Dietary intake and major food sources of polyphenols in people with type 2 diabetes: The TOSCA.IT Study.

PURPOSE: Proper evaluation of polyphenols intake at the population level is a necessary step in order to establish possible associations with health outcomes. Available data are limited, and so far no study has been performed in people with diabetes. The aim of this work was to document the intake of polyphenols and their major food sources in a cohort of people with type 2 diabetes and in socio-demographic subgroups. METHODS: We studied 2573 men and women aged 50-75 years. Among others, anthropometry was measured by standard protocol and dietary habits were investigated by food frequency questionnaire (EPIC). The intake of polyphenols was evaluated using US Department of Agriculture and Phenol-Explorer databases. RESULTS: The mean total polyphenol intake was 683.3 ± 5.8 mg/day. Non-alcoholic beverages represented the main food source of dietary polyphenols and provided 35.5% of total polyphenol intake, followed by fruits (23.0%), alcoholic beverages (14.0%), vegetables (12.4%), cereal products and tubers (4.6%), legumes (3.7%) and oils (2.1%); chocolate, cakes and nuts are negligible sources of polyphenols in this cohort. The two most important polyphenol classes contributing to the total intake were flavonoids (47.5%) and phenolic acids (47.4%). Polyphenol intake increased with age and education level and decreased with BMI; furthermore, in the northern regions of Italy, the polyphenol intake was slightly, but significantly higher than in the central or southern regions. CONCLUSIONS: The study documents for the first time the intake of polyphenols and their main food sources in people with diabetes using validated and complete databases of the polyphenol content of food. Compared with published data, collected in people without diabetes, these results suggest a lower intake and a different pattern of intake in people with diabetes.

Difference in carotid artery elasticity in subjects with different brachial artery kinetic of vasodilatation.

Increased carotid stiffness and impaired brachial artery flow-mediated dilatation (FMD) associate with cardiovascular events. We have previously reported three FMD patterns based on the time of maximal dilatation. The aim of the present study was to verify whether different FMD patterns associate with carotid artery stiffness. In all, 133 subjects were enrolled. All participants underwent complete clinical examination, blood sampling and ultrasound study. FMD was used as a measure of endothelial function. Based on the maximal brachial artery FMD, subjects were divided into Early dilators (peak FMD at 50 s), Late dilators (peak FMD over 50 s) and No dilators. Echo-Doppler evaluation of carotid arteries was performed in order to calculate elastic indexes (strain, ß-stiffness index and distensibility). In all, 64 subjects were classified as Early FMD, 36 as Late FMD and 33 as No dilators. Age, gender and cardiovascular risk factors were comparable among three groups. Early FMD had higher values of strain compared with both Late and no Dilators (P<0.001). Furthermore, Early dilators showed a significantly lower stiffness and higher distensibility compared with Late and No dilators. No significant differences between Late FMD and No Dilators were detected. Our results demonstrate that common carotid artery elasticity indexes significantly differ among Early, Late and No dilators. Subjects with delayed or absent brachial artery dilatation have stiffer common carotid arteries compared with subjects with early dilatation. In conclusion, our research suggests that the assessment of the kinetics of FMD in a clinical setting might represent a useful screening tool to improve the cardiovascular risk stratification.

Blood urea impairs brachial artery flow mediated dilation.

AIM: Urea, the main product of protein catabolism, is a biochemical marker of renal function. Though it is known that serum urea impairs vascular health, the relationship between its concentration and vascular reactivity in vivo has not been explored. Our study was undertaken to investigate possible association between serum urea and endothelial function in subjects without chronic kidney disease (CKD). METHODS: Eighty free-living subjects with serum creatinine ≤1 mg/dL and without CKD were enrolled for the present study. Serum analyses and evaluation of endothelial function were performed in all subjects. Endothelial function was measured using the flow-mediated dilation (FMD) technique. Simple and multiple regression analyses were used to test the association between FMD and considered variables. RESULTS: In correlation analyses FMD was found directly associated with HDL cholesterol (r=0.21; P=0.05) and eGFR (r=0.25; P=0.02) and inversely associated with age (r=-0.26; P=0.02), serum urea (r=-0.37; P<0.01), serum creatinine (r=-0.31; P<0.01) and brachial artery baseline diameter (r=-0.41; P<0.01). In multiple regression analysis only baseline artery diameter and serum urea predicted FMD; age, gender and cardiovascular risk factors did not relate with FMD. CONCLUSION: Our study demonstrates the association between serum urea and FMD, suggesting that the accumulation of waste products of protein metabolism may impair vascular health in subjects without CKD.

Time course analysis of brachial artery flow mediated dilatation in subjects with gingival inflammation.

AIM: Several investigations report an inverse association between periodontal disease and endothelial function measured by brachial artery Flow-Mediated-Dilatation (FMD) technique. These studies examined endothelial function by using the traditional approach to FMD calculation, that is from diameters assessed at 60 seconds after deflation. Nevertheless, possible relationship between gingival inflammation and endothelial dysfunction observed over this temporal threshold remains still unexplored. The purpose of our study was to explore the relationship between gingival inflammation and endothelial function, by considering the time course of brachial FMD. METHODS: Forty-six free-living white subjects, participating in a cardiovascular disease prevention campaign, were enrolled. FMD was measured at 60s and at 2 and 3 min after forearm ischemia. Maximal FMD was calculated (Peak FMD), for each patient. Gingival Index (GI) was evaluated as measure of gingival inflammation. RESULTS: In univariate analyses, GI was associated with both FMD at 60 sec (r=-0.30, P=0.038) and Peak FMD (r=-0.41, P=0.004). In multiple regression analyses including GI, age, gender, and known risk factors for atherosclerosis, only GI and age were independently and inversely associated with Peak FMD and FMD at 60 s, but this association was stronger with Peak FMD. Moreover, when we divided subjects on the basis of GI value, patients with GI > 1 presented lower Peak FMD and higher prevalence of absent FMD. CONCLUSION: The present study extends previous observations about the negative effects of periodontal disease on endothelial function, highlighting the importance of the evaluation of time course of vascular reactivity.

Markers of insulin resistance and carotid atherosclerosis. A comparison of the homeostasis model assessment and triglyceride glucose index.

AIMS: The present investigation was designed to test the association between carotid atherosclerosis and two simple markers of insulin resistance, i.e. HOMA-Index and TyG-Index. MATERIALS AND METHODS: The study was performed in two different cohorts. In the first cohort, 330 individuals were enrolled. Blood pressure, lipids, glucose, waist and cigarette smoking were evaluated. HOMA-IR and TyG-Index were calculated as markers of prevalent hepatic and muscular insulin resistance respectively. Carotid atherosclerosis was assessed by Doppler ultrasonography. The association between cardiovascular risk factors, markers of insulin resistance and carotid atherosclerosis was assessed by multiple logistic regression analyses. In the second cohort, limited to the evaluation of TyG-Index, 1432 subjects were studied. RESULTS: In the first cohort, TyG-Index was significantly associated with carotid atherosclerosis in a model including age, sex, diabetes, cigarette smoking and LDL cholesterol, while HOMA-IR was not. When components of metabolic syndrome were added to the model as dichotomous variables (absent/present), TyG-Index retained its predictive power. The same result was obtained when the metabolic syndrome was added to the model (absence/presence). The association between TyG-Index and carotid atherosclerosis was confirmed in the second cohort. CONCLUSIONS: The present findings suggest that TyG-Index is better associated with carotid atherosclerosis than HOMA-IR.

The effect of aging on blood and plasma viscosity. An 11.6 years follow-up study.

OBJECTIVE: Alterations of blood and plasma viscosity can promote atherosclerosis. The relationship between viscosity and aging is still controversial. The present study evaluated the influence of aging on blood and plasma viscosity in a group of subjects followed for 11.6 years. METHODS: Forty-five subjects have been evaluated twice 11.6 years apart for hemorheological parameters and coronary heart disease (CHD) risk factors. Plasma viscosity and blood viscosity have been measured with a cone-plate viscometer. Tk has been calculated as index of red blood cell rigidity. CHD risk factors, i.e. obesity, hypertension, hyperlipidemia and diabetes, have been evaluated by routine methods. RESULTS: Hematocrit and plasma viscosity did not change during the study, whereas blood viscosity (shear rate 225/sec: 4.46 ± 0.49 vs. 4.81 ± 0.54 cP, p < 0.0001; shear rate 45/sec: 6.19 ± 0.67 vs. 6.65 ± 0.79 cP, p < 0.0001) and Tk (0.80 ± 0.05 vs. 0.83 ± 0.06, p < 0.005) significantly increased. The percent variation in blood viscosity was not associated with the percent variation in any of the CHD risk factors. Furthermore, the increase in blood viscosity was similar in males and females and in subjects with CHD risk profile worsening or not. CONCLUSION: The present findings demonstrate that blood viscosity increases with age. This increase seems independent of classical CHD risk factors and is disjoined from haematocrit and plasma viscosity, suggesting a possible direct effect of aging on red blood cells.

Metabolic syndrome in subjects at high risk for type 2 diabetes: the genetic, physiopathology and evolution of type 2 diabetes (GENFIEV) study.

BACKGROUND AND AIM: We evaluated the relationship between insulin resistance (IR) and insulin secretion with the metabolic syndrome (MS) in 885 subjects (377 men/508 women, age 49±11 years, BMI 29±5.2kgm(-2)) at risk of diabetes enrolled in the genetics, pathophysiology and evolution of type 2 diabetes (GENFIEV) study. METHODS AND RESULTS: All subjects underwent a 75-g oral glucose tolerance test (OGTT) for the estimation of plasma levels of glucose and C-peptide, as well as fasting insulin and lipid profile. IR was arbitrarily defined as HOMA-IR value above the 75th centile of normal glucose tolerance (NGT) subjects. Overall MS prevalence (National Cholesterol Treatment Panel-Adult Treatment Panel (NCEP-ATPIII) criteria) was 33%, 19% in subjects with NGT, 42% in impaired fasting glucose (IFG), 34% in impaired glucose tolerance (IGT), 74% in IFG+IGT subjects, and 56% in newly diagnosed diabetic patients. Prevalence was slightly higher with IDF criteria. MS prevalence was >50% in subjects with 2h glucose >7.8mmoll(-1), independently of fasting plasma glucose. IR prevalence was higher in subjects with MS than in those without (63% vs. 23%; p<0.0001) and increased from 54% to 73% and 88% in the presence of three, four or five traits, respectively. IR occurred in 42% of subjects with non-diabetic alterations of glucose homeostasis, being the highest in those with IFG+IGT (IFG+IGT 53%, IFG 45%, IGT 38%; p<0.0001). Individuals with MS were more IR irrespective of glucose tolerance (p<0.0001) with no difference in insulinogenic index. Hypertriglyceridaemia (OR: 3.38; Confidence Interval, CI: 2.294.99), abdominal obesity (3.26; CI: 2.18-4.89), hyperglycaemia (3.02; CI: 1.80-5.07) and hypertension (1.69; CI: 1.12-2.55) were all associated with IR. CONCLUSIONS: These results show that in subjects with altered glucose tolerance (in particular IFG+IGT) MS prevalence is high and is generally associated to IR. Some combinations of traits of MS may significantly contribute to identify subjects with IR.

Association among low whole blood viscosity, haematocrit, haemoglobin and diabetic retinopathy in subjects with type 2 diabetes.

OBJECTIVES: Haemorheological variables influence endothelial function through the release of several factors. Clinical studies have described an association among blood viscosity, haematocrit, haemoglobin and macro-angiopathy. Few data are reported about the association between haemorheological variables and micro-angiopathy. The aim of the present study was to evaluate the association between these variables and retinopathy in subjects with type 2 diabetes. METHODS: 111 men, 79 postmenopausal women, and 95 healthy age- and sex-matched controls were recruited. Haematocrit and haemoglobin were measured by standard methods. Blood viscosity was calculated according to the formula (0.12× haematocrit)+(0.17× (plasma proteins-2.07)). Subjects were grouped according to the presence or absence of diabetic retinopathy, while the severity of retinopathy was classified according to the Early Treatment Diabetic Retinopathy Study scale. RESULTS: Haemoglobin, haematocrit and whole blood viscosity were significantly lower in subjects with retinopathy compared to subjects without retinopathy in both sexes. These variables significantly decreased with increasing severity of retinopathy. A multiple logistic regression analysis confirmed the independent inverse association among viscosity, haematocrit, haemoglobin and retinopathy (p<0.01). CONCLUSION: Results demonstrate the association among low viscosity, haemoglobin, haematocrit and diabetic retinopathy. The mechanisms responsible for this association can be hypothesised. Reduced haemoglobin might cause direct organ damage. Low blood viscosity, through the reduction of shear stress, might inhibit the anti-atherogenic functions of endothelial cells.

Primary hyperlipidemias in children: effect of plant sterol supplementation on plasma lipids and markers of cholesterol synthesis and absorption.

Plant sterols lower serum cholesterol concentration. Available data have confirmed the lipid-lowering efficacy in adults, while there is a relative dearth of data in children and almost exclusively restricted to subjects with familial hypercholesterolemia (FH). Aim of the present study was to evaluate the efficacy, tolerability and safety of plant sterol supplementation in children with different forms of primary hyperlipidemias. The effect of plant sterol consumption on plasma lipids was evaluated in 32 children with heterozygous FH, 13 children with Familial Combined Hyperlipidemia (FCH) and 13 children with Undefined Hypercholesterolemia (UH) in a 12-week open-label intervention study using plant sterol-enriched yoghurt. Plasma lipids and apolipoproteins were measured by routine methods. Markers of cholesterol synthesis (lathosterol) and absorption (campesterol and sitosterol) were measured by GC-MS. Tolerability and adherence to recommended regimen was very high. A significant reduction was observed in LDL-cholesterol in the three groups (10.7, 14.2 and 16.0% in FH, FCH and UH, respectively). Lathosterol concentrations were unchanged, reflecting a lack of increased synthesis of cholesterol. Of the two absorption markers, only sitosterol showed a slight but significant increase. Daily consumption of plant sterol dairy products favorably changes lipid profile by reducing LDL-cholesterol. To our knowledge, this is the first report of the use of plant sterols-enriched foods in treating children with primary hyperlipidemia such as FCH and UH, likely to be the most frequent form also in the young age in the western populations.

Plasma and blood viscosity in metabolic syndrome.

BACKGROUND AND AIM: The relationship between metabolic syndrome (MS) and blood and plasma viscosity has been scarcely investigated. In the present study we have evaluated the difference in blood and plasma viscosity between subjects with and without MS, in order to verify whether viscosity measurement can add more information on the overall cardiovascular risk connected with the presence of the MS. METHODS AND RESULTS: Two hundred and sixty nine women and 520 men have been enrolled. Blood and plasma viscosity have been measured with a cone-plate viscometer equipped with a cp-40 spindle. MS has been defined according to the third report of the National Cholesterol Education Program, Adult Treatment Panel III. Eighty four women and 154 men fulfilled the criteria for MS. Hematocrit adjusted blood viscosity was higher in subjects with MS compared to those without the syndrome, both in males (shear rate 225 s(-1): 4.60+/-0.38 vs. 4.52+/-0.33 cP, p<0.01) and females (4.57+/-0.28 vs. 4.46+/-0.31 P, p<0.01). Blood viscosity was correlated with all components of MS but glucose, and after adjustment for them the difference between subjects with or without MS was completely abolished. Plasma viscosity was significantly higher only in females with MS. CONCLUSIONS: These data demonstrate that blood viscosity is increased in subjects with MS, but the increase seems to depend on the metabolic alterations of the syndrome. The independent contribution of the rise in blood viscosity to the cardiovascular risk connected with the presence of MS seems therefore negligible. The increased plasma viscosity in females with MS needs further clarification.

Stromelysin gene promoter polymorphism and common carotid geometry in diabetic subjects.

AIM: Stromelysin (MMP3), through its action on collagen and other matrix metalloproteinases, influences arterial wall remodeling. In healthy subjects, the 5A/6A polymorphism located in the promoter of the MMP3 gene is associated with common carotid remodeling, 6A/6A subjects having increased arterial diameter, wall thickness (intima-media thickness, IMT) and decreased wall shear stress (WSS). In the present study, we have investigated the influence of the 5A/6A polymorphism on common carotid remodeling in subjects with diabetes mellitus. METHODS: Diabetic subjects (N.=136) and age-matched healthy male controls (N.=101) have been studied. Common carotid diameter, IMT and flow velocity have been measured by echo-Doppler. Blood viscosity has been measured by a cone/plate viscometer. WSS has been calculated. RESULTS: Diabetic patients had increased common carotid diameter, IMT, and decreased flow velocity and WSS (all P<0.05), compared with controls. In controls, subjects homozygous for the 6A allele had increased diameter, IMT and decreased WSS. In diabetics, no difference was observed in vascular parameters among the three genotypes. CONCLUSION: The 5A/6A polymorphism of the MMP3 gene influences arterial remodeling of the common carotid artery in healthy subjects, but not in patients with diabetes mellitus. Therefore, the significance of the 5A/6A polymorphism as a marker of risk in this high cardiovascular risk population seems to be somehow blunted.

Beta-sitosterolaemia: a new nonsense mutation in the ABCG5 gene.

BACKGROUND: Sitosterolaemia is a rare autosomal recessive disorder characterised by elevated plasma levels of plant sterols and cholesterol. Sitosterolaemia is caused by gene mutations in either of two ATP-binding cassette (ABC) half transporters, ABCG5 and ABCG8. The plasma sterol profile and genetic analysis of a 10-year-old girl who had tuberous xanthomas is the subject of this report. MATERIALS AND METHODS: Genomic DNA was isolated from white blood cells from the proband, her family and a control group of healthy people. All exons of ABCG5 and ABCG8 were sequenced. Plasma cholesterol and triglycerides were measured by routine methods. All other plasma sterols were measured by Gas Chromatography coupled to Mass Spectrometry. RESULTS: The proband was found to be homozygous for a single nucleotide mutation in exon 10 of the ABCG5 gene, consisting of a C to T transition at nucleotide 1336 of the coding sequence, which results in the premature termination of the ABCG5 protein at amino acid 446 (Arg446X). Her mother and brother were also homozygous for the same mutation and all had elevated plasma beta-sitosterol levels. The father was heterozygous and showed normal beta-sitosterol levels. This mutation was not found in healthy normolipidaemic subjects. CONCLUSIONS: We describe a novel nonsense mutation in exon 10 of the ABCG5 gene in a 10-year-old girl showing clinical and biochemical features of sitosterolaemia. This family study broadens the spectrum of the ABCG5/ABCG8 mutations causing sitosterolaemia and helps highlight the correlations between such gene mutations, biochemical phenotype and the development of cardiovascular disease.

Flow-mediated vasodilatation of the brachial artery and intima-media thickness of carotid artery in never-treated subjects.

AIM: Data on the association between brachial artery flow-mediated dilatation (FMD) and common carotid intima-media thickness (IMT) are contrasting. The present study investigated the relationship between FMD and IMT and carotid atherosclerosis in never treated subjects. METHODS: Seventy-seven subjects were investigated: 46 had no coronary heart disease (CHD) risk factors, 21 had only one, and 10 had more than one risk factor. IMT of the common carotid was measured by ultrasonography and FMD was evaluated according to standardized methods. RESULTS: IMT increased with increasing number of risk factors (0.66+/-0.12, 0.69+/-0.12 and 0.8+/-0.17 mm, respectively, ANOVA P<0.05). FMD decreased with increasing number of risk factors (10.44+/-5.2, 6.52+/-7.11 and 7.35+/-4.42%, respectively, P<0.05). Endothelium-independent vasodilatation was similar in the 3 groups. IMT and FMD did not correlate neither in subjects without risk factors (r=-0.151, P=0.3), nor in those with 1 (r=-0.196, P=0.4) or with 2 or more risk factors (r=-0.387, P=0.2), while in the group as a whole the correlation was borderline significant (r=-0.217, P=0.058). Eleven subjects had carotid atherosclerosis and higher values of IMT, but not reduced FMD. In multiple regression analysis, diabetes and IMT, but not FMD, were associated with carotid atherosclerosis. CONCLUSIONS: The present findings indicate that, in never treated subjects, FMD is not strictly associated with IMT or atherosclerosis of the carotid arteries.

Effects of iodinated contrast media on common carotid and brachial artery blood flow and wall shear stress.

The aim of our study was to evaluate the effect of the intravenous contrast media iomeprol on wall shear stress, blood flow and vascular parameters in the common carotid and brachial artery. Thirty outpatients undergoing thoracic or abdominal spiral CT scans were studied. The internal diameter and flow velocity of the common carotid and brachial artery were evaluated by ultrasound, and blood viscosity was measured before and after low osmolality iomeprol (Iomeron 350) injection. The wall shear stress, blood flow and pulsatility index were calculated. To test the differences between groups, the Wilcoxon rank test and Mann Whitney U test were applied. Blood viscosity decreased slightly, but significantly after contrast media (4.6+/-0.7 vs. 4.5+/-0.7 mPa.s, P = 0.02). Contrarily, blood flow and wall shear stress did not change in the common carotid artery, but significantly decreased in the brachial artery (0.9+/-0.4 vs. 0.6+/-0.3 ml/s, P < 0.0001, and 41.5+/-13.9 vs. 35.3+/-11.0 dynes/cm2, P < 0.002, respectively), whereas the pulsatility index significantly increased in the brachial artery (5.0+/-3.3 vs. 7.5+/-5.3, P < 0.001). Iomeprol injection causes blood flow and wall shear stress reduction of the brachial artery; the rise in the pulsatility index suggests an increase in peripheral vascular resistance. Further investigation is needed to evaluate whether these modifications can be clinically relevant.

A multiplex PCR-based DNA assay for the detection of paraoxonase gene cluster polymorphisms.

Paraoxonase (PON) is a high-density lipoprotein (HDL) associated protein which is supposed to protect low-density lipoprotein (LDL) against oxidation and to play a role in the development of atherosclerosis. Interindividual variability in serum PON activity is attributable to common variants in components of the PON gene cluster on chromosome 7. We describe experimental conditions that permit the simultaneous determination of three common PON polymorphisms (PON1-192, PON1-55 and PON2-311) that are tightly associated with an increased risk of atherosclerosis. We used a multiplex PCR-based DNA assay using mismatch primers that introduce a unique recognition site for the endonuclease HinfI in the PCR products in case of presence of the R allele of PON 1-192, of the L allele of PON1-55 and of the S allele of PON2-311. The restriction analysis with HinfI allows to identify an electrophoretic band pattern which is specific for the combination of the three polymorphisms. This technique could be applied in the association studies aimed at assessing the role of PON and their polymorphisms in many clinical settings. In a preliminary study on a small population sample from south Italy about 10% of chromosomes exhibited the presumed risk-related haplotype R(192)/L(55)/S(311).

Comparison of endothelial function evaluated by strain gauge plethysmography and brachial artery ultrasound.

Strain gauge plethysmography and brachial artery ultrasound are widely used to study endothelial function. No data on correlation between these two procedures are reported. The present study compared these two methods and investigated the correlation between vasodilation and brachial wall shear stress. In six healthy subjects and ten patients with hypertension or obesity, strain gauge plethysmography was performed in resting conditions and after infusion of 7.5,15 and 30 microg/min of acetylcholine, and brachial artery ultrasound in resting conditions and after 5 min hand ischemia. Wall shear stress was calculated as: blood viscosity x blood velocity/internal diameter. Forearm blood flow following acetylcholine infusion increased more in healthy subjects than in patients with hypertension or obesity. In addition, brachial artery dilated more in the former group. Change in brachial artery diameter correlated with change in forearm blood flow, calculated as area under the curve of acetylcholine infusion (r=0.739, P<0.001). Wall shear stress was higher in healthy subjects (67.8+/-20.0 dynes/cm(2)) than in patients with either hypertension or obesity (39.2+/-16.7, P<0.001), and correlated with variations of diameter (r=0.796, P<0.0002), and marginally of blood flow (r=0.516, P<0.05). The present findings demonstrate that there is a high correlation between endothelial function evaluated by strain gauge plethysmography and brachial artery ultrasound. Wall shear stress correlates with brachial artery diameter change following hand ischemia, and marginally with blood flow change following acetylcholine infusion.

Association between wall shear stress and flow-mediated vasodilation in healthy men.

Wall shear stress contributes to the endothelial production of vasoactive mediators, like nitric oxide (NO). Brachial artery vasodilation that follows increased blood flow is regulated by NO release. Aim of the present study was to investigate whether resting wall shear stress of the brachial artery is related to flow-mediated vasodilation (FMD) induced by forearm ischemia. Wall shear stress was calculated according to the following formula: Wall shear stress=Blood viscosity x Blood velocity/Internal diameter. FMD was calculated as percentage change of brachial artery diameter following forearm ischemia. Twenty-seven healthy male subjects were investigated. Peak wall shear stress and FMD were 37.3+/-12.8 dynes/cm(2) and 110.7+/-5.6%, respectively (mean+/-S.D.). In simple regression analyses, age was inversely associated with wall shear stress (r=48, P<0.01) and, marginally, with FMD (r=0.33, P=0.08). Wall shear stress and FMD were directly related (r=0.60, P<0.001). In multiple regression analysis, including wall shear stress, age, blood pressure, lipids, glucose and Body Mass Index as independent variables, wall shear stress was the only variable independently associated with FMD (standardized beta coefficient=0.690, P

Lack of association between carotid intima-media thickness and methylenetetrahydrofolate reductase gene polymorphism or serum homocysteine in non-insulin-dependent diabetes mellitus.

We assessed the contribution of the serum homocysteine (Hcy) level, an independent risk factor for vascular disease, and methylene tetrahydrofolate reductase (MTHFR) gene polymorphism to the variability of intimal-medial thickness (IMT) of the common carotid artery in middle-aged non-insulin-dependent diabetes mellitus (NIDDM) subjects. One hundred thirty NIDDM patients (60 males and 70 females) with a mean age of 53 +/- 10 years and a mean diabetes duration of 11.3 +/- 7.9 years were enrolled for the study. Exclusion criteria included liver, heart, kidney, or other major-organ disease. Fasting total serum Hcy, folate, and vitamin B12 and clinical chemistry analyte levels were measured. MTHFR polymorphism was determined by polymerase chain reaction (PCR). IMT and plaques or stenosis in the common carotid were measured by ultrasonography. Serum Hcy was inversely correlated with vitamin levels and was slightly higher in subjects with the Val/Val genotype versus Ala/Val and Ala/Ala (P = .02); no differences in genotype were found in subjects with folate or vitamin B12 at or above the median level. In univariate analysis, common carotid IMT was significantly associated with age (P = .00001), the body mass index ([BMI] P = .0003), uric acid (P = .004), systolic blood pressure (P = .03), glycemia (P = .03), and total cholesterol (P = .04). No significant association was found between serum Hcy or MTHFR polymorphism and IMT. In multiple regression analysis, age (P = .0001), uric acid (P = .03), glycemia, and the BMI (P = .05) were independently associated with IMT and explained about 42% of IMT variability. In 130 NIDDM patients without nephropathy, basal levels of serum Hcy, as well as MTHFR polymorphism, did not predict significant changes in common carotid IMT.

Genetic variation in human stromelysin gene promoter and common carotid geometry in healthy male subjects.

A common variant in the promoter of the human stromelysin gene, causing reduced enzyme expression, has been associated with the progression of coronary atherosclerosis. On the other hand, increased stromelysin activity may promote plaque rupture. The present study was undertaken to investigate the relationship between the genetic variation in the human stromelysin gene promoter and common carotid geometry. Forty-two healthy male subjects without major coronary heart disease risk factors were investigated. The polymorphism in the stromelysin gene promoter was studied through polymerase chain reaction amplification with the use of mutagenic primers. Age, blood pressure, lipids, glucose, viscosity, and body mass index were similar in homozygotes for the 5A allele (5A/5A), heterozygotes (5A/6A), and homozygotes for the 6A allele (6A/6A). Serum matrix metalloproteinase-3 levels did not differ significantly among genotypes. Common carotid diameters and intima-media thickness, measured by noninvasive ultrasonography, were significantly larger in 6A/6A subjects (for respective 6A/6A, 5A/6A, and 5A/5A subjects, diameter at the R wave was 0.63+/-0.09, 0.55+/-0.06, and 0.53+/-0.04 cm [mean+/-SD], P<0.005 by ANOVA; intima-media thickness was 765+/-116, 670+/-116, and 630+/-92 microm [mean+/-SD], P<0.05 by ANOVA). Wall shear stress, calculated as blood velocityxblood viscosity/internal diameter, was significantly lower in 6A/6A subjects (for respective 6A/6A, 5A/6A, and 5A/5A subjects, mean wall shear stress was 10.4+/-2.9, 13.5+/-3.5, and 12.6+/-1.9 dyne/cm(2) [mean+/-SD], P<0.05 by ANOVA). The results demonstrate that the gene polymorphism in the promoter region of stromelysin is associated with structural and functional characteristics of the common carotid artery in healthy male subjects without major risk factors for atherosclerosis. Individuals with the 6A/6A genotype (associated with lower enzyme activity) show a triad of events, namely, increased wall thickness, enlarged arterial lumen, and local reduction of wall shear stress, which might predispose them to atherosclerotic plaque localization.

[Statins: similarities and differences in the pharmacological, clinical and laboratory aspects]. / Statine: analogie e differenze negli aspetti farmacologici, clinici e di laboratorio.

The inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase (or statins) are the most powerful drugs affecting lipid and lipoprotein levels in plasma. Results obtained from large controlled trials using simvastatin, pravastatin and lovastatin for the primary or secondary prevention of coronary heart disease have demonstrated that treatment with statins is associated with a significant reduction in coronary morbidity and mortality and in total mortality. This is probably due to a more general anti-atherogenic effect of these drugs beyond their lipid-lowering activity. Meta-analysis of data from these large trials indicates that statins have an impact also on the incidence of cerebrovascular events. Currently, six statins have been approved for therapeutic use in different countries. In spite of the similarities in their chemical structure and mechanisms of action, statins may differ in many aspects such as pharmacological properties (hydrophilic vs lipophilic, elimination half-life, cytochrome P450 metabolism, etc.), effects on lipid and other biochemical variables, or pleiotropic effects on different metabolic processes related to atherosclerosis (endothelial function, platelet aggregation, immune function, etc.). In general, the safety and tolerability profile for all statins currently in use is good with a < 2% incidence of undesirable effects.