part of a polyclonal IgA response. Whether this association is a cause or an effect of atherosclerotic disease is presently unknown.