C.R. Sirtori

SOYBEAN-PROTEIN DIET IN THE TREATMENT OF TYPE-II HYPERLIPOPROTEINÆMIA

A soybean textured protein induced a 14% decrease of plasma-cholesterol levels after two weeks and 21% after three when substituted for animal proteins in a group of 20 patients with type-II hyperlipoproteinaemia. Comparison of soybean diet with a standard low-lipid diet in the same patients, according to a cross-over protocol, indicated that this hypocholesterolaemic effect was not due to differences in the lipid composition of the two diets. The hypothesis that a soy protein has a hypocholesterolaemic action per se is supported by the results of a subsequent experiment in 8 type-II patients in whom the addition of cholesterol (500 mg/day) to soy protein did not modify the hypocholesterolaemic response.

Inhibitor of proliferation of arterial smooth-muscle cells by fluvastatin

decrease; p<0·01) was detected with sera obtained 6 h after the last dose, when fluvastatin concentrations are below the detection limit (figure). This effect appears, therefore, not to be directly related to the presence of the drug but rather the end result of an inhibition of the mevalonate-derived isoprenoids, such as farnesol or geranylgeraniol. The latter compounds, when added to rapidly growing cells, prevent the inhibitory effect of statins. The inhibition of HMG-CoA reductase and isoprenoids biosynthesis by fluvastatin may thus prevent isoprenylation and membrane attachment of key G proteins involved in the signal transduction of mitogenic stimuli. No effect was observed on either SMC proliferation or cholesterol biosynthesis with sera from patients treated with pravastatin. These present findings are the first demonstration in man of the antiproliferative activity of an HMG-CoA reductase inhibitor. These findings may provide a basis for the potential effect of fluvastatin in the ongoing clinical trials (Lipoprotein and Coronary Atherosclerosis Study [LCAS]) investigating the progression and/or regression of atherosclerotic lesions, and (fluvastatin angioplasty restenosis [FLARE]) on the prevention of coronary restenosis after angioplasty. In addition, the presented model may provide a simple and useful test for evaluating the potential of different drugs in reducing cell proliferation in man.

Plasma lipoprotein(a) is an independent factor associated with carotid wall thickening in severely but not moderately hypercholesterolemic patients

BACKGROUND AND PURPOSE To evaluate whether high levels of low-density lipoprotein cholesterol (LDL-C) may promote the atherogenic effect of lipoprotein(a) [Lp(a)], we investigated the association between elevated Lp(a) levels and thickening of intima plus media in the common carotid artery (CC-IMT) in patients with different degrees of hypercholesterolemia. METHODS One hundred type II hypercholesterolemic patients and 25 normolipidemic subjects were selected for the study. Plasma lipid and lipoprotein levels were determined enzymatically; Lp(a) levels were determined by enzyme-linked immunosorbent assay. An Lp(a) concentration > 30 mg/dL was arbitrarily considered a risk factor. For each patient mean CC-IMT was determined by B-mode ultrasound; in 60 patients and in the 25 control subjects, the maximal IMT in the entire carotid tree was also determined. RESULTS CC-IMT values were higher in hypercholesterolemic patients with plasma Lp(a) levels > 30 mg/dL than in those with lower levels (P < .01). CC-IMT and maximal IMT directly and independently correlated with plasma levels of Lp(a) (r = .33 and r = .25, respectively; both P < .05). The effect of LDL-C concentrations on the relationship between IMT and Lp(a) was investigated by dividing the patients into quartiles of plasma LDL-C levels. After stratification, CC-IMT significantly correlated with plasma Lp(a) levels in the patients with severe hypercholesterolemia (LDL-C > 5.2 mmol/L) but not in patients in the lowest quartile, ie, those with moderate hypercholesterolemia. No correlation between CC-IMT and Lp(a) was found in normolipidemic control subjects. CONCLUSIONS Elevated plasma levels of Lp(a) can be considered an additional independent factor associated with thickening of the common carotid arteries in patients with severe hypercholesterolemia but not in those with moderate hypercholesterolemia or in normocholesterolemic subjects.

Bezafibrate lowers plasma lipids, fibrinogen and platelet aggregability in hypertriglyceridaemia

SummaryThe effects of bezafibrate 400 mg/day (slow release formulation) on plasma lipids/lipoproteins and on selected haemostatic parameters were evaluated in a double blind cross-over study in patients with Type IIb and IV hyperlipoproteinaemia.Placebo treatment did not influence any of those parameters, but the drug significantly reduced plasma triglycerides (−45%) and VLDL cholesterol, as well as causing a 12 % fall in total cholesterol and a 20 % increase in HDL cholesterol. Apo AI levels were significantly increased following bezafibrate and Apo B was reduced by about 20 %. In addition to changes in the plasma lipid profile, bezafibrate reduced the sensitivity of platelets to the aggregatory effect of collagen, with no effect on TXB2 production. Fibrinogen levels after bezafibrate treatment were significantly lowered, the effect being more marked in patients with hyperfibrinogenaemia. Bezafibrate did not influence the plasma fibrinolytic profile.It is concluded that bezafibrate, besides its beneficial effects on the plasma lipoprotein profile, can exert beneficial changes on specific haemostatic parameters.

Treatment with low dose metformin in patients with peripheral vascular disease

Low dose metformin (500 mg b.i.d.) was tested in 11 patients with symptomatic peripheral vascular disease (PVD) in an open design. At -1, 0, 1, 4, 7 months the major lipid and lipoprotein parameters, arterial function, and fibrinolytic activity were monitored. Arterial function changes were similar to those found with a high dose (850 mg t.i.d.) metformin but plasma lipids did not change to an appreciable extent. Post-ischaemic blood flow, by plethysmography, rose 30%; the exercise capacity, evaluated by treadmill test, also increased significantly by 105.7% for relative and 53.3% for absolute claudication. Total fibrinolytic activity did not change during the treatment but the antigens of two of the major components of the fibrinolytic system, i.e. t-PA and PAI-1, were significantly reduced at the end of the study. This study gave results quite consistent with those obtained with higher metformin doses, associated with a potentially higher risk of lactic acidosis.

Elevated triglycerides and low HDL cholesterol in transgenic mice expressing human apolipoprotein A-IMilano

In general, plasma concentrations of high density lipoproteins (HDL) are inversely related to the incidence of coronary artery disease. One exception to this trend is individuals with apolipoprotein A-I(Milano) (apo A-IM), a molecular variant of apo A-I, which results in very low plasma apo A-I and HDL-cholesterol levels. Despite these low levels, and other lipoprotein defects, individuals with this mutation have no increased risk for cardiovascular disease. As a first step in proving why apo A-IM carriers appear to be protected from the pro-atherogenic effect of a low HDL, transgenic mice expressing apo A-IM were generated. Mice expressing either wild-type human apo A-I or apo A-IM, together with human apo A-II, were crossed into mice lacking murine apo A-I. Apo A-IM/A-II mice had lower cholesterol and HDL plasma levels compared to apo A-I/A-II mice. Moreover, as in human carriers, apo A-IM mice were characterized by elevated triglyceride plasma levels and by the presence of a population of very small HDL particles. These results indicate that the expression of apo A-IM in a mouse model reproduces the major lipid/lipoprotein abnormalities observed in human carriers. Thus, apo A-IM transgenic mice appear to be a suitable model in which to assess whether the mutation has an anti-atherogenic effect.

Fraudulent (and non fraudulent) fatty acids for human health

A number of fatty acid molecules are proposed for the prevention of diseases and/or for the treatment of specific syndromes (metabolic and others). Major fatty acids are found in the daily diet and are roughly divided into saturated and unsaturated. Unsaturated, compared to saturated fatty acid intake undoubtedly leads to lower levels of plasma lipids, both as relates to cholesterol [l] as well as to triglycerides [2]. The mechanism of the plasma lipoprotein reduction has been variously interpreted [3]; at present, there is a consensus that monounsaturated (mainly oleic acid) and polyunsaturated fatty acids (these latter of the n-6 series, the major one being linoleic acid) reduce cholesterol to a similar extent [4], but the former may have a somewhat greater raising activity on high density lipoprotein (HDL) cholesterol [5 ] . Highly unsaturated fatty acids of the n-3 series, derived from fish, are also potent triglyceride-lowering agents, with some activity on plasma cholesterol, particularly in hypercholesterolaemia [6]. A series of synthetic fatty acids have also gained an established role in lipid-lowering therapy. They are the so-called ‘Jibric acids’ or ‘Jbrates’ [7]. These compounds have well documented effects on plasma triglycerides as well as on cholesterol. This pattern of activity is, to some extent, remindful of that of n-3 fatty acids, with, however, a more potent and sustained action. The possibility that different fatty acids, both natural and synthetic, may exert their impact on a common liver regulatory pathway, has been suggested by the recognition of a nuclear receptor in hepatocytes, a member of the steroid hormone receptor superfamily [8]. This receptor, named ‘peroxisome proliferator activated receptor’ (PPAR), was associated with the typical stimulatory effect of fibric acids and related compounds on the proliferation of peroxisomes (organelles containing catalase and other peroxidative enzymes) in rodent liver [9]. Peroxisomes lodge a very

Effects of smoking regular or light cigarettes on brachial artery flow-mediated dilation

BACKGROUND AND PURPOSE To compare the effects of regular cigarettes (RCs) and light cigarettes (LCs) on brachial artery flow-mediated dilation (FMD) and sublingual glyceryl trinitrate-induced dilation (GTN), markers of endothelial dependant and independent function, respectively. METHODS 206 subjects (age 51.5 ± 12.8 yr, 122 men) had their smoking habits recorded and FMD and GTN measured by B-mode ultrasound. Cigarettes were categorized as RCs or LCs according to their content of tar, nicotine and CO. The chronic effect was assessed in current smokers of RCs (n = 85) or LCs (n = 53) and in never smokers (NS; n = 68). The acute effect was assessed in current smokers by measuring FMD before and 10-min after smoking a single regular (n = 29) or light (n = 51) cigarette. RESULTS FMD was significantly lower in consumers of RCs (6.26%, 95% C.I. 5.58, 6.94) or LCs (5.59%, 95% C.I. 4.74, 6.45) compared to NS (8.68%, 95% C.I. 7.92, 9.44) (both P < 0.0001), but did not differ (P > 0.05) when compared to each other. GTN was similar in the three groups. Analyses adjusted for clinical confounders and for markers involved in oxidative stress, arginine/nitric oxide pathway, and inflammation provided identical results. Smoking a single cigarette, either regular or light, reduced FMD (-0.88% and -1.17%, respectively, both P < 0.05), without significant difference between cigarette type. RCs and LCs produced analogous chronic and acute effects when FMD was calculated with respect to the last 60 s of the low-flow phase (FMD60s). CONCLUSIONS LCs impair endothelial-dependant vasodilation as much as RCs. Thus, smoking LCs cannot be considered an alternative to the only safe choice of a complete and permanent smoking cessation.

Increased postprandial lipemia in Apo A-IMilano carriers.

Plasma lipid/lipoprotein changes were monitored after a fat load (65 g fat per square meter body surface area) in six carriers of the apolipoprotein A-IMilano (A-IM) variant and six age- and sex-matched control subjects. The magnitude of postprandial lipemia, calculated as the area under the curve (AUC) described by plasma triglyceride (TG) level versus time, was threefold higher in the A-IM carriers; however, after correction for the different baseline TG levels, it was similar to control subjects. Moreover, the magnitude of postprandial lipemia was positively correlated with baseline TG in both A-IM carriers (r = 0.77) and control subjects (r = 0.80), indicating that fasting TGs are a major determinant of postprandial response in all subjects. Postprandial lipemia was also inversely correlated with high density lipoprotein (HDL) and HDL2 cholesterol in both groups (A-IM, r = -0.81 and -0.79; control subjects, r = -0.87 and -0.94). Different from those in control subjects, the plasma apo A-I levels in the A-IM carriers decreased progressively while apo B increased up to 4 hours but decreased thereafter. Postprandial rises of low density lipoprotein TG but not of HDL-TG AUC were significantly higher in the A-IM carriers, even after normalization for the different fasting concentrations. These data show that the low plasma HDL levels of A-IM carriers, which are secondary to a primary structural alteration of the major HDL apolipoprotein, are associated with elevated fasting and postprandial TG levels and an anomalous postprandial redistribution of TG among lipoprotein classes.

Correlation between plasma levels of fenofibrate and lipoprotein changes in hyperlipidaemic patients

SummaryEleven hyperlipidaemic patients received two formulations of fenofibrate (differing in in vitro dissolution) in randomized sequence, each for 6 weeks. Formulation N, giving a 2–3-fold higher plasma fenofibrate level compared to R, lowered both the cholesterol and triglyceride levels far more than R. Changes in the total and high density lipoprotein cholesterol levels were not significantly correlated with the fenofibrate level. A highly significant correlation was detected for triglycerides in Type IV patients, and for changes both in very low density lipoprotein (VLDL) cholesterol and triglycerides in the entire group of patients. In conditions of widely distributed steady state levels of an absorbable hypolipidaemic drug, a significant correlation may thus be detected between the plasma level and the reduction of VLDL — associated lipids.