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Background: Longitudinal Displacement (LD) is the relative motion of the intima-media upon adventitia of the arterial wall during the cardiac cycle, probably linked to atherosclerosis. It has a direction, physiologically first backward in its main components with respect to the arterial flow. Here, LD was investigated in various disease and in presence of a unilateral carotid stent., Methods: Carotid acquisitions were performed by ultrasound imaging on both body sides of 75 participants (150 Arteries). LD was measured in its percent quantity and direction., Results: Obesity (p = 0.001) and carotid plaques (p = 0.01) were independently associated to quantity decrease of LD in the whole population. In a subgroup analysis, it was respectively 143% in healthy (n = 48 carotids), 129% (n = 34) in presence of cardiovascular risk factors, 121% (n = 20) in MACE patients, 119% (n = 24) in the carotid contralateral to a stent, 110% (n = 24) in carotids with stents. Regarding the direction of LD, in a subgroup analysis an inverted movement was identified in aged (p = 0.001) and diseased (p = 0.001) participants who also showed less quantity of LD (p = 0.001), but independently with age only (p = 0.002) in the whole population., Conclusions: This observational study suggests that LD within carotid wall layers is lower additively with ageing, cardiovascular risk factors, cardiovascular diseases, and stent. Even if stent is surely beneficial, these data might shed some light on stent restenosis, emphasising the need for interventional studies.

Background: Statin therapy is a cornerstone of cardiovascular disease treatment and prevention. Unfortunately, 7%-29% of statin-treated patients complain of muscular fatigue, cramps, and/or pain (statin-associated muscle symptoms [SAMS]). In recent years, the important role of vitamin D in muscle health maintenance has been highlighted. In addition, hypovitaminosis D is very prevalent, and might be a reversible risk factor for SAMS occurrence. Methods: In our controlled intervention study, patients suffering from both SAMS and hypovitaminosis D underwent vitamin D replacement for 6 months. SAMS intensity and its impact on the quality of life were evaluated with a questionnaire during follow-up. A subgroup of patients who were not at the low-density lipoprotein cholesterol (LDL-C) target attempted a statin rechallenge after 3 months. Control subjects, with SAMS only, were not treated. Results: Blood vitamin D levels reached 261% of baseline values. Pain intensity was reduced by 63%, and all life quality indicators improved. At follow-up, percentage variations in SAMS intensity and in vitamin D levels were inversely related ( r  = 0.57, P  = 0.002). In a multiple regression analysis, this association was found to be independent. Among the rechallenge subgroup, 75% successfully tolerated high-intensity statins during the follow-up. The parameters of interest were unchanged in control subjects. Conclusions: In our findings, the amount of increase in vitamin D concentrations is directly related to SAMS improvement. Although randomized studies are needed, 25(OH)D levels can be measured, and eventually supplemented, in all patients suffering from SAMS, and this can be done together with a statin rechallenge after 3 months for patients who are not at the LDL-C target. Register: The study protocol was registered with the EudraCT clinical trial register [ID: 2019-003250-83] in date April 8, 2020.

Background: Type 1 diabetes (T1D) is frequently associated with autoimmune thyroiditis (AT) and coeliac disease (CD). Whether the coexistence of multiple autoimmune diseases increases cardiovascular risk is uncertain. We evaluated the effects of AT and CD on arterial wall thickening and endothelial function in patients with T1D., Methods: This observational study analyzed data from T1D patients regularly followed by the Diabetes Care Centre. Clinical and biochemical characteristics and micro and macrovascular complications were collected from the electronic medical records. All subjects performed Echo-Doppler to evaluate Intima-Media Thickness (IMT) of the common carotid artery (CCA) and endothelial function by the flow-mediated dilation (FMD) technique. The statistical analyses were performed by SPSS for Macintosh. Comparison between means was performed using the t-test for unpaired data and the Mann-Whitney U test. The ANalysis Of VAriance and the Tukey posthoc test were applied to compare patients with and without other autoimmune diseases, and control subjects. The p-value for statistical significance was set at p < 0.05., Results: A total of 110 patients were enrolled. Among these, 69 had T1D and 41 T1D and AT and or CD, of whom 33 AT, 7 CD, and 1 both AT and CD. The mean age was 35 years, mean HbA1c was 7.6%, and mean diabetes duration 18 years. The IMT of the CCA was not significantly different between T1D patients with and without concomitant autoimmune diseases (with AT and CD: right CCA 603 ± 186 µ, left 635 ± 175 µ; without AT and CD: right CCA 611 ± 176 µ, left CCA 631 ± 200 µ). FMD was also comparable between T1D groups, with AT and CD 7.9 ± 4.2%; without AT and CD 8.8 ± 4.4%., Conclusion: Patients with T1D and concomitant AT and or CD show no worse morphological or functional vascular damage, evaluated by CCA IMT and brachial artery flow-mediated dilation, than patients with T1D alone., (© 2022. The Author(s).)

Coronavirus disease 2019 (COVID-19) is a new viral disease complicating with acute thrombophylic conditions, probably also via an inflammatory burden. Anticoagulants are efficacious, but their optimal preventive doses are unknown. The present study was aimed to compare different enoxaparin doses/kg of body weight in the prevention of clot complications in COVID-19 pneumonia. Retrospective data from a cohort of adult patients hospitalized for COVID-19 pneumonia, never underwent to oropharyngeal intubation before admission, were collected in an Internal Medicine environments equipped for non-invasive ventilation. Unfavorable outcomes were considered as: deep venous thrombosis, myocardial infarction, stroke, pulmonary embolism, cardiovascular death. Fourteen clinical thromboembolic events among 42 hospitalized patients were observed. Patients were divided into two group on the basis of median heparin dose (0.5 mg-or 50 IU-for kg). The decision about heparin dosing was patient by patient. Higher enoxaparin therapy (mean 0.62±0.16 mg/kg) showed a better thromboprophylactic action (HR=0.2, p=0.04) with respect to lower doses (mean 0.42±0.06 mg/kg), independently from the clinical presentation of the disease. Therefore, COVID-19 pneumonia might request higher enoxaparin doses to reduce thromboembolic events in hospitalized patients, even if outside intensive care units., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: In this study, we aimed to highlight the common early-stage clinical and laboratory variables independently related to the acute phase duration in patients with uncomplicated coronavirus disease (COVID-19) pneumonia., Methods: In hospitalized patients, the acute phase disease duration was followed using the Brescia-COVID respiratory severity scale. Noninvasive ventilation was administered based on clinical judgment. Patients requiring oropharyngeal intubation were excluded from the study. For parameters to be measured at the hospital entrance, age, clinical history, National Early Warning Score 2 (a multiparametric score system), partial pressure of oxygen in arterial blood/fraction of inspired oxygen (P/F ratio), C-reactive protein, and blood cell count were selected., Results: In 64 patients, age (direct relationship), P/F, and platelet number (inverse relationship) independently accounted for 43% of the acute phase duration of the disease (P < .001)., Conclusions: For the first time, the present results revealed that the acute phase duration of noncomplicated pneumonia, resulting from severe acute respiratory syndrome coronavirus 2, is independently predicted from a patient's age, as well as based on the hospital entrance values of P/F ratio and peripheral blood platelet count., (© 2020 The Authors. Journal of Medical Virology Published by Wiley Periodicals LLC.)

Background: The relationship between blood viscosity (BV) and endothelial function is rather complex. An increase in BV causes an increase in blood flow resistance, with negative hemodynamic effects; on the other hand, a moderate increase in BV causes an increase in wall stress shear (WSS), and consequent beneficial effects. As a matter of fact, the effect of changes in BV on endothelial function is not yet clear., Objectives: Aim of the present study was to evaluate in-vivo the effects of the acute reduction in BV on endothelial function, in healthy male subjects., Methods: Fourteen healthy male blood donors were studied before and 48 hours after blood donation. Blood and plasma viscosity were measured at 37C° with a cone-plate viscometer. Endothelial function was evaluated through flow mediated vasodilation (FMD)., Results: Blood viscosity was reduced after blood donation (BV225 (cP) 4.53±0.59 vs.4.18±0.31, p < 0.05). FMD 50 s after cuff deflation was unchanged: 6.23±3.84 vs. 6.62±4.81, p = NS. The vasodilation, however, lasted longer and the area under the curve of FMD was significantly increased: 8.74±8.77 vs.16.14±8.65, p < 0.005., Conclusions: The present results demonstrate that the acute reduction of BV prolongs vasodilation, without affecting the amount of vasodilatation, possibly as adaptive reaction allowing more time for oxygen release.

Endothelial dysfunction, wall thickening and plaque are progressive manifestations of atherosclerosis. Delayed or absent brachial artery dilation after ischemic stimulus has been associated with severity of extracoronary and coronary atherosclerosis. In the current study, we aimed to verify if delayed or absent dilation associates with critical coronary stenosis. We also evaluated the association between coronary stenosis, carotid artery wall thickness and peripheral artery disease. Endothelial function was investigated by flow-mediated dilation of the brachial artery up to 3 min after ischemia, and patients classified as early, late or no dilators. Coronary angiography was performed through transradial or femoral artery approach. Computerized quantitative angiography was used to obtain percent stenosis of all lesions, while the Gensini score was used to evaluate the severity of coronary atherosclerosis. Seventy-four patients were enrolled. Carotid wall thickness and plaque, and peripheral artery disease were detected by ultrasound. Subjects with critical coronary stenosis showed a higher prevalence of delayed or absent dilation (coronary stenosis ≥70 per cent: late dilators 50 per cent, no dilators 35 per cent; coronary stenosis ≤70 per cent : late dilators 27 per cent, no dilators 6 per cent). The Gensini score was progressively higher in late dilators and no dilators compared with early dilators (early: 4.5±13.5; late 17.5±27.1; no 39.7±55.0; P<0.02). Carotid atherosclerosis and peripheral artery disease were more prevalent in subjects with critical coronary stenosis. Delayed or absent dilation associates with coronary stenosis and different degree of coronary atherosclerosis. The kinetic of arterial dilation seems to be relevant as the magnitude of dilation., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Blood viscosity (BV) might influence glucose delivery to peripheral tissues and play an important role in insulin resistance and diabetes mellitus. However, the exact relationship between BV and insulin resistance is not yet clear., Objectives: Aim of the present study is to evaluate the effects of the acute reduction in BV on insulin resistance, in healthy male subjects., Methods: Fifteen healthy male blood donors have been studied before and 48 hours after blood donation. Blood and plasma viscosity have been measured at 37°C with a cone-plate viscometer. Insulin resistance has been evaluated by euglycemic/hyperinsulinemic clamp in eight subjects, and by iHOMA2 Index in further seven subjects., Results: Blood viscosity was markedly reduced after blood donation (BV225 (cP) 4.53 ± 0.59 vs. 4.18 ± 0.31, p < 0.05). Insulin resistance was unchanged: MFFM clamp: 5.6 ± 4.5vs. 4.4 ± 2.2 and iHOMA2 Index 1.2 ± 0.6 vs. 1.2 ± 0.5, before vs. after respectively, p = NS. Blood pressure and lipids were unchanged after blood donation., Conclusions: The present results demonstrate that acute reduction of BV in healthy male subjects does not change the insulin resistance, measured using both euglycemic/hyperinsulinemic clamp and iHOMA2 Index. Further intervention studies are needed to assess the effect that the reduction in BV can have in subjects with insulin resistance.

The purpose of this work is to present and validate a novel approach for ultra-sound-based speckle tracking to measure the carotid artery longitudinal displacement, and to assess the apparent sliding between of Intima-Media Complex (IMC) and Adventitia (Ad) layers. This method utilizes feature detectors and descriptors to localize and track keypoints for local motion quantification. The procedure was tested and validated on an in silico dataset and on 18 heathy volunteers and 16 patients. Accuracy measured on in silico data gave a mean ± standard deviation of 23 ± 15 and 19 ± 18 μm for IMC and Ad respectively, and thus smaller than the pixel size (0.0925 mm). Robustness analysis was performed on in vivo images, obtaining a maximum variation coefficient, over 5 repeated measures, of 9.5 and 13.8% for IMC and Ad, respectively. The novel method capability for detecting the relative motion of IMC vs. Ad was compared with visual assessment performed by 2 physicians, leading to a correlation coefficient R of 0.7 in the worst case. (Healthy group scored by rater #1.) In conclusion, our results provide evidence that the novel method is able to accurately and reliably track carotid artery layer motion and that it overcomes limitations currently present in the literature, therefore providing an automatic tool for clinical evaluation of IMC vs. Ad relative displacement.

Background: In recent years, new measures of body adiposity have been introduced: lipid accumulation product (LAP), body adiposity index (BAI) and body shape index (ABSI). These indices have been demonstrated to better associate with cardiovascular disease than other measures of adiposity., Objectives: The aim of the present study was to evaluate if LAP or BAI better associate with blood viscosity than other measures of adiposity (body mass index, BMI; waist circumference, WC; waist-to-hip ratio, W/HR; waist-to-height ratio, W/HtR)., Methods: 344 subjects were recruited for the present investigation. Exclusion criteria were: diabetes, elevated triglycerides, smoking and drug use. Blood lipids and glucose were measured by routine methods. Blood and plasma viscosity were measured by a cone-plate viscometer. Adiposity measures were computed as previously described., Results: In simple correlation analyses, blood viscosity (BV) correlated with BMI, BAI, and LAP in males and with LAP in females. Correlations between plasma viscosity and adiposity indices were weak and not statistically significant. Other variables significantly related with BV were: gender, HDL- and LDL-Cholesterol, and triglycerides (p < 0.05). In multiple regression analysis only LAP was associated with BV., Conclusions: Our data suggest that LAP index is strongly associated to blood viscosity. This result, along with previous evidence, identifies LAP index as a potential cardiovascular risk marker.

Background and Aims: Atherosclerosis is associated with clinical, biochemical and haemodynamic risk factors. In a group of subjects studied twelve years apart, we evaluated carotid plaque development in relation to baseline and to changes at follow-up in common carotid haemodynamic profile., Methods: Forty-eight participants were recruited to a cardiovascular disease prevention programme. Atherosclerotic plaques were evaluated and scored by echography. Endothelial shear stress, circumferential wall tension, and Peterson's elastic modulus as an index of arterial stiffness, were computed by echo-Doppler, along with blood viscosity data. Binary logistic regression analyses were used to test the association among the development of atherosclerosis, cardiovascular risk factors and haemodynamic variations. Analyses were also performed on participants who presented at the follow-up with carotid haemodynamic variations in the left or right common carotid only., Results: Participants (69% male) were aged 64.5 ± 9.7 years at follow-up. Peak and mean endothelial shear stress was significantly lower at follow-up as previously reported; circumferential wall tension and arterial stiffness were significantly higher. Carotid plaque scores increased after 12 years (0.39 ± 0.72 vs. 0.67 ± 0.86, p < 0.01). Of the 96 common carotids analysed, shear stress reduction with aging was an independent predictor of carotid atherosclerosis (B = -0.063; odds ratio = 0.94; p = 0.01). Out of 48 participants, 21 (44%) showed shear stress reduction with aging in only one side of the body and, on this side, the plaque score increased (0.52 ± 0.98 vs. 0.90 ± 0.94, p < 0.05), remaining unchanged in the contralateral carotid tree., Conclusions: Aging-related shear stress reduction is an independent predictor of atherosclerosis development., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

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, β-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.

High blood viscosity is associated with increased peripheral resistance and high blood pressure (BP). Prehypertension refers to a systemic BP of 120-139 mm Hg systolic (SBP) and/or 80-89 mm Hg diastolic (DBP). Subjects with prehypertension have an increased risk of overt hypertension and incident cardiovascular disease compared with subjects who have optimal BP. In the present study, we investigated the hemorheological profiles of subjects with prehypertension. A total of 418 apparently healthy subjects were enrolled. BP, plasma lipids and glucose were measured using routine methods. Blood and plasma viscosity were measured using a cone-plate viscometer. The participants were grouped according to BP into the following categories: 'normotensive' (n=100), 'prehypertensive' (n=172), and 'hypertensive' (n=146). The blood viscosity, plasma viscosity and hematocrit of the prehypertensive subjects were higher than those of the normotensive subjects (P<0.01), but they were comparable to those of the hypertensive subjects. In simple correlation analyses, SBP and DBP were directly and significantly correlated with age, body mass index (BMI), blood glucose, hematocrit, plasma viscosity and blood viscosity. In multiple regression analyses, age, fasting blood glucose and plasma viscosity were independently related with SBP, whereas blood viscosity, fasting blood glucose and BMI significantly predicted DBP. These data demonstrate that BP in the range of so-called prehypertension is accompanied by important hemorheological changes, which are similar to those observed in people with overt hypertension. These results could explain the increased cardiovascular risk observed in these subjects as well as their susceptibility to hypertension.

Objective: Red blood cell distribution width (RDW) is a numerical measure, reported as part of a standard complete blood count, usually employed for differential diagnosis of anemic state. Some lines of evidence demonstrate that RDW associates with type 2 diabetes incidence and its complications. To further explore the role of RDW as predictor of abnormal glucose metabolism, we have analyzed the relationship between RDW and 2-hours plasma glucose concentration during an oral glucose tolerance test (OGTT)., Methods: Forty-five outpatients were enrolled for the present study. Participants underwent 75 g OGTT and measurements of hematological parameters. Cardiovascular disease risk factors (blood pressure, blood lipids, cigarette smoking, obesity) were evaluated by routine methods., Results: In simple regression analysis 2-hours post-load glucose was directly associated with age (r = 0.36, p = 0.01), fasting glucose levels (r = 0.40, p = 0.002) and RDW (r = 0.31, p = 0.037). In multiple regression analysis fasting glucose, RDW, triglycerides and age significantly and independently predicted 2-hours plasma glucose (p <  0.01 for all coefficients)., Conclusion: The present findings demonstrate that RDW associates with plasma glucose concentration after a 75-g oral glucose tolerance test. Our results highlight the role of RDW as predictor of glucose metabolism disturbance.

Aim: Flow-mediated vasodilation (FMD) of the brachial artery measures the ability of the artery to dilate after a forearm ischemia lasting for 5 min. During ischemia, and therefore in conditions of low flow, constriction of the brachial artery (L-FMC) has sometimes been reported. The meaning of L-FMC is still unclear. The aims of our study were to establish the prevalence of subjects with L-FMC, to determine whether the magnitude of L-FMC correlates with magnitude of FMD, and to determine whether L-FMC can be used to predict FMD timing., Methods: A total of 179 outpatients were studied, and the brachial artery diameter was measured every minute during the 5 min forearm ischemia. Subjects who had at least one measurement showing a constriction of ＞ 1% during ischemia were defined as constrictors. FMD was evaluated at 50 s, 2 min, and 3 min after cuff release. On the basis of time, the subjects in whom maximal dilation had occurred were divided into Early, Late, or No dilators., Results: The brachial artery diameter of 70 subjects (39%) constricted during ischemia. Higher the constriction during ischemia, lower was the dilation after ischemia. Constrictors were more likely to have Late (OR 2.6; ICs 95% 1.19-5.81, p=0.02) or No dilation (OR 4.8; ICs 95% 1.90-12-16, p=0.02) compared with no constrictors., Conclusions: The present study reveals that almost 40% of the subjects had brachial artery L-FMC and a more pronounced constriction during ischemia correlated with a lower dilation after ischemia. Finally, the prevalence of subjects showing L-FMC was significantly higher among subjects with delayed or no vasodilation, suggesting that L-FMC may be a marker of endothelial dysfunction.

Objective: Elastic properties of the vessel wall are associated with atherosclerosis and major cardiovascular events. Several physiological and pathological conditions can affect arterial elasticity, but few studies have considered the role of hemorheological parameters. The present study aimed to investigate the relationship between hemorheological parameters and vascular stiffness in the carotid artery district., Methods: One hundred and two individuals were enrolled. Blood and plasma viscosity were measured by a cone-plate viscometer (Wells-Brookfield DV-III, Stoughton, U.S.A.). Echo-Doppler evaluation of carotid arteries was performed in order to calculate elastic indexes (strain, β-stiffness index and distensibility). The association between hemorheological parameters and carotid elasticity indexes was assessed by simple and multiple regression analyses., Results: In simple correlation analysis, only blood viscosity was directly associated with β-stiffness index (r = 0.20, p = 0.05) and inversely with strain (r =-0.26, p = 0.01) and distensibility (r =-0.34, p = 0.001). After adjusting for cardiovascular risk factors, blood viscosity, but not plasma viscosity or hematocrit, was independently associated carotid arterial measures, together with age, obesity, hypertension, and dyslipidemia., Conclusions: The results of the present study demonstrate a strong association between blood viscosity and common carotid elasticity indexes.

Periodontal disease is associated with endothelial dysfunction of the brachial artery and hemodynamic alterations of the common carotid artery. Periodontal therapy improves endothelial function. It is not known if it is able also to improve the hemodynamics of the carotid artery. The aim of the current study was to evaluate the efficacy of 2 different periodontal treatments on carotid hemodynamics: scaling and root planing (SRP) alone or together with low-level laser therapy (LLLT). Forty patients were recruited and randomly treated with SRP (n = 20) or SRP + LLLT (n = 20). Periodontal indices (plaque, gingival, and probing depth indices) were measured before and 5 months after treatment. Blood viscosity, common carotid wall shear stress, circumferential wall tension, and Peterson elastic modulus were evaluated before, soon after and 5 months after treatment. It was found that the periodontal indices improved in both groups, but significantly more so for SRP + LLLT than for SRP (decrease in gingival index 69.3% versus 45.4%, respectively, P = 0.04). In the SRP + LLLT group, after a transient reduction by 5% immediately after therapy, shear stress increased by 11% after 5 months. In SRP only group, however, shear stress variations were less marked. No significant changes were found for the other hemodynamic parameters in either of the groups. Periodontal disease treatment by SRP + LLLT can therefore be said to improve common carotid wall shear stress. This suggests a possible mechanism by which the treatment of periodontal disease has beneficial effects on the cardiovascular system.

Objectives: The aim of the study was to identify factors associated with progressive beta-cell failure in a cohort of nonselected subjects with type 2 diabetes., Methods: Two hundred twenty-four medical records were evaluated. Progressive beta-cell failure was defined as the following: glycated hemoglobin is higher than 7.5% despite combined drug therapy and appropriate diet (ie, isocaloric or hypocaloric diet depending on body weight) and absence of any illness causing acute hyperglycemia. The following factors were considered as possible predictors: diabetes-related symptoms, fasting plasma glucose at the onset of disease, family history of type 2 diabetes, number of visits per year, and residency. Further potential predictors were disease duration, age, body mass index, estimated glomerular filtration rate, and hypertension and/or hyperlipidemia at the enrollment in the study., Results: The prevalence of beta-cell failure was 41%. Independent predictors of failure were longer disease duration (hazard ratio [HR] for each year of diabetes, 1.03; confidence intervals (CIs), 1.01-1.05; P = 0.03), history of hypertension (HR, 1.90; CIs, 1.73-2.89; P = 0.04), hyperlipidemia (HR, 1.65; CIs, 1.06-2.58; P = 0.03), residence in suburb (HR, 1.78; CIs, 1.06-3.01; P = 0.03), and presence of symptoms at the onset of disease (HR, 2.47; CIs, 1.51-4.03; P = 0.0001)., Conclusions: Patients with long disease duration, hypertension, and hyperlipidemia who are residents in suburbs and had diabetes-related symptoms at diagnosis might deserve intensive treatment to obtain adequate and stable glycemic control.

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.

Background: Type 2 diabetes mellitus T2DM has a huge and growing burden on public health, whereas new care models are not implemented into clinical practice; in fact the purpose of this study was to test the effectiveness of a program of integrated care for T2DM, compared with ordinary diligence., Methods: "Progetto Diabete Calabria" is a new organizational model for the management of patients with diabetes mellitus, based on General Practitioners (GPs) empowerment and the use of a web-based electronic health record, shared in remote consultations among GPs and Hospital Consultants. One-year change in glucose and main cardiovascular risk factors control in 104 patients (Cases) following this integrated care program has been evaluated and compared with that of 208 control patients (Controls) matched for age, gender, and cardiometabolic profile, and followed in an ordinary outpatient medical management by the Consultants only. Both patient groups had Day Hospitals before and after the study period., Results: The mean number of accesses to the Consultants during the study was 0.6 ± 0.9 for Cases, and 1.3 ± 1.5 for Controls (p<0.0001). At follow-up, glycated hemoglobin (HbA1c) significantly decreased from 58 ± 6 to 54 ± 8 mmol/mol in Cases only (p=0.01); LDL cholesterol decreased in both groups; body mass index decreased in Cases only, from 31.0 ± 4.8 to 30.5 ± 4.6 kg/m(2) (p=0.03)., Conclusions: The present study demonstrates that a health care program based on GPs empowerment and taking care plus remote consultation with Consultants is at least as effective as standard outpatient management, in order to improve the control of T2DM.

Purpose: Flow-mediated dilation (FMD) is a complex mechanism involving several mediators, and different hemodynamic forces. Temporally distinct FMD patterns can be elicited by ischemic stimulus. Some subjects dilate early after cuff release, while others dilate later or do not dilate at all. Aim of the present research was to verify if hemorheological and hemodynamic factors might influence different FMD pattern., Methods: 148 free-living subjects were studied. FMD was measured at 50 s, 2 min and 3 min. Blood viscosity was measured and shear stress calculated. Shear stress stimulus was quantified as the area under the curve after ischemia (SSAUC) over the first 40-s post-occlusion., Results: Based on the timing or absence of arterial dilation, 82 subjects were classified as Early dilators, 37 as Late dilators and 29 as No dilators. Peak FMD was 7.9 ± 4.3 % in Early dilators, and 9.1 ± 5.7 in Late dilators (p = NS). SSAUC was not significantly different among three groups, while blood viscosity was significantly higher in Late FMD subjects. Regression analyses showed the independent predictive role of age and blood viscosity on FMD patterns, and the lack of any association between FMD pattern and the magnitude of SS., Conclusions: The present study demonstrates that age and blood viscosity but not the magnitude of SS explain the different timing of the dilatory response to ischemia.

Objective: Heparin-induced Extracorporeal Low Density Lipoprotein Precipitation (HELP) Apheresis gives beneficial reductions in Low Density Lipoprotein (LDL) cholesterol levels; otherwise, extracorporeal circulation settings might elicit inflammation and platelet aggregation. The net effect of these variations on carotid hemodynamic has not been established. Aim of the present study was to investigate periprocedural variations of common carotid artery wall shear stress, circumferential wall tension, and Peterson's elastic modulus., Methods: Measurements were sequentially performed on 22 procedures: immediately before apheresis (T1), within one hour after (T2), after 24 (T3) and 48 hours (T4). In order to confirm acute effects, in additional 30 procedures measurements were performed at T1 and T2., Results: Mean shear stress was decreased at T2, with an improvement at T4. Mean circumferential wall tension showed an improvement at T4; arterial stiffness showed the same trend, but only close to statistical significance. The following 30 procedures, where measurements were performed at T1 and T2 only, confirmed previous results, showing a deep wall shear stress decrease at T2 (-21%)., Conclusion: LDL apheresis seems to have a biphasic effect on common carotid hemodynamics: the acute worsening of shear stress, probably mediated by extracorporeal circulation, was followed by its improvement, possibly driven by LDL cholesterol reduction.

Objective: Peripheral artery occlusive disease (PAOD) is associated with increased cardiovascular risk (CVR). Recently it has been reported that also the increased stiffness of lower limb arteries is associated with increased CVR. In particular, subjects with poorly compressible arteries (PCA) appear to have a CVR even higher than that of subjects with PAOD. Limited data are available on the role of hemorheological factors in determining increase in arterial stiffness. Our study aimed to investigate possible association between blood and plasma viscosity and elevated ankle brachial index (ABI)., Methods: Subjects were free-living participants to a cardiovascular disease screening campaign. Sixty-two subjects with ABI ranging 1.3-1.4, and 20 with ABI >1.4 were matched with 124 and 40 control subjects, respectively. Cardiovascular disease risk factors (blood pressure, blood lipids, glucose, cigarette smoking, obesity) were evaluated by routine methods. Blood and plasma viscosities were measured by a cone-plate viscometer. Ankle-brachial index was computed as measure of arterial stiffness., Results: Compared with controls, who were carefully matched for age, sex and all cardiovascular risk factors, subjects with elevated ABI values had increased levels of plasma viscosity (1.42 ± 0.11 vs. 1.35 ± 0.10 cP, p <  0.001, for subjects with ABI ranging 1.3-1.4, and 1.41 ± 0.10 vs. 1.33 ± 0.10 cP, p <  0.01, for subjects with ABI >1.4). No difference in blood viscosity was observed., Conclusion: The present investigation provides evidence that plasma viscosity is increased in subjects with elevated ABI values, independently of other cardiovascular risk factors. This finding contributes to explain the high CVR of patients with PCA.

The interaction between platelets and endothelium in vivo is a complex phenomenon. Our aim was to develop an in vitro system that mimics the in vivo environment and investigate platelet function in a common pathological condition. Human umbilical vein endothelial cells were used and platelets from 28 type 2 diabetes patients were studied under shear stress conditions. Mean coefficient of variation of platelet aggregation was 10% in dynamic conditions in the presence of endothelium. Endothelial cells increased the concentration of inductor needed to achieve 50% platelet aggregation to adenosine diphosphate from 2.6 ± 1.3 in static conditions to 3.7 ± 1.3 µM in dynamic conditions. A similar pattern was observed when collagen was used for platelet activation. Incubation of endothelium with a nitric oxide inhibitor abolished this effect, indicating platelet inhibitory effect of endothelial cells is nitric oxide mediated. Platelet reactivity of healthy controls was less influenced by the presence of endothelial cells and displayed reduced basal platelet reactivity compared with platelets from diabetes patients. We show that platelet aggregation in diabetes as commonly reported in vitro may not fully reflect the in vivo pathophysiological process. Future studies are warranted to investigate other pathological conditions and analyse the effects of antiplatelet agents using this system., (© The Author(s) 2014.)

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.

Vascular adhesion and endothelial transmigration are critical steps in the establishment of distant metastasis by circulating tumor cells (CTCs). Also, vascular inflammation plays a pivotal role in steering CTCs out of the blood stream. Here, long circulating lipid-polymer nanoparticles encapsulating curcumin (NANOCurc) are proposed for modulating the vascular deposition of CTCs. Upon treatment with NANOCurc, the adhesion propensity of highly metastatic breast cancer cells (MDA-MB-231) onto TNF-α stimulated endothelial cells (HUVECs) reduces by ~70%, in a capillary flow. Remarkably, the CTCs vascular deposition already reduces up to ~50% by treating solely the inflamed HUVECs. The CTCs arrest is mediated by the interaction between ICAM-1 on HUVECs and MUC-1 on cancer cells, and moderate doses of curcumin down-regulate the expression of both molecules. This suggests that NANOCurc could prevent metastasis and limit the progression of the disease by modulating vascular inflammation and impairing the CTCs arrest., From the Clinical Editor: In this novel study, lipid nanoparticles encapsulating curcumin were able to prevent metastasis formation and limited the progression of the disease by modulating vascular inflammation and impairing the circulating tumor cells' arrest as a result of down-regulation of ICAM1 and MUC1 in a highly metastatic breast cancer cell line model., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Flow-mediated dilation (FMD) of the brachial artery is widely used to assess cardiovascular risk. In recent years, much attention has been paid to the kinetics of vasodilation in an attempt to better characterize the endothelial function. Here, we investigated whether FMD magnitude and/or latency are most related to individual cardiovascular risk., Materials and Methods: Four hundred subjects were recruited. Individual risk prediction was estimated by Framingham cardiovascular risk score and CUORE project calculator. Subjects were divided into Early dilators (peak FMD at 50 s), Late dilators (peak FMD over 50 s) and No dilators., Results: Cardiovascular risk was highest in No dilators and significantly higher in Late than Early dilators despite comparable peak FMD. When divided according to peak FMD quintiles, Early and Late dilators showed decreased cardiovascular risk with increasing magnitude of vasodilation. However, subjects in the first three quintiles of Late dilators had a markedly higher risk score despite a peak vasodilation similar to that of Early dilators., Conclusion: These results suggest that the magnitude of the FMD and its latency are both important for identifying patients at risk of cardiovascular disease. Subjects with a delayed though significant vasodilation associated with a blunted early response exhibit the highest cardiovascular risk., (© 2014 Stichting European Society for Clinical Investigation Journal Foundation.)

Objective: Blood viscosity (BV) is higher in diabetic patients and might represent a risk factor for the development of insulin resistance and type 2 diabetes. However, data in subjects with normal glucose or prediabetes are missing. In the current study, we evaluated the relationship between BV and blood glucose in subjects with normal glucose or prediabetes., Research Design and Methods: Enrolled subjects were divided into three groups according to blood glucose: group A (n = 74), blood glucose <90 mg/dL; group B (n = 96), blood glucose ranging from 90 to 99 mg/dL; and group C (n = 94), blood glucose ranging from 100 to 125 mg/dL. BV was measured at 37°C with a cone-plate viscometer at shear rates ranging from 225 to 22.5 s(-1)., Results: Blood pressure, blood lipids, fibrinogen, and plasma viscosity were similar in the three groups. BMI and waist circumference were significantly increased in group C. Hematocrit (P < 0.05) and BV (P between 0.01 and 0.001) were significantly higher in groups B and C compared with group A. Blood glucose was significantly and inversely correlated with HDL cholesterol and directly with BMI, waist, hematocrit (r = 0.134), and BV (from 225 s(-1) to 22.5 s(-1); r ranging from 0.162 to 0.131). BV at shear rate 225 s(-1) was independently associated with blood glucose., Conclusions: The current study shows a direct relationship between BV and blood glucose in nondiabetic subjects. It also suggests that, even within glucose values considered completely normal, individuals with higher blood glucose levels have increased BV comparable with that observed in subjects with prediabetes.

Objectives: Alterations in wall shear stress contribute to both clinical and subclinical atherosclerosis. Several conditions such as hypertension, diabetes, and obesity can impair shear stress, but the role of insulin resistance has never been investigated. The present study was designed to investigate whether insulin resistance assessed by TyG Index associates with wall shear stress in the common carotid artery., Methods: One hundred six individuals were enrolled. Blood pressure, lipids, glucose, and cigarette smoking were evaluated. TyG Index was calculated as log[fasting triglycerides × fasting glucose / 2]. Subjects underwent blood viscosity measurement and echo-Doppler evaluation of carotid arteries to calculate wall shear stress. The association between TyG Index and carotid wall shear stress was assessed by simple and multiple regression analyses., Results: TyG Index was significantly and inversely associated with carotid wall shear stress both in simple (r = -0.44, P < 0.001) and multiple regression analyses accounting for age, sex, and major cardiovascular risk factors. The association was further confirmed after exclusion of subjects with diabetes, dyslipidemia, fasting blood glucose greater than 100 mg/dL, and triglycerides greater than 150 mg/dL., Conclusions: The present findings suggest that increasing insulin resistance, as assessed by TyG Index, associates with atherosclerosis-prone shear stress reduction in the common carotid artery.

Background and Aim: The relationship between hyperlipidemia and blood and plasma viscosity is not completely clear. While increasing viscosity is often reported with increasing blood lipids, lipid-lowering treatments are often unable to normalize the viscosity values. Aim of this study is to try to clarify the relationship between blood lipids and viscosity., Methods and Results: Apparently healthy subjects were enrolled (n = 410). Smokers, diabetics, obese, and hypertriglyceridemic (above 400 mg/dl) were excluded. Blood (at shear rate 225/s) and plasma viscosity were measured at 37°C. Erythrocyte rigidity (Tk) was calculated according to Dintenfass. Blood lipids and glucose were measured by routine methods. Hyperlipidemic subjects (n = 315) had higher values of plasma viscosity (1.44 ± 0.13 vs. 1.40 ± 0.12 cP, p = 0.007), and blood viscosity (4.51 ± 0.54 vs. 4.35 ± 0.55 cP, p = 0.013), compared to normolipidemic subjects (n = 95). In simple correlation analysis, plasma viscosity was directly associated with LDL cholesterol, and inversely with Tk and HDL cholesterol. In multiple regression analysis the association with LDL and HDL was strengthened, though these two variables as a whole accounted for only 5% (adjusted R2) of the variability of plasma viscosity. Blood viscosity was significantly associated with haematocrit, plasma viscosity, Tk and all considered variables but age in simple correlation analysis, but only with haematocrit, plasma viscosity and Tk in multiple regression analysis., Conclusions: LDL cholesterol and HDL cholesterol influence plasma viscosity, but not blood viscosity. Triglycerides up to values of 400 mg/dl do not seem to have important effects, at least in apparently healthy subjects and at the shear rates used in the present study. The contribution of LDL and HDL cholesterol to plasma viscosity seems however quite limited.

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., (© 2013 John Wiley & Sons Ltd.)

Aim: In patients affected by periodontal disease, hypertension and systemic inflammation might cause an arterial hemodynamic derangement; this, in turn, can act as a mediator of the atherogenic process often seen in these patients. This study aimed at a comprehensive hemodynamic evaluation in periodontal patients., Methods: Fourty-eight subjects participating to a cardiovascular prevention programme were enrolled. Periodontitis, classical risk factors for atherosclerosis, and shear and tensile forces in both carotid and brachial arteries were evaluated. Calculated periodontal indexes were plaque, gingival and pocket deep (PD) indexes. Simple and multiple regression analyses were performed. Afterwards, 30 of them with normal PD index were compared with 30 carefully - matched patients with periodontitis., Results: Brachial and carotid parietal tension were significantly associated with periodontal indexes, especially PD-Sum, in both simple (r = 0.42, p < 0.001 for carotid artery and r = 0.36, p < 0.02 for brachial artery) and multiple regression analyses. Shear stress gave similar results. In case-control analysis, shear stress was lower by 15% and 30%, respectively, in carotid and brachial artery in patients with high PD; common carotid parietal tension was higher. Arterial stiffness resulted not associated with periodontitis., Conclusions: Periodontal disease is associated to a complex atherosclerotic prone hemodynamic derangement, particularly in large elastic arteries., (© 2013 John Wiley & Sons A/S.)

Objective: The influence of lipids on blood and plasma viscosity has not been fully elucidated. In this study we evaluated the contribution of HDL cholesterol to blood and plasma viscosity, in healthy subjects., Methods: One hundred and forty-four (80 males and 64 females) subjects were enrolled among free-living participants to a cardiovascular disease screening. Exclusion criteria were: diabetes, elevated triglycerides, elevated LDL cholesterol, smoking and drug use. Blood lipids were measured by routine methods. Blood and plasma viscosity were measured by a cone-plate viscometer (Wells-Brookfield DV-III, Stoughton, U.S.A.). Subjects were divided in two groups: at low (<50 mg/dl) and high HDL cholesterol (>50 mg/dl)., Results: Blood and plasma viscosity were similar in subjects at low and high HDL cholesterol. In univariate analysis none of the lipid variables was significantly correlated with blood and/or plasma viscosity. In multivariate analysis only LDL cholesterol was marginally associated with blood viscosity., Conclusion: HDL cholesterol does not influence blood and plasma viscosity in healthy normolipidemic subjects. LDL cholesterol is marginally associated with blood viscosity.

Background: In a previous study, we identified temporally distinct postischaemic flow-mediated dilation (FMD) patterns comparing the standard clinical measurement time of 50s postcuff release with measurement at 2 min. The comparison revealed a cohort with the highest FMD at 50s (Early FMD), another cohort with the highest FMD at 2 min (Late FMD) and a third cohort with no FMD (Absent FMD). The aim of this study was to examine whether these temporally distinct FMD patterns associated with different degrees of carotid atherosclerosis., Materials and Methods: One hundred and twenty-four free-living white subjects, participating in a cardio-vascular disease prevention campaign, were enrolled. FMD was measured at 50s, 2 min and 3 min after forearm ischaemia. The intima-media thickness (IMT) of the common carotid artery was measured, and the artery was evaluated for the presence and number of carotid plaques., Results: Fifty-seven subjects had Early FMD, 34 had Late FMD and 33 had Absent FMD. The three groups were comparable for age, sex and cardiovascular risk factors. The number of plaques in the carotid arteries, and IMT, increased progressively from Early, to Late, and to Absent FMD (P < 0·03), indicating that the FMD pattern is an independent predictive variable for IMT and carotid atherosclerosis., Conclusions: The present study demonstrates that temporal patterns associated with the degree of atherosclerosis of the carotid arteries. Patients with delayed vasodilation (Late FMD) had a higher degree of atherosclerosis than those with early vasodilation (Early FMD), and subjects with no postischaemic vasodilation (Absent FMD) had the most atherosclerosis., (© 2012 The Authors. European Journal of Clinical Investigation © 2012 Stichting European Society for Clinical Investigation Journal Foundation.)

The GLP-1 receptor agonist exenatide has been approved for adjunctive treatment of type 2 diabetes. Continuous GLP-1 infusion improves endothelial function in vivo; no evidence about a beneficial effect of exenatide on vascular function has been published. The aim of our observational study was to evaluate whether exenatide would improve brachial artery function evaluated by the flow mediated dilation (FMD) technique, compared with glimepiride, in subjects with type 2 diabetes. FMD time course was assessed by ultrasound, after 5 min forearm ischaemia, at baseline and after 16-week treatment. At the end of the study FMD was significantly higher in subjects who assumed exenatide compared with glimepiride (9.1 ± 3.6 vs. 5.6 ± 1.0, p = 0.01). Even if limited by the small number of studied subjects, who were not matched in the two treatment groups, this research study represents the first FMD evidence suggesting that chronic administration of exenatide improves arterial dilation.

Hemodynamic forces play a role in the development of atherosclerosis. Their variations with age have been assessed in cross-sectional, but not longitudinal, studies. The aim of the present study was to investigate in both sexes the age-dependent change in wall shear stress and arterial stiffness in subjects studied twice 12 years apart. Forty-eight subjects (15 women and 33 men) were studied twice 12 years apart. Subjects underwent blood viscosity measurement and echo-Doppler of carotid arteries, from which the intima-media thickness (IMT) was measured and the wall shear stress and Peterson's elastic modulus were calculated. Blood viscosity increased in both sexes, more markedly in women (+13.2%) than men (+7.2%). Common carotid diameter increased in both sexes, but in men (+7.4%) more than in women (+5.5%). Peak and mean velocity decreased at follow-up by 10.7% and 18.9% in women and by 14.2% and 18.1% in men. Peak and mean shear stress significantly decreased in men by 13.0% and 17.5%, respectively, while in women only the mean shear stress was reduced (-11.8%). The IMT of the common carotid artery increased by 29% in women and 20% in men. Arterial stiffness significantly increased (+74.5% in women and +28.0% in men). The percent change in mean shear stress was significantly and inversely associated with the percent change in IMT. The data of this study show that, in a middle-aged population observed for almost 12 years, the mean shear stress decreases significantly in both sexes, while peak shear stress decreases significantly only in men. The change in mean shear stress is inversely associated with changes in IMT. Arterial stiffness, on the other hand, increases with aging.

The spreading of tumor cells to secondary sites (tumor metastasis) is a complex process that involves multiple, sequential steps. Vascular adhesion and extravasation of circulating tumor cells (CTCs) is one, critical step. Curcumin, a natural compound extracted from Curcuma longa, is known to have anti-tumoral, anti-proliferative, anti-inflammatory properties and affect the expression of cell adhesion molecules, mostly by targeting the NF-κB transcription factor. Here, upon treatment with curcumin, the vascular behavior of three different estrogen receptor negative (ER(-)) breast adenocarcinoma cell lines (SK-BR-3, MDA-MB-231, MDA-MB-468) is analyzed using a microfluidic system. First, the dose response to curcumin is characterized at 24, 48, and 72 h using a XTT assay. For all three cell lines, an IC(50) larger than 20 µM is observed at 72 h; whereas no significant reduction in cell viability is detected for curcumin concentrations up to 10 µM. Upon 24 h treatment at 10 µM of curcumin, SK-BR3 and MDA-MB-231 cells show a decrease in adhesion propensity of 40% (p = 0.02) and 47% (p = 0.001), respectively. No significant change is documented for the less metastatic MDA-MB-468 cells. All three treated cell lines show a 20% increase in rolling velocity from 48.3 to 58.7 µm/s in SK-BR-3, from 64.1 to 73.77 µm/s in MDA-MB-231, and from 57.5 to 74.4 µm/s in MDA-MB-468. Collectively, these results suggest that mild curcumin treatments could limit the metastatic potential of these adenocarcinoma cell lines, possibly by altering the expression of adhesion molecules, and the organization and stiffness of the cell cytoskeleton. Future studies will elucidate the biophysical mechanisms regulating this curcumin-induced behavior and further explore the clinical relevance of these findings.

Incident diabetes and the worsening of diabetes have recently been linked to hepatic steatosis. Aim of our study was to determine whether oral hypoglycemic agent failure is associated with higher transaminase levels (valid measure of liver steatosis). We selected 200 patients, attenders (3 consecutive annual evaluations) in our clinic, with type 2 diabetes among which 100 with oral hypoglycemic agents failure and 100 who were still responsive to oral therapy. Failure to therapy was defined as glycated hemoglobin >7.5% despite maximal-dose oral therapy. We analyzed patient histories and laboratory data. Compared with oral-therapy-responsive patients, those with failure had a significantly higher level mostly of alanine aminotransferase at the time of therapy failure and 2 years before. They were more likely to have had symptoms of hyperglycemia at the time of diabetes diagnosis. Regression analysis indicated that each 5-unit increase in transaminase levels independently increased the risk for oral hypoglycemic agents failure by 1.70. Higher liver transaminase levels, especially in patients who had symptomatic hyperglycemia at diabetes diagnosis, associate with oral hypoglycemic agent failure. The possible pathogenetic link between transaminase and declining islet function might consist of insulin resistance and increased circulating fatty acid levels, in turn causing liver steatosis and beta-cell dysfunction.

Objective: A direct relationship between blood pressure and viscosity has frequently been reported, although clear data are not available. To better understand the relationship between these two variables, we evaluated blood viscosity and blood pressure in a group of healthy subjects without cardiovascular risk factors., Methods: Healthy subjects were selected from participants in a campaign of prevention of cardiovascular disease (n = 103). They underwent blood sampling for measurement of plasma and blood viscosity, haematocrit, blood lipids and glucose. The quantity and distribution of body fat was assessed by body mass index and waist/hip ratio, respectively., Results: Systolic blood pressure (SBP) correlated significantly with age (r = 0.222) and waist/hip ratio (r = 0.374). Diastolic blood pressure (DBP) correlated significantly with waist/hip ratio (r = 0.216), haematocrit (r = 0.333) and blood viscosity (r = 0.258). Multiple linear regression analyses demonstrated that the only variable significantly associated with SBP was age, while haematocrit was the only variable significantly associated with DBP. Blood viscosity was closely related to waist/hip ratio., Conclusion: These findings show that SBP, in healthy subjects, is not influenced by haematocrit and blood viscosity. In contrast, DBP is related to the values of haematocrit. Among classical cardiovascular risk factors, waist/hip ratio is closely related to blood viscosity.

Background: Daily glycemic fluctuation leads to development of long-term complications. The aim of our pilot study was to determine if exenatide reduces glycemic variability, assessed with a continuous glucose monitoring (CGM) system, compared with glimepiride., Methods: We enrolled six consecutive subjects with type 2 diabetes, for whom exenatide was suggested as second-line treatment, and six control subjects, for whom glimepiride was suggested as second-line treatment. CGM was performed at baseline and after 16 weeks of treatment. As measures of glycemic variability we calculated the total daily mean glucose (MG), SD, and mean amplitude of glycemic excursions (MAGE)., Results: Exenatide significantly reduced MG, SD, and MAGE, whereas glimepiride did not. Fasting glucose and glycated hemoglobin were lowered in both groups, even if the reduction was not significant., Conclusion: Exenatide can reduce glycemic variability compared with glimepiride, providing additional beneficial effects in controlling glucose homeostasis.

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.

Objective: The link between periodontal disease and atherosclerosis has not yet been clarified, though systemic inflammation seems to be the common soil for both conditions. Inflammation influences also hemodynamic forces, that act as local risk factors for carotid plaques. It is not known if the link between periodontitis and carotid atherosclerosis is mediated, at least in part, by physical forces. Therefore, aim of the present study was to evaluate the association between carotid shear stress force and periodontal disease., Methods: Thirty-three subjects underwent complete cardiovascular screening, carotid hemodynamic evaluation and dental inspection. Presence of classical risk factors for atherosclerosis, common carotid peak and mean wall shear stress values and periodontal indices of disease (plaque index, gingival index and pocket deep) have been evaluated., Results: Worse periodontal health was associated to the presence of carotid atherosclerosis. Patients with carotid plaques (n=19) had higher periodontal indices compared with subjects without plaques (n=14) (gingival index: 1.40 ± 0.71 vs. 0.69 ± 0.64, p=0.006). These relations were independent of the presence of cardiovascular risk factors in multiple logistic regression analysis. In the 66 examined common carotids, wall shear stress was inversely related to all periodontal indices (r=0.54, p<0.00001 for peak wall shear stress and gingival index). These relations remained significant also in multiple regression analysis, after correction for cardiovascular risk factors, gender and age., Conclusions: The present study identifies for the first time a link between periodontal indices and wall shear stress, suggesting that an alteration of hemodynamic profile might contribute to atherosclerosis in subjects with periodontal disease., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

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.

OBJECTIVE To determine whether the association observed between poor glycemic control and low HDL cholesterol in type 2 diabetes is dependent on obesity and/or hypertriglyceridemia. RESEARCH DESIGN AND METHODS We performed a cross-sectional study of 1,819 patients with type 2 diabetes and triglycerides <400 mg/dl enrolled at three diabetes centers in Italy. The risk for low HDL cholesterol was analyzed as a function of A1C levels. Odds ratios (ORs) were calculated after adjustment for confounding factors. RESULTS A 1% increase in A1C significantly increased the risk for low HDL cholesterol (OR 1.17 [95% CI 1.1-1.2], P = 0.00072); no changes were observed when age, sex, smoking, and lipid-lowering therapy were included in the model (1.17 [1.1-1.2], P = 0.00044). The association remained strong after adjustments for obesity and hypertriglyceridemia in multivariate analysis (1.12 [1.05-1.18], P = 0.00017). CONCLUSIONS Poor glycemic control appears to be an independent risk factor for low HDL cholesterol in type 2 diabetes.

Objective: Body fatness and fat distribution are widely accepted as coronary heart disease risk factors. In this study, we have evaluated the contribution of generalized adiposity, assessed by body mass index (BMI), to carotid atherosclerosis, in participants with or without metabolic syndrome (MetS)., Methods: We have analysed 840 female and 1002 male participants in a regional Cardiovascular Disease Prevention Campaign. Blood glucose and lipids were analysed by standard methods. According to BMI, calculated as weight (in kilograms)/height (in square metres), participants were divided into normal weight (BMI <25 kg/m2), overweight (BMI between 25 and 29.9 kg/m2) and obese (BMI>29.9 kg/m2). Carotid atherosclerosis was evaluated by echo Doppler., Results: Blood pressure, waist circumference, triglycerides and glucose were significantly higher, and high-density lipoprotein was lower, in overweight and obese participants, compared with normal weight. MetS was more frequent among obese and overweight than normal-weight participants (51.7 vs. 21.5 vs. 9.8%, respectively). The prevalence of carotid atherosclerosis was 45.29% in participants with MetS, significantly higher than in participants without MetS (33.04%, P<0.0001), but it was similar across the three weight categories. Furthermore, in multiple regression analyses BMI was not significantly associated with carotid atherosclerosis., Conclusion: The present findings suggest that increasing body weight favours the clustering of coronary heart disease risk factors. Overweight and obesity, however, do not independently associate with carotid atherosclerosis.

Purpose: Hepatic steatosis is frequently observed in subjects with metabolic syndrome (MS). In type 2 diabetics, it is independently associated with cardiovascular diseases. In order to confirm and extend this finding, a large group of patients with risk factors for atherosclerosis was studied., Methods: Carotid atherosclerosis was investigated by echo-Doppler, and hepatic steatosis by ultrasound and transaminase values. Strict exclusion criteria were chosen in order to avoid secondary forms of fatty liver and interference on transaminase values., Results: Among 970 enrolled patients, about 20% were diabetics, half had MS and 76% presented echographic hepatic steatosis. In multivariate analyses, fatty liver and MS were associated with carotid atherosclerosis [odds ratio (95% confidence intervals) 2.15 (1.27-3.63) and 1.72(1.12-2.64), respectively], whereas HOMA index was not. Aspartate aminotransferase and alanine aminotransferase were not independently associated with carotid atherosclerosis, whereas gamma-glutamyl transferase showed a link with atherosclerosis beyond MS and steatosis presence. The analyses of the 780 non diabetics recruited showed similar results., Conclusions: The results of the present study demonstrate that hepatic steatosis measured by echography is associated with carotid atherosclerosis in a large population mostly carrying cardiovascular or metabolic risk factors, independently of MS, cardiovascular diseases, diabetes mellitus and/or insulin resistance.

Endothelial function is widely evaluated by vasodilatation of the brachial artery induced by ischemia (flow-mediated vasodilatation, FMD). The function of the endothelium, in this setting, is to sense wall shear stress (WSS) increase and to release vasodilators. Following current guidelines FMD is measured 50-60s after ischemia. It is not known whether this lapse of time is sufficient to observe maximal vasodilatation, especially in diseased subjects. Sixty-six subjects with type 2 diabetes and 30 controls underwent FMD-test. Brachial artery WSS was measured at rest and during the first 15s after ischemia as index of peripheral resistances vessels reactivity, and FMD at 50, 120, 180, and 300s after ischemia as index of conduit vessel function. All controls exhibited increased WSS and peak FMD at 50s. Among subjects with diabetes three groups were identified based on the time at which peak FMD occurred. Twenty subjects with diabetes exhibited peak at 50s (Early FMD), 28 at 2 min (Late FMD), and 18 showed no FMD (Absent FMD). Peak FMD in Late FMD subgroup was comparable to peak in control subjects and significantly higher than peak in other subjects with diabetes. The "Absent FMD" group showed also impaired WSS. The present findings demonstrate that brachial artery response to ischemia is heterogeneous in type 2 diabetes, suggesting different mechanisms responsible for FMD alteration in this condition.

According to the focal nature of atherosclerosis, ischemic stroke is frequently unilateral. Atherosclerotic plaques are favoured by local hemodynamic factors as low wall shear stress and/or elevated circumferential wall tension. Aim of the present study was to investigate the possible association between hemodynamic forces and cerebrovascular disease. Common carotid mean wall shear stress and circumferential wall tension, Peterson's elastic modulus, and blood flow were measured in 25 patients with a recent unilateral large-artery stroke presenting non-stenotic plaques of the carotid arteries (large-artery group), and in 10 patients affected by a recent unilateral cardioembolic stroke without carotid plaques (cardioembolic group). In the large-artery group, atherosclerosis was slightly more evident in the side of cerebral ischemia. All hemodynamic factors were more unfavourable at the affected side in this group (shear stress: 6.2+/-3.0 versus 8.6+/-4.0 dynes/cm2, p<0.0001; wall tension: (7.3+/-1.3)x10(4) versus (6.6+/-1.3)x10(4) dynes/cm, p<0.00001; Peterson's modulus: (16.8+/-11.9)x10(5) versus (12.4+/-5.7)x10(5) dynes/cm2, p=0.06). No difference was detectable in blood flow and in cardioembolic group. The present data demonstrate an unfavourable hemodynamic profile in the common carotid artery supplying the area of a single large-artery stroke and might help to explain the frequent one-sidedness of this disease.

Elevated blood pressure is among the factors that contribute to the metabolic syndrome (MetS). It is not known whether subjects with MetS and elevated blood pressure are at the same cardiovascular risk as subjects with MetS but without elevated blood pressure. To clarify this point, we have evaluated the prevalence of carotid atherosclerosis in subjects with MetS with or without elevated blood pressure. A large population was examined (842 women and 1011 men). Blood pressure, lipids, glucose, and waist were measured by routine methods. Carotid atherosclerosis was evaluated by echo Doppler examination. The prevalence of MetS was 24.4% in women and 28.7% in men. The prevalence of carotid atherosclerosis was 35.1% in women and 37.3% in men (p=NS), and increased with increasing number of MetS components. Age, smoking, and systolic blood pressure (SBP) were associated with the presence of carotid atherosclerosis (logistic model), whereas age, high-density lipoprotein cholesterol, and SBP were associated with the extent of atherosclerosis (linear model). When comparing subjects with an equal number of MetS components, the prevalence of carotid atherosclerosis was significantly higher in subjects with elevated blood pressure than in those without. No difference in carotid atherosclerosis prevalence was found in subjects bearing or not bearing components of the syndrome other than elevated blood pressure. The present findings demonstrate that subjects with MetS and elevated blood pressure have increased carotid atherosclerosis compared with subjects with MetS but without elevated blood pressure. The diagnosis of MetS per se might not adequately identify subjects at elevated cardiovascular risk.

Background and Purpose: Systemic and local coronary heart disease (CHD) risk factors participate in atherogenesis. The role of wall shear stress, a major local risk factor, remains to be elucidated., Methods: Two hundred thirty-four subjects were carefully characterized for the presence of hypertension, hyperlipidemia, diabetes mellitus, obesity, and cigarette smoking and were divided into low- and high-risk groups. They underwent echo-Doppler examination of the carotid arteries. Atherosclerotic plaques and stenoses were detected, intima-media thickness (IMT) was measured, and wall shear stress was calculated., Results: One hundred eight subjects were classified as low-risk individuals. The prevalence of carotid atherosclerosis in this group was 18.5%. Wall shear stress was 24.23+/-7.21 dyne/cm(2) in individuals without atherosclerosis and 16.89+/-5.48 in those with atherosclerosis (P<0.000). In multiple regression analyses, wall shear stress, body mass index, and HDL cholesterol were inversely associated and total cholesterol was directly associated with the presence of atherosclerosis; only wall shear stress was associated with IMT. In the high-risk group the prevalence of atherosclerosis was 45.2%. Wall shear stress was 20.44+/-6.82 dyne/cm(2) in subjects without atherosclerosis and 17.84+/-6.88 dyne/cm(2) in those with atherosclerosis (P=0.037). Age was the only variable associated with both carotid atherosclerosis and IMT., Conclusions: In subjects traditionally considered at low CHD risk, intima-media thickening and carotid atherosclerosis are significantly associated with low wall shear stress. In contrast, in subjects at high CHD risk, the contribution of wall shear stress seems to be masked, and age becomes the only factor significantly associated with both carotid atherosclerosis and IMT.