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.

Indexes of obesity and all-causes mortality in Italian epidemiological data.

BACKGROUND: The relationships of body mass index and skinfold thickness to all-causes mortality during a 10-year follow-up were assessed in 8,341 men and 1,100 women ages 30-69 years from different Italian population samples. RESULTS: Among men, both univariate and multivariate analyses showed a clear-cut parabolic (inverse J-shaped) relationship, whose left branch became less steep after the exclusion of smokers, people carrying severe diseases at entry, those who died during the first 5 years, or all of them. The minimum risk was almost always located around 28 units of body mass index, and it decreased to smaller levels of body mass index when the exclusions were adopted. The analysis of skinfold thickness showed similar but less clear-cut results. Among women, due to the limited number of fatal events, the analysis was unable to show any clear relationship of body mass index or skinfold thickness to all-causes mortality. The multivariate analysis showed a similar parabolic relationship of body mass index to all-causes mortality. The estimated multivariate risk of death broken down into five quintiles was unrelated to the mean level of body mass index for each quintile. From the multivariate model it was estimated that an excess of 10 kg in body weight (above the body mass index corresponding to the minimum risk level and everything else being equal) carries the same excess of risk produced by 5 mm Hg of systolic blood pressure or by less than 5 cigarettes smoked per day. CONCLUSION: These results suggest that high levels of obesity indicators are only slightly associated with an excess mortality and that overweight and obesity are health hazards only if they are accompanied by an elevation of other risk factors, mainly of blood pressure.

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.

[Obesity and mortality. Italian epidemiologic data]. / Obesità e mortalità. Dati epidemiologici italiani.

The relationship of indicators of obesity, such as the body mass index (BMI) and the skinfold thickness in some areas (SKIN) to all causes mortality have been analyzed in three italian epidemiological studies. They are the Seven Countries Study--italian areas conducted on 2480 men at entry and followed-up for 25 years; the Brisighella study conducted on 1123 men and 1100 women aged 30-69 and followed-up for 15 years; and the NFR study in Rome conducted on 3395 men aged 46-66 and followed-up of 6.5 years. The univariate analysis concerning the BMI for various age groups, the two sexes, and variable periods of follow-up has almost systematically showed a parabolic inverted J shaped relationship with minimal levels of risk for BMI values of 27-29 units. However this was not the case for the women group and for the oldest men where no clear relationship was found. The analysis concerning the SKIN provided similar but less clear-cut results. The multivariate analysis has confirmed the parabolic relationship of BMI to all causes mortality even in the presence of other 4-5 covariates. The left branch of risk is higher than the right one and its slope could be reduced, although not completely, by the exclusion of heavy smokers, of those who died within the first 5 years of follow-up, of those who were carriers of severe diseases at entry examination.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Pravastatin in heterozygous familial hypercholesterolemia: low-density lipoprotein (LDL) cholesterol-lowering effect and LDL receptor activity on skin fibroblastS.

The cholesterol-lowering effect of provastatin, a new competitive inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase, was studied in 10 patients with heterozygous familial hypercholesterolemia (FH). Residual low-density lipoprotein receptor (LDL-R) activity was also evaluated in cultured skin fibroblasts prior to treatment, and showed a wide range of reduction from 30% to 70% of the normal value. Treatment with pravastatin 40 mg once daily reduced total and LDL cholesterol (LDL-C) after 6 months by 19.7% and 25.4%, respectively (P less than .001). Serum apolipoprotein (apo) B levels decreased significantly by 29.1% (P less than .001). No significant changes were observed in mean serum total triglycerides or high-density lipoprotein cholesterol (HDL-C) levels. A positive correlation between residual LDL-R activity and maximum percent reduction of LDL-C levels was observed (r = .676, P less than .05). No clinically important side effects were recorded and the treatment was well tolerated. Thus, pravastatin effectively reduces LDL in heterozygous FH, and this effect appears to be related to LDL-R status.

Dietary treatment for familial hypercholesterolemia--differential effects of dietary soy protein according to the apolipoprotein E phenotypes.

Familial hypercholesterolemia, one form of type IIa hyperlipidemia, usually responds poorly to standard low-lipid diets. To define the responsiveness to a soy-protein diet in this disease, one homozygous and twenty heterozygous type IIa patients were submitted to a 4-wk traditional hypocholesterolemic diet followed by 4 wk in which animal protein was substituted with texturized soy protein. Soy was then withdrawn for a further 4 wk. No significant changes in plasma lipids were observed during low-lipid diets. The soy diet, however, caused a marked decrease in total (-20.8%) and low-density-lipoprotein (-25.8%) cholesterol and in apolipoprotein B (-14.1%). The plasma cholesterol reduction was higher in patients with apolipoprotein E3/E3 or E3/E4 vs an almost negligible effect on E3/E2. These results confirm that soy-protein diets can lower cholesterol in type IIa patients with familial disease. Data on the sensitivity of patients with different apo-E isoforms agree with recent hypotheses suggesting that soy proteins may activate B,E receptors.

The Brisighella Heart Study: an interim report.

In 1972, the Brisighella Study was initiated to monitor the spontaneous trend of risk factors for atherosclerosis and the incidence of coronary heart disease (CHD) in a rural population. This study, which is one of the largest Italian studies on the epidemiology of atherosclerosis and cardiovascular disease, established a strong correlation between increased cholesterol levels and the incidence of CHD. The apparent unwillingness of the population to alter dietary and exercise habits independently led the researchers to establish the Brisighella Heart Study in 1984. This study attempted to reduce the risk of CHD by modifying the population's dietary habits through a nutritional education program. While the nutritional education program succeeded in lowering total cholesterol, a segment of the population still remained at risk. At this point, the high-risk strategy arm of the study was initiated. In 1988, those participants whose total cholesterol level was greater than 239 mg dl-1 were started on a twice-daily regimen of 600 mg of gemfibrozil. The Brisighella Heart Study High-Risk Project will continue for at least 5 years, during which all participants will be followed-up every 6 months and all fatal and non-fatal events will be recorded.

Double-blind multicenter trial on a new medium molecular weight glycosaminoglycan. Current therapeutic effects and perspectives for clinical use.

The ability of glycosaminoglycans to bind to a wide number of biologically active macromolecules has already been investigated. Recent clinical trials on the possible therapeutic benefits of glycosaminoglycans must be placed in perspective, even if they appear to be particularly encouraging, especially as regards the glycosaminoglycan effects on certain coagulation factors. A multicenter, medium-term, double-blind, crossover trial was performed by several Italian Lipid Clinics to determine whether administration of a medium molecular weight glycosaminoglycan (Sulodexide) has a significant clinical effect. Patients affected by peripheral vascular disease and/or hyperlipidemia (type IIa, IIb and IV) were submitted to a 4-week wash-out period, followed by parenteral Sulodexide (S) or placebo (P) administration for 2 weeks, another 2 week wash-out period, parenteral crossover drug or P administration for 2 weeks and, finally, oral S administration for 6 months. Sulodexide lowered plasma viscosity and plasma fibrinogen in all patients. There was also a drop in triglycerides together with a rise in apo A-I and HDL-C in type IV hyperlipoproteinemics, whereas there was no significant effect on total or LDL-plasma cholesterol in type IIa and IIb patients. Moreover, there was a percent increase in peak flow and rest flow in the lower limbs of peripheral vascular disease patients. No side effects or intolerance phenomena were detected. The results indicate that Sulodexide administration may be useful in long-term treatment of patients with peripheral vascular disease and a concomitant increase in plasma triglycerides and/or fibrinogen and/or viscosity.

Plasma lipid lowering activity of acipimox in patients with type II and type IV hyperlipoproteinemia. Results of a multicenter trial.

A multicenter study was carried out in 130 out-patients to assess the plasma lipid lowering activity of acipimox in type IIa, IIb and IV hyperlipoproteinemia. The study consisted of two periods, an 8-week randomized, double-blind comparison of active drug versus placebo and a 16-week open follow-up with acipimox (400 mg and 250 mg t.i.d., respectively, in type II and IV patients). During the double-blind phase acipimox, compared to placebo, showed a highly significant triglyceride lowering effect in type IV patients (-43% vs. +4%, P less than 0.01), while reducing plasma cholesterol significantly in type II patients (-7% vs. -3%, P less than 0.05). Further reductions in plasma lipids were obtained in both types of hyperlipoproteinemia after the 16-week follow-up. In type II patients, total cholesterol fell by 9% in the former acipimox group and 17% in the former placebo group, whereas a 34% reduction in triglycerides was found in type IV patients previously treated with placebo. Treatment had to be discontinued in 4 patients during the double-blind phase and in 5 patients during follow-up, because of adverse events such as skin reactions and gastric disturbances. Statistical analysis of hematological and biochemical variables expressing safety did not show any significant change during treatment.

A stochastic process approach to the development of atheroma.

This study aims at formulating a dynamic model of particle sedimentation as applied to lipoprotein deposition during atheroma progression. The basic assumption is that all particles are identical and that the number of sedimented particles is relatively great. It is hypothised that sedimentation of a given particle is random; according to the theory of stochastic processes, the probability of a certain number of particles to sediment or deposit changes with time. The stochastic approach may explain some aspects of atherosclerosis development, i.e. its progression or regression.

Hypercholesterolaemia treated by soybean protein diet.

After a period of stabilisation on a controlled low lipid low cholesterol diet with animal proteins a group of 16 children with familial hypercholesterolaemia were given a textured soybean protein based diet, with a similar fat composition. All the children had a highly significant reduction in total cholesterol, averaging -21.8% against the baseline after eight weeks. Compliance became less strict afterwards, but more than half of the patients have regularly continued the diet and results have been maintained for one year. Minimal changes were noted in triglyceridaemia and in high density lipoprotein cholesterol concentrations, which showed a slight rise only at the end of treatment. The children's growth during the trial was normal. In view of the psychological difficulties of prescribing treatment with drugs to children with severe hypercholesterolaemia before puberty and of the relative ineffectiveness of standard low lipid diets in this condition the soybean protein diet may offer a satisfactory alternative.

Cholesterol-lowering and HDL-raising properties of lecithinated soy proteins in type II hyperlipidemic patients.

Plasma lipoprotein changes were evaluated in 65 type II patients undergoing sequential 4-week dietary treatments with: (I) standard low-lipid diet; (II) low-lipid diet with total replacement of animal proteins with textured soy proteins containing 6% of lecithin (L-TVP); (III) standard low-lipid diet; (IV) low-lipid diet with a 50% substitution of animal proteins with L-TVP. Total cholesterolemia was significantly reduced in both periods of L-TVP administration: -18.6% during phase II (total replacement) and -13.2% during phase IV (partial replacement). High-density lipoprotein (HDL) cholesterol levels tended to increase during L-TVP administration. However, only patients in the mid- and low tertiles for HDL cholesterolemia showed a significant increase of HDL levels during L-TVP. This 'normalizing' activity of L-TVP on plasma lipoproteins, even when administered as a partial dietary substituent, may be of clinical interest for subgroups of patients at high vascular risk.

Controlled evaluation of pantethine, a natural hypolipidemic compound, in patients with different forms of hyperlipoproteinemia.

Pantethine (P), the stable disulphate form of pantetheine, major component and precursor of coenzyme A, was evaluated within a double-blind protocol (8 weeks for P or for a corresponding placebo) in 29 patients, 11 with type IIB hyperlipoproteinemia, 15 with type IV, and 3 with an isolated reduction of high density lipoprotein cholesterol (HDL-C) levels. In type IIB patients, P (300 mg t.i.d.) determined a highly significant lowering of plasma total and low density lipoprotein (LDL) associated cholesterol (-13.5% for both parameters). In the same patients, HDL-C levels increased about 10% at the end of treatment. Switching from P to placebo was associated with a rapid return to the baseline cholesterolemia. Both in type IIB and type IV patients, plasma triglyceride levels were reduced around 30%, when P was given as the first treatment; when it was preceded by placebo, reductions were less striking (respectively, -17.8% for type IIB and -13.0% for type IV, at the end of P treatment). HDL-C levels were not increased by P, either in type IV, and in the patients with low HDL cholesterolemia. In type IV, LDL cholesterol levels showed a variable response to P: they tended to increase when below 132 mg/dl, prior to treatment, and to be reduced when above this level. This study provides evidence for a significant hypocholesterolemic effect of P, a natural compound free of overt side effects. It also indicates that P may raise HDL-C levels in type IIB patients, while moderately reducing triglyceridemia.

[The Brisighella survey: a study of dietary habits]. / L'indagine di Brisighella: studio delle abitudini alimentari.

In the course of studies evaluating diet as risk factor of atherosclerotic disease, an epidemiological study among 1491 males and 1448 females living in Brisighella, a small village in the Tuscan-Emilian Appenines, was carried out. The methods used in estimating alimentary habits have been described in detail. The weights of all foods eaten by each subject in a 7 day period were also recorded. We considered total intake of proteins, fats and carbohydrates in g/kg of ideal weight/day and total calories/kg of ideal weight/day and related such values to those given by FAO/WHO. It was observed that mean intake of proteins and fats in g/kg/day and cal/kg/day was always more elevated when compared with those given by FAO/WHO for males and females. Mean intake of carbohydrate, in both sexes, agreed with FAO/WHO values. Therefore, we can affirm that the people of Brisighella have faulty dietary habits, mainly concerning fats. In addition, their daily calorie-intake is too high.

[Myocardial infarct: an acute dysmetabolic disease]. / L'infarto del miocardio: malattia dismetabolica acuta.

It is hypothesised, on the basis of experimental observations on post-heparin plasma samples collected under post-prandial conditions, that variations in the activity of endothelial lipoproteinlipasic systems may be correlated to reductions in blood flow at coronary capillary level. More specifically, it is shown that a change in these enzymatic systems could determine "functional kidnapping" of heparin or other substances (glicosaminoglycans) engaged in the activation of Antithrombin III, with noteworthy haemorrheological consequences mediated by a variety of mechanisms. Relations between such haemorheological and metabolic changes further to activation of lipoprotein lipase are discussed and stress is laid on the importance both might have in the pathogenesis of myocardial infarction.