Alighiero Bondioli

Carotid Artery Intima-Media Thickness Measured by Ultrasonography in Normal Clinical Practice Correlates Well With Atherosclerosis Risk Factors

Background and Purpose The intima-media thickness (IMT) of extracranial carotid arteries determined by B-mode ultrasound is a measurable index of the presence of atherosclerosis. The ultrasonographic scan protocol and the scan reading techniques used until now to measure IMT are, however, time consuming and require the participation of specialized research centers. In this study we present a cross-sectional study of 963 patients attending the Enrica Grossi Paoletti Center in Milan, Italy, with the aim of assessing whether ultrasonographic measurements of carotid artery in routine clinical practice can yield the same results as those obtained with quantitative methods used until now in clinical trials. Methods Maximum and mean maximum IMT of carotid arteries were assessed by B-mode ultrasound with the use of the electronic caliper of the machine in real time. Results The intraobserver and interobserver variability of IMT of carotid arteries performed with the electronic caliper in real time was similar to that of quantitative processing of frozen images (coefficients of variation of intraobserver and interobserver mean maximum IMT measurements were 4.2% and 7.3%, respectively). Carotid artery IMT thus measured correlated with most of the known atherosclerosis risk factors and discriminated between patients with and without previous history of cardiovascular events. IMT was linearly related to the total number of vascular risk factors both in the whole group and after stratification of patients into 3 age classes. Conclusions These observations establish a strong correlation between B-mode imaging of carotid atherosclerosis evaluated in normal clinical practice and data provided by clinical trials and validate this simple reading technique as a means of identifying IMT as another possible risk factor in patients at high risk of vascular disease.

Disposition of metformin (N,N‐dimethylbiguanide) in man

Kinetic parameters ol metformin (N,N‐dimethylbiguanide), an anti‐diabetic reported to be associated with a lower number of episodes of lactic acidosis than phenformin, were determined in volunteers with normal renal function and in patients with different degrees ol renal impairment. Drug in body fluids was measured by a highly specific and sensitive mass fragmentographic method, alter the formation of a triazine derivative, obtained with heptafluorobutyric anhydride. The half‐life (t½) for the elimination ol drug from plasma after intravenous injection in 5 normal subjects (1.52 ± 0.3 hr) (mean ± SD) was shorter than that reported for phenformin by a similar assay method (7 to 15 hr). The mean t½ in 5 renal patients was 4.94 ± 1.11 hr, and a correlation was observed between t½ of drug from plasma and creatinine clearance. After oral administration of metlormin tablets, drug recovery in urines was only 37.6%, possibly not as a consequence of low bioavailability (a similar low recovery was found after oral administration of the metformin solution usedlor the intravenous studies), but of binding to the intestinal wall, as shown in animal and clinical studies with metformin and other biguanides. Metformin is rapidly eliminated through active secretion by the kidney (mean renal clearance, 440.8 ml/min)—it is neither metabolized nor protein‐bound in plasma. The very brief plasma t½ makes significant cumulation, with a standard tid regimen, unlikely. These findings may help explain the lower incidence of toxic effects, particularly lactic acidosis, than after phenformin.

Metformin Improves Peripheral Vascular Flow in Nonhyperlipidemic Patients with Arterial Disease

The clinical activity of metformin (N,N-dimethyl biguanide), a widely used antidiabetic agent, on arterial blood flow was evaluated in 15 patients with peripheral atherosclerosis. Flow was determined by quantitative strain-gauge plethysmography; plasma lipid, lipoprotein, and apoprotein levels were repeatedly tested during the cross-over trial, comparing 6 months of drug and placebo administration. Metformin (850 mg tid) significantly increased arterial flow after a standardized ischemia (+ 17.3% after 3 months and + 40.0% after 6 months). The increase in arterial flow was reversible after the switch to placebo was made. The drug was similarly effective, although to a lesser extent (+ 18.6% after 6 months), when given after the placebo. A highly significant effect of drug treatment, as well as of the sequence of administration, could be established by analysis of variance. In spite of the minimal changes of plasma lipid levels during metformin, a highly significant increase of high density lipoprotein cholesterol (+ 8.3% during the whole treatment) was demonstrated; plasma levels of isoprotein AI-1 were also raised during the metformin period. This controlled experiment confirms data from previous open studies, as well as from a longstanding clinical experience. Although the mechanism of the metformin effect cannot, at present, be defined, the reported results indicate that treatments not markedly affecting plasma lipid-lipoprotein levels may improve vascular function in selected arterial districts.

Hypocholesterolaemic effects of lupin protein and pea protein/fibre combinations in moderately hypercholesterolaemic individuals.

The present study was aimed to evaluate the effect of plant proteins (lupin protein or pea protein) and their combinations with soluble fibres (oat fibre or apple pectin) on plasma total and LDL-cholesterol levels. A randomised, double-blind, parallel group design was followed: after a 4-week run-in period, participants were randomised into seven treatment groups, each consisting of twenty-five participants. Each group consumed two bars containing specific protein/fibre combinations: the reference group consumed casein+cellulose; the second and third groups consumed bars containing lupin or pea proteins+cellulose; the fourth and fifth groups consumed bars containing casein and oat fibre or apple pectin; the sixth group and seventh group received bars containing combinations of pea protein and oat fibre or apple pectin, respectively. Bars containing lupin protein+cellulose ( - 116 mg/l, - 4·2%), casein+apple pectin ( - 152 mg/l, - 5·3%), pea protein+oat fibre ( - 135 mg/l, - 4·7%) or pea protein+apple pectin ( - 168 mg/l, - 6·4%) resulted in significant reductions of total cholesterol levels (P<0·05), whereas no cholesterol changes were observed in the subjects consuming the bars containing casein+cellulose, casein+oat fibre or pea protein+cellulose. The present study shows the hypocholesterolaemic activity and potential clinical benefits of consuming lupin protein or combinations of pea protein and a soluble fibre, such as oat fibre or apple pectin.

Reproducibility Validation Study Comparing Analog and Digital Imaging Technologies for the Measurement of Intima-Media Thickness

BACKGROUND AND PURPOSE New advances in B-mode imaging technologies have led to improved quality in the detection of minute changes in the surface of intima-media thickness (IMT) and plaques. The new digital systems, with increased numbers of imaging channels, multiple frequency probes, and increased microprocessing speeds, now generate images comparable to those of the analog predecessors. Can these digital systems have reproducibility comparable to that of a pure analog system? We compared the Biosound 2000II (analog) system with the Esaote AU4 (digital) system. METHODS Twenty-two subjects were chosen who had varying degrees of IMT on the far wall of the common carotid artery. Common carotid IMT was determined twice: the first time with the analog system and the second time with the digital system. With each system, replicate scans were made within 2 weeks. RESULTS The intramethod agreement was high with the analog system, with a bias between readings of -0.010+/-0.033 mm, mean absolute difference of 0.027+/-0.020 mm, repeatability coefficient of 0.067, and correlation coefficient of 0.97. The digital system provided the highest reproducibility with a bias between readings of 0.002+/-0.016 mm, mean absolute difference of 0.012+/-0.011 mm, repeatability coefficient of 0.033, and correlation coefficient of 0. 99. When the analog and digital systems were compared, the bias between readings was -0.011+/-0.024 mm with good agreement between the 2 systems; the repeatability coefficient was 0.047, with all points within +/-2 SDs of the mean difference. The mean absolute difference between the 2 measurements was 0.018+/-0.015 mm with a correlation coefficient of 0.98. CONCLUSIONS The digital system for IMT evaluation compares well with the more widely used analog system and provides a reliable technology for common carotid IMT measurement that can be applied to clinical trials.

Reduced HDL2 levels in myocardial infarction patients without risk factors for atherosclerosis

Out of a total of 170 patients with a first myocardial infarction, aged below 65 years, consecutively admitted to the Coronary Care Unit of a large urban hospital, only 14 did not present with any risk factor(s) for atherosclerosis (smoking, hypertension, diabetes and obesity). None of these 14 patients showed significant hyperlipidemia. Compared to a control series of normal individuals of the same age (50.0 +/- 5.8 years for males and 61.6 +/- 3.0 years for females), they showed a significant reduction of high-density lipoprotein (HDL)-cholesterol and of apolipoprotein A-I (respectively -18.2 and -9.5%). However, the most striking abnormality was a 30% decrease of the HDL2 mass and of HDL2 cholesterol; both HDL2 and HDL3 had a reduced cholesteryl ester content in the patients. Reduced HDL2 mass and cholesterol levels in plasma, accompanied by significant alterations in HDL subfraction composition, are consistent with a defective cholesterol esterification in HDL. HDL2 deficiency may be a primary alteration in myocardial infarction patients without other significant risk factors.

Differential effects of fenofibrate and extended-release niacin on high-density lipoprotein particle size distribution and cholesterol efflux capacity in dyslipidemic patients.

BACKGROUND The effectiveness of therapies that raise high-density lipoprotein cholesterol (HDL-C) to lower cardiovascular disease risk is currently under debate, and further research into the relationship between HDL-C and function is required. OBJECTIVE o investigate whether 2 established HDL-C-raising therapies had differential effects on parameters of high-density lipoprotein (HDL) quality and function, such as HDL particle profile and cholesterol efflux capacity (CEC), in patients with dyslipidemia. METHODS AND RESULTS Sixty-six patients with dyslipidemia, 24 with low HDL-C levels (<40 mg/dL) and 42 with normal HDL-C levels (40-59 mg/dL), were treated for 6 weeks with fenofibrate (160 mg/d) or extended-release (ER) niacin (0.5 g/d for 3 weeks, then 1 g/d) with 4 weeks of washout between treatments. Lipoprotein particle size distribution was determined using nuclear magnetic resonance, and pathway-specific serum CECs were assessed in J774 macrophages, hepatoma, and Chinese hamster ovary-human adenosine triphosphate-binding cassette transporter G1 cells. Comparable increases in HDL-C and apolipoprotein A-I levels were seen with fenofibrate and ER niacin. There was a shift toward larger HDL, predominantly to medium-size HDL particles for fenofibrate (+209%) and to large HDL particles for ER niacin (+221%). Minor changes in serum CECs were observed with fenofibrate and ER niacin for all the efflux pathways measured. Small increases in plasma cholesteryl ester transfer protein and lecithin: cholesterol acyltransferase concentrations, and decreases in cholesteryl ester transfer protein activity were seen with both drugs. CONCLUSIONS Fenofibrate and ER niacin increased plasma HDL-C level similarly, but modulated HDL particle size distribution differently; however, these changes did not result in differential effects on serum CECs.

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.

Increased apoprotein B in very low density lipoproteins of patients with peripheral vascular disease.

Lipoproteln compositional studies were carried out in 20 patients with atherosclerotic peripheral vascular disease. Twelve of these patients were normollpldemlc, the other eight, hypertriglycerldemic. Ten normollpldemlc and 10 hypertriglyceridemlc age-matched subjects were used as controls. High density lipoprotein cholesterol levels were markedly reduced in the hypertriglyceridemlc subjects, both with (35.1 ± 5.0 mg/dl) and without (36.2 ±11.7 mg/dl) peripheral vascular disease, as compared to the normolipldemic patients (47.0 ± 6.3 mg/dl) and controls (48.1 ± 10.0 mg/dl). A decreased relative content of apo C-ll in very low density lipoproteins in the hypertriglyceridemic subjects, as compared to the normolipidemics, was detected by isoelectric focusing. Hypertriglyceridemla in patients with peripheral vascular disease shows a typical Type IV lipoprotein and apoprotein profile. Apoprotein B levels In very low and low density lipoproteins were determined by electroimmunodiffusion and selective precipitation with tetramethylurea (r = 0.981 between the two methods). All the patients with peripheral vascular disease showed an increased apo B content in very low density lipoproteins (VLDL) as compared to controls (apo B cholesterol In VLDL = 0.431 ± 0.124 for peripheral vascular disease patients and 0.236 ± 0.086 for controls, p < 0.001). A significant correlation between VLDL cholesterol and apo B levels was detected both in peripheral vascular disease patients and in controls; however, two distinct populations could be clearly separated (slopes of the regression lines: peripheral vascular disease patients = 0.350; controls = 0.215, p < 0.001). The data suggest a possible discriminatory power of VLDL-apo B levels in patients with peripheral vascular disease independent from other lipoprotein and lipid parameters.

Soy milk with a high glycitein content does not reduce low-density lipoprotein cholesterolemia in type II hypercholesterolemic patients.

In order to evaluate acceptability and effectiveness of a partial addition of soy protein to the daily diet in well-established type II hypercholesterolemic individuals, a double-blind study was carried out with a soy milk providing 25 g/day of protein versus an identically formulated cow’s milk. Twenty patients with type II hypercholesterolemia, 4 males and 16 females, age range 38–76 years, all with cholesterol levels >7 mmol/l and low-density lipoprotein cholesterol <5.5 mmol/l, were selected. Significant triglyceride elevations (WHO Fredrickson type IIB) were present in 4 patients, and the body mass index was 24.2 ± 3.47 kg/m2. Different from prior studies, either with isoflavone-free products or with a moderately isoflavone-rich milk, the milk in the present study did not reduce total and low-density lipoprotein cholesterolemia. A detailed analysis of the composition showed significant differences in the isoflavone content versus products used in prior studies with a positive outcome. Soy milk isoflavones were, in fact, characterized by a high glycitein content and a low genistein/daidzein ratio. Glycitein is a minor component in most soy products, and its role in cholesterol regulation is unclear. In view of the high interest in the use of soy products for the prevention of coronary diseases, the metabolic behavior of different isoflavones in man should be better characterized, and the role of isoflavone composition of soy products given for the control of cholesterolemia needs further clarification.