Early Marker Of Vascular Damage Research Articles

Calculated whole blood viscosity in non-diabetic subjects with asymptomatic carotid atherosclerosis: How insulin resistance may affect blood viscosity.

Asymptomatic atherosclerosis is an important early marker of vascular damage and, among its risk factors, hemorheological alterations play an important role. In a cohort of 85 non-diabetic subjects with asymptomatic carotid atherosclerosis (ACA), we have measured whole blood viscosity (cWBV) according to the haematocrit and plasma fibrinogen level. The cWBV distinguish the subgroup of ACA subjects with 3-5 cardiovascular risk factors (CRFs) from that with 1-2 CRFs and the same behavior is present for haematocrit and plasma fibrinogen level. Therefore, we divided the whole group of ACA subjects according to the medians of the four surrogate indexes with an insulin resistance degree of TG/HDL-C, TyG, VAI and LAP. The analysis of the correlation between cWBV and each index of insulin resistance has shown that no correlation is present in the whole group and in the group of ACA subjects with 1-2 CRFs, while in the subgroup with 3-5 CRFs there is a positive correlation between cWBV with TG/HDL-C and TyG at a low degree of statistical significance. The date underline that subjects with this clinical condition have an unaltered evaluation of the cWBV compared to the other indices.

SUBCLINICAL TARGET ORGAN DAMAGE IN PATIENTS WITH RESTLESS LEGS SYNDROME. A PRELIMINARY OBSERVATIONAL STUDY

Objective: Restless legs syndrome (RLLS) is a frequent and often underdiagnosed type of insomnia. Since other types of insomnia present a strict association with cardiovascular disease, our study aimed to evaluate the possible association of RLLS with some early markers of cardiovascular organ damage. Design and method: Patients with other types of insomnia and those with central nervous system diseases were excluded. Twenty-eight patients (mean age: 63,1±13,9 years; 28.6% males) participated in the study. Fourteen subjects with diagnosis of RLLS according to International diagnostic criteria (Allen RP et al. 2014 Sleep Medicine) (disease mean duration 9.6±9.2 years; International Restless Legs Scale score 22.9±5.2) were matched for sex, age and major cardiovascular risk factors with 14 controls. In both groups, peripheral Blood Pressure (pBP), central Blood Pressure (cBP) and Pulse Wave Velocity (PWV) were assessed by the SphygmoCorXCEL. Carotid Intima-Media Thickness (cIMT) and the carotid Distensibility Coefficient (cCD) were assessed by ultrasound connected with an image acquisition and analysis system (CardiovascularSuite). Results: We did not find any significant difference between the two groups in the indices of subclinical vascular damage. In the RLS group, blood pressure measurements significantly correlated with all the markers of subclinical vascular damage, particularly pSBP was associated with PWV (r = 0.53, p = 0.009), Pulse Pressure correlated with cIMT (r = 0.58, p = 0.01) and cDBP was inversely related to cDC (r = -0.53; p = 0.03). Conclusions: Our data did not show significant differences in markers of early vascular damage between patients with RLS and matched controls. As expected, the markers of vascular damage were associated with BP. The present is only a pilot study; further studies with a larger sample size are required to confirm our findings.

Risk factors for pre-clinical atherosclerosis in adolescents with type 1 diabetes

AimsTo assess whether, besides “traditional” risk factors, overall oxidative stress, oxidized lipoproteins, and glycemic variability are associated with early macro-vascular damage in type 1 diabetes (T1D). MethodsIn 267 children/adolescents with T1D (130 girls, age 9.1–23.0 years) we evaluated: derivatives of reactive oxygen metabolites [d-ROMs], serum total antioxidant capacity [TAC] and oxidized LDL-cholesterol [oxLDL]; markers of early vascular damage (Lipoprotein-associated phospholipase A2 [Lp-PLA2], z-score of carotid intima-media thickness [z-cIMT] and carotid–femoral pulse wave velocity [z-PWV]); CGM metrics of four weeks preceding the visit, central systolic/diastolic blood pressures (cSBP/cDBP), and HbA1c, z-score of BP (z-SBP/z-DBP) and circulating lipids longitudinally collected since T1D onset.. Three general linear models were built with z-cIMT, z-PWV adjusted for current cDBP, and Lp-PLA2 as independent variables. ResultsThe z-cIMT was associated with male gender (B = 0.491, η2 = 0.029, p = 0.005), cSBP (B = 0.023, η2 = 0.026, p = 0.008) and oxLDL (B = 0.022, η2 = 0.022, p = 0.014). The z-PWV was associated with diabetes duration (B = 0.054, η2 = 0.024, p = 0.016), daily insulin dose (B = 0.52, η2 = 0.018, p = 0.045), longitudinal z-SBP (B = 0.18, η2 = 0.018, p = 0.045) and dROMs (B = 0.003, η2 = 0.037, p = 0.004). Lp-PLA2 was associated with age (B = 0.221, η2 = 0.079, p = 3*10−6), oxLDL (B = 0.081, η2 = 0.050, p = 2*10−4), longitudinal LDL-cholesterol (B = 0.031, η2 = 0.043, p = 0.001) and male gender (B = -1.62, η2 = 0.10, p = 1.3*107). ConclusionsOxidative stress, male gender, insulin dose, diabetes duration and longitudinal lipids and blood pressure, contributed to the variance of early vascular damage in young patients with T1D.

IN TYPE 1 DIABETES MELLITUS, CAROTID INTIMA-MEDIA THICKNESS SHOWS DIFFERENCES BETWEEN GENDERS EARLY AFTER PUBERTY

Objective: Type 1 diabetes mellitus (T1DM) is characterized by the early development of macrovascular damages in both genders but could manifest earlier in males. Traditional risk factors, along with T1DM per se, are associated with this process in T1DM. If specific differences in early vascular damage are viewable even during childhood in T1DM is unknown. Design and method: Arterial structural changes (carotid intima-media thickness [cIMT]) and vascular elasticity (carotid coefficient of distensibility [cDC] and Pulse Wave Velocity [PWV]) were measured in 180 children and adolescents with T1DM by carotid ultrasonography and the SphygmoCor XCel device. Hemodynamic and metabolic risk factors (peripheral and central systolic/diastolic blood pressure [pSBP/pDBP; cSBP], body mass index (BMI), glycated haemoglobin, triglycerides, total cholesterol, nonHDL/HDL-cholesterol ratio were also assessed. The sample was divided according to Tunner's stages (pre-pubertal-pubertal vs. post-pubertal) and gender: seventy-four subjects were classified as pre-pubertal-pubertal (44 male, mean age±SD 12 ± 2 years: 30 females, 12 ± 1.5 years) and 106 as post-pubertal (43 males, 16 ± 1 years; 63 females; age: 15.5 ± 1.5 years). Sex-specific linear regression models, adjusted for the pubertal state, BMI, duration of diabetes, glycated haemoglobin, nonHDL/HDL-cholesterol ratio, were constructed to assess the relation between risk factors and the markers of early vascular damage. Results: No differences in cIMT, cDC, PWV and the respective z-score were found between males and females in the pre-pubertal-prepubertal sub-group. In the post-pubertal group, males had higher cIMT (0.05 ± 0.01 mm; p-value: 0.001) and Z-score cIMT (0.62 ± 0.02; p-value: 0.04) but no differences in cDC and PWV were found. In linear regression models, the only risk factors independently associated with z-cIMT, were the nonHDL/HDL-cholesterol ratio (b ± SEM:0.267 ± 0.30; p-value:0.03) in males and z-cSBP in females (b ± SEM:0.286 ± 0.13; p-value:0.01). z-PWV and z-cDC showed associations with different types of BP values both in males and females. Conclusions: Gender-specific differences in cIMT are present early after puberty in adolescents with T1DM but seem associated with different risk factors in males and females. Different preventive strategies could be beneficial in males and females with T1DM, starting during adolescence.

Gla-Rich Protein (GRP) as an Early and Novel Marker of Vascular Calcification and Kidney Dysfunction in Diabetic Patients with CKD: A Pilot Cross-Sectional Study.

Vascular calcification (VC) is one of the strongest predictors of cardiovascular risk in chronic kidney disease (CKD) patients. New diagnostic/prognostic tools are required for early detection of VC allowing interventional strategies. Gla-rich protein (GRP) is a cardiovascular calcification inhibitor, whose clinical utility is here highlighted. The present study explores, for the first time, correlations between levels of GRP in serum with CKD developmental stage, mineral metabolism markers, VC and pulse pressure (PP), in a cohort of 80 diabetic patients with mild to moderate CKD (stages 2–4). Spearman’s correlation analysis revealed a positive association of GRP serum levels with estimated glomerular filtration rate (eGFR) and α-Klotho, while a negative correlation with phosphate (P), fibroblast growth factor 23 (FGF-23), vascular calcification score (VCS), PP, calcium (x) phosphate (CaxP) and interleukin 6 (IL-6). Serum GRP levels were found to progressively decrease from stage 2 to stage 4 CKD. Multivariate analysis identified low levels of eGFR and GRP, and high levels of FGF-23 associated with both the VCS and PP. These results indicate an association between GRP, renal dysfunction and CKD-mineral and bone disorder. The relationship between low levels of GRP and vascular calcifications suggests a future, potential utility for GRP as an early marker of vascular damage in CKD.

Assessment of Carotid Intima-Media Thickness as an Early Marker Of Vascular Damage In Hypertensive Children.

BackgroundThe increased carotid intima-media thickness (CIMT) correlates with the presence of atherosclerosis in adults and describes vascular abnormalities in both hypertensive children and adolescents.ObjectiveTo assess CIMT as an early marker of atherosclerosis and vascular damage in hypertensive children and adolescents compared with non-hypertensive controls and to evaluate the influence of gender, age, and body mass index (BMI) on CIMT on each group.MethodsObservational cohort study. A total of 133 hypertensive subjects (male, n = 69; mean age, 10.5 ± 4 years) underwent carotid ultrasound exam for assessment of CIMT. One hundred and twenty-one non-hypertensive subjects (male, n = 64; mean age, 9.8 ± 4.1 years) were selected as controls for gender, age (± 1 year), and BMI (± 10%).ResultsThere were no significant difference regarding gender (p = 0.954) and age (p = 0.067) between groups. Hypertensive subjects had higher BMI when compared to control group (p = 0.004), although within the established range of 10%. Subjects in the hypertensive group had higher CIMT values when compared to control group (0.46 ± 0.05 versus 0.42 ± 0.05 mm, respectively, p < 0.001; one-way ANOVA). Carotid IMT values were not significantly influenced by gender, age, and BMI when analyzed in both groups separately (Student's t-test for independent samples). According to the adjusted determination coefficient (R²) only 11.7% of CIMT variations were accounted for by group variations, including age, gender, and BMI.ConclusionsCarotid intima-media thickness was higher in hypertensive children and adolescents when compared to the control group. The presence of hypertension increased CIMT regardless of age, gender, and BMI.

Non-alcoholic fatty liver disease fibrosis score and preclinical vascular damage in morbidly obese patients

BackgroundNon-alcoholic fatty liver disease (NAFLD) is strongly related with enhanced morbidity and mortality from cardiovascular disease. In obese patients with both NAFLD and features of the metabolic syndrome, the cardiovascular risk is further increased. AimThe aim of this study is to investigate the relationship between severity of liver fibrosis evaluated by NAFLD fibrosis score (NAFLD-FS), Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), other obesity-related markers and preclinical atherosclerosis in morbidly obese patients with previously diagnosed NAFLD. MethodsLaboratory parameters, visceral fat area (VFA), flow-mediated dilatation (FMD), intima-media thickness (IMT), HOMA-IR and NAFLD-FS were determined in 196 morbidly obese patients. ResultsPatients with higher NAFLD-FS or HOMA-IR show higher left max-IMT and lower FMD (p<0.001). VFA and NAFLD-FS, but not HOMA-IR, were independent predictors of reduced FMD (respectively β −0.268, p=0.001 and β −0.165, p=0.039, p of the model<0.001) and increased left max-IMT (respectively β 0.165, p=0.031 and β 0.301, p<0.001, p of the model<0.001). ConclusionsIn morbidly obese patients, NAFLD-FS correlates with markers of early vascular damage. NAFLD-FS, easier to obtain than VFA, seems to be a better score than HOMA-IR to categorize such subjects who are potentially at risk of future cardiovascular events.

Early Vascular Damage in Young Women with DM-1 and Its Relation to Anti-Müllerian Hormone: A Cross-Sectional Study.

Vascular function is suggested to be associated with ovarian reserve, but the relationship with microvascular function has never been studied. In this cross-sectional pilot study, the relationship of microvascular damage markers with AMH was studied in premenopausal women. Twenty-two regularly cycling women with type 1 diabetes (DM-1) and a reference group of 20 healthy regularly cycling women were included, from whom blood was drawn in the early follicular phase of the menstrual cycle. The main outcome was the correlation between circulating progenitor cells (CPCs), markers for early vascular damage, and AMH, a marker for ovarian reserve. Secondary endpoints for early vascular impairment were circulating angiogenic cells and additional biomarkers. Median AMH levels were 2.2 µg/L [1.2–3.5] in the DM-1 group and 2.1 µg/L [0.85–3.8] in the reference group. CPCs were significantly decreased in women with DM-1; 1204 ± 537 CD34+/CD45dim cells were counted in the DM-1 group, compared to 2264 ± 1124 in the reference group. CPCs and other markers of early vascular damage were not correlated with AMH levels in a multivariable analysis. These results underscore previous findings of early vascular damage in DM-1 and suggest that there may not be a relationship between vascular function and ovarian reserve. Trial Registration. This trial is registered with Clinicaltrials.gov NCT01665716.

Insulin-resistance HCV infection-related affects vascular stiffness in normotensives

Background and Aims. Arterial stiffness evaluated as pulse wave velocity, is an early marker of vascular damage and an independent predictor for cardiovascular events. We investigated if the insulin resistance/hyperinsulinemia chronic hepatitis C virus infection-related could influence arterial stiffness. Methods. We enrolled 260 outpatients matched for age, body mass index, gender, ethnicity: 52 with never-treated uncomplicated chronic hepatitis C virus infection (HCV+), 104 never-treated hypertensives (HT) and 104 healthy subjects (NT). Pulse wave velocity was evaluated by a validated system employing high-fidelity applanation tonometry. We also measured: fasting plasma glucose and insulin, total, LDL- and HDL-cholesterol, triglyceride, creatinine, e-GFR-EPI, HOMA, quantitative HCV-RNA. Results. HCV+ patients with respect to NT had an increased pulse wave velocity (7.9 ± 2.1 vs 6.4 ± 2.1 m/s; P < 0.0001), similar to that observed in HT group (8.8 ± 3.2 m/s). HCV+ patients, in comparison with NT, had higher triglyceride, creatinine, fasting insulin and HOMA (3.2 ± 1.3 vs 2.5 ± 1.0; P < 0.0001). At linear regression analysis, the correlation between pulse wave velocity and HOMA was similar in HT (r = 0.380, P < 0.0001) and HCV+ (r = 0.369, P = 0.004) groups. At multiple regression analysis, HOMA resulted the major determinant of pulse wave velocity in all groups, explaining respectively 11.8%, 14.4% and 13.6% of its variation in NT, HT and HCV+. At correlational analysis hepatitis C virus-RNA and HOMA demonstrated a strong and linear relationship between them, explaining the 72.4% of their variation (P = 0.022). Conclusions. We demonstrated a significant and direct correlation between HOMA and pulse wave velocity in HCV+ patients, similar to that observed in hypertensives.

The impact of the ketogenic diet on arterial morphology and endothelial function in children and young adults with epilepsy: A case–control study

PurposeThe present study aimed to assess the impact of the ketogenic diet on arterial morphology and endothelial function of the big vessels of the neck and on cardiac diastolic function, in a cohort of epileptic children and young adults treated with the ketogenic diet. MethodsPatients were recruited based on the following inclusion criteria: (1) patients who were or had been on the ketogenic diet for a time period of at least six months. Each patient underwent measurement of carotid intima media thickness, carotid artery stiffness, echocardiography, and diastolic function assessment. Patients with drug resistant epilepsy, matched for number, age and sex and never treated with ketogenic diet, were recruited as controls. ResultsThe population study was composed by 43 epilepsy patients (23 males), aged between 19 months and 31 years (mean 11 years). Twenty-three patients were or had been treated with ketogenic diet, and 20 had never been on it (control group). Subjects treated with the ketogenic diet had higher arterial stiffness parameters, including AIx and β-index and higher serum levels of cholesterol or triglycerides compared to those who had never been on the diet (control group) (p<0.001). ConclusionsArterial stiffness is increased in children and young adults treated with the ketogenic diet, before the increase of the intima media thickness. This supports that arterial stiffness is an early marker of vascular damage.

A Prothrombotic State is Associated with Early Arterial Damage in Hypertensive Patients

A prothrombotic state is associated with organ damage in hypertensive patients. Carotid intima-media thickness (IMT) is an early marker of vascular damage that anticipates the development of atherosclerotic plaques. The aim of the present study was to investigate the relationships between subclinical carotid damage and markers of the prothrombotic state in hypertension. In 258 essential hypertensive patients who were consecutively recruited at a hypertension clinic an ultrasound carotid scan was performed with assessment of the IMT and plasma levels of C-reactive protein, fibrinogen, fibrin D-dimer, prothrombin fragment 1+2, homocysteine, and lipoprotein(a) were measured. Patients with an IMT above the median of the distribution (800 µm) were older and had greater BMI, pulse pressure, duration of hypertension, and prevalence of coronary heart disease than patients with an IMT below the median. Patients with higher IMT had also greater levels of C-reactive protein, fibrinogen, fibrin D-dimer, and homocysteine. Regression analysis showed a direct relationship of IMT with age, waist circumference, pulse pressure, fibrinogen, fibrin D-dimer, and number of cigarettes smoked per day, and an inverse relationship with creatinine clearance. On multivariate analysis, age, pulse pressure, and fibrin D-dimer were independently related with IMT. In hypertensive patients, subclinical carotid damage is related with evidence of activated coagulation system suggesting a prothrombotic state. This might contribute to the development of hypertensive arterial damage even in the earliest stages.

Effect of a fatty meal on inflammatory markers in healthy volunteers with a family history of type 2 diabetes

A family history of type 2 diabetes (T2D) confers a high risk of developing the disease, independent of that due to other common risk factors. Postprandial state is a pro-inflammatory condition associated with a transiently impaired endothelial function; an increased oxidative stress is considered as a mediator of such effects in T2D. We evaluated the short-term effect of a lipid meal on markers of early vascular damage in subjects at risk of developing T2D. A total of thirty-two healthy volunteers, divided according to the presence (FHD+) or absence (FHD-) of a family history of T2D, underwent a fatty meal test. We measured the monocyte mRNA expressions of IL-6, IL-8 and IL-1β, and IL-6, soluble CD40 ligand (sCD40L), vascular cellular adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1) and nitrotyrosine plasma concentrations at baseline and in the post-meal phase, relating them to the lipid profile and other biochemical parameters. The basal expression of the cytokines did not differ in FHD- and FHD+ subjects; neither was it modified by the meal ingestion. IL-6 and sCD40L plasma levels, similar in the two groups in the fasting state, did not vary after the meal. VCAM-1 and ICAM-1 increased in FHD+ subjects but not in FHD- subjects. Nitrotyrosine, similar between the FHD- and FHD+ subjects at baseline, increased more in FHD+ subjects than in FHD- subjects after the meal. In conclusion, the presence of a familial history of T2D confers an abnormal endothelial activation after an oral lipid meal, coupled with an increased oxidative stress, supporting the hypothesis of an early endothelial dysfunction already present in healthy individuals prone to develop T2D.

Increased monocyte chemoattractant protein-1 levels indicating early vascular damage in lean young PCOS patients

Serum levels of monocyte chemoattractant protein-1 and C-reactive protein levels, as early signs of vascular damage and cardiovascular disease, were increased in young, lean patients with polycystic ovary syndrome. Serum monocyte chemoattractant protein-1 levels were positively correlated with serum LH, T, and C-reactive protein levels.

Selection on albuminuria enhances the efficacy of screening for cardiovascular risk factors

As many subjects with a cardiovascular (CV) risk factor are undiagnosed, guidelines to prevent cardiovascular disease argue for case finding on those risk factors. Such an approach is, however, labour and cost intensive. An elevated urinary albumin loss is an early marker of vascular damage and is associated with an increased CV risk. As albuminuria is easy to measure, we tested whether a screening approach in which detailed risk factor measurement is done only after selection of subjects with an elevated albuminuria results in a higher yield of subjects at risk. A random sample of the general population as investigated in the Prevention of Renal and Vascular End-Stage Disease study was used. Plasma glucose, blood pressure, serum cholesterol and renal function were measured in an overall random sample of the population, in subgroups according to their urinary albumin concentration (UAC) of one first morning urine void and in subgroups in whom the elevated albuminuria level was confirmed with two 24 h urine collections for measurement of urinary albumin excretion (UAE). In the overall population, the number of subjects with any newly found CV risk factor was higher than the number of subjects already known with any CV risk factor (n = 1331 versus 370; 39.2 versus 10.9%). The prevalence of subjects with any newly diagnosed CV risk factor was higher in the group of 267 subjects with a first morning UAC of ≥ 20 mg/L (61.0%; P < 0.05) compared to the overall population (39.2%). Although the sensitivity of a UAC ≥ 20 mg/L to detect a subject with at least one CV risk factor was relatively low (12%), the specificity was very high (96%). The positive predictive value was 70%. When the elevated UAC could be confirmed in two subsequent 24-h urine collections, the diagnostic yield still further improved. The prevalence of undiagnosed CV risk factors in the general population is much higher than the prevalence of known risk factors. After a selection of subjects with an elevated albuminuria, the relative prevalence of subjects with newly diagnosed CV risk factors increases while the number of subjects to test for presence of CV risk factors is smaller. Such an approach facilitates a more effective and simple strategy for risk factor screening.

Metformin Reduces Arterial Stiffness and Improves Endothelial Function in Young Women With Polycystic Ovary Syndrome: A Randomized, Placebo-Controlled, Crossover Trial

Polycystic ovary syndrome (PCOS) is characterized by increased insulin resistance and an increased risk of type 2 diabetes. These abnormalities most likely are associated with increased risk of cardiovascular mortality in women with PCOS, although this has not been demonstrated in epidemiological studies. Endothelial dysfunction is an early marker of vascular damage in women with PCOS. Increased arterial stiffness (assessed by pulse wave velocity [PWV]) correlates with insulin resistance and is a strong independent predictor of cardiovascular mortality in patients with type 2 diabetes. Since it is also increased in women with PCOS, insulin resistance may be an important therapeutic target. The oral biguanide, metformin, improves insulin sensitivity in women with PCOS and reduces circulating concentrations of markers of cardiovascular risk. However, its effects on vascular function are unclear because of conflicting data and the absence of randomized controlled studies. This randomized, double-blind, placebo-controlled crossover study investigated the effects of short-term metformin therapy on arterial stiffness and endothelial function in women with PCOS. The participants were 30 obese women (mean body mass index: 34.9) with PCOS, who were assigned, using a crossover design, to receive consecutive 12-week treatment periods of metformin or placebo separated by an 8-week washout. The primary study outcomes were changes in measures of arterial stiffness (augmentation index [Alx], brachial PWV, aortic PWV, central blood pressure), and endothelial function. Secondary outcome measures were changes in anthropometric measures (weight, body mass index, and waist and hip circumference), androgens (testosterone), and metabolic biochemistry (adiponectin, high-sensitivity C-reactive protein, homeostasis model of assessment for insulin resistance, triglycerides, and plasminogen activator inhibitor-1). Metformin improved measures of arterial stiffness including AIx (−6.1%; 95% confidence interval (CI) for the difference −8.5% to −3.5%); bPWV (−0.73 m/s; 95% CI for the difference −1.09 to −0.38); aPWV (−0.76 m/s; 95% CI for the difference −1.12 to −0.4 m/s); and central blood pressure (all comparisons, P < 0.001). Endothelium-dependent (AIx after albuterol, P < 0.003) and endothelium-independent (Alx after nitroglycerin; P < 0.001) vascular responses also improved. Metformin significantly reduced body weight (P < 0.001), waist circumference (P < 0.001), and triglycerides (P < 0.004). Increases were observed for adiponectin (P < 0.001). No changes were observed in testosterone or other metabolic measures. Both the study medication and placebo were well tolerated. These findings suggest that metformin improves important parameters of vascular function in young obese women with PCOS and may have therapeutic benefits for this study population.

Metformin reduces arterial stiffness and improves endothelial function in young women with polycystic ovary syndrome:a randomized, placebo-controlled, crossover trial

Polycystic ovary syndrome (PCOS) is characterized by increased insulin resistance and an increased risk of type 2 diabetes. These abnormalities most likely are associated with increased risk of cardiovascular mortality in women with PCOS, although this has not been demonstrated in epidemiological studies. Endothelial dysfunction is an early marker of vascular damage in women with PCOS. Increased arterial stiffness (assessed by pulse wave velocity [PWV]) correlates with insulin resistance and is a strong independent predictor of cardiovascular mortality in patients with type 2 diabetes. Since it is also increased in women with PCOS, insulin resistance may be an important therapeutic target. The oral biguanide, metformin, improves insulin sensitivity in women with PCOS and reduces circulating concentrations of markers of cardiovascular risk. However, its effects on vascular function are unclear because of conflicting data and the absence of randomized controlled studies. This randomized, double-blind, placebo-controlled crossover study investigated the effects of short-term metformin therapy on arterial stiffness and endothelial function in women with PCOS. The participants were 30 obese women (mean body mass index: 34.9) with PCOS, who were assigned, using a crossover design, to receive consecutive 12-week treatment periods of metformin or placebo separated by an 8-week washout. The primary study outcomes were changes in measures of arterial stiffness (augmentation index [Alx], brachial PWV, aortic PWV, central blood pressure), and endothelial function. Secondary outcome measures were changes in anthropometric measures (weight, body mass index, and waist and hip circumference), androgens (testosterone), and metabolic biochemistry (adiponectin, high-sensitivity C-reactive protein, homeostasis model of assessment for insulin resistance, triglycerides, and plasminogen activator inhibitor-1). Metformin improved measures of arterial stiffness including AIx (−6.1%; 95% confidence interval (CI) for the difference −8.5% to −3.5%); bPWV (−0.73 m/s; 95% CI for the difference −1.09 to −0.38); aPWV (−0.76 m/s; 95% CI for the difference −1.12 to −0.4 m/s); and central blood pressure (all comparisons, P < 0.001). Endothelium-dependent (AIx after albuterol, P < 0.003) and endothelium-independent (Alx after nitroglycerin; P < 0.001) vascular responses also improved. Metformin significantly reduced body weight (P < 0.001), waist circumference (P < 0.001), and triglycerides (P < 0.004). Increases were observed for adiponectin (P < 0.001). No changes were observed in testosterone or other metabolic measures. Both the study medication and placebo were well tolerated. These findings suggest that metformin improves important parameters of vascular function in young obese women with PCOS and may have therapeutic benefits for this study population.

Association of CC chemokine ligand 5 genotype with urinary albumin excretion in the non-diabetic Japanese general population: the Takahata study

Albuminuria is an early marker of vascular damage, and its development in diabetic nephropathy is associated with genotype of inflammatory CC chemokine ligand 5 (CCL5). This study investigated whether the association of CCL5 and albuminuria is a general phenomenon. We characterized a Japanese population consisting of 2,749 non-diabetic individuals over 40 years in Takahata, Japan. The urine albumin-creatinine ratio (UACR) was obtained from morning spot urine. We genotyped SNPs within the CCL5 gene that displayed frequent minor allele frequencies in Japanese (i.e., rs2107538, rs2280789, rs3817655 and rs9909416). Assessment of possible association and linkage disequilibrium (LD) revealed that all four SNP genotypes are correlated significantly with UACR (P = 0.004-0.005), and these four SNPs variations showed an obvious consistency of genotypes by detecting almost complete linkage disequilibrium (D' = 1 and r (2) > 0.95). We found two exclusive haplotypes in the CCL5 gene (haplotype1: rs2107538G/rs2280789T/rs3817655T/rs9909416G, frequency 0.64 and haplotype2: rs2107538A/rs2280789C/rs3817655A/rs9909416A, frequency 0.35) among the population. A significant association with elevated UACR was identified with haplotype1 (P = 0.002). Homozygotes for haplotype1 displayed strikingly-elevated UACR (48.5 +/- 6.6 mg/g, n = 1,116) compared to the rest (28.6 +/- 1.6 mg/g, n = 1,530) (P = 0.001). In conclusion, these results suggested that genetic variation of CCL5 might be an important risk factor for albuminuria in the non-diabetic Japanese general population.

Measuring endothelial glycocalyx dimensions in humans: a potential novel tool to monitor vascular vulnerability

The endothelial glycocalyx is increasingly considered as an intravascular compartment that protects the vessel wall against pathogenic insults. The purpose of this study was to translate an established experimental method of estimating capillary glycocalyx dimension into a clinically useful tool and to assess its reproducibility in humans. We first evaluated by intravital microscopy the relation between the distance between the endothelium and erythrocytes, as a measure of glycocalyx thickness, and the transient widening of the erythrocyte column on glycocalyx compression by passing leukocytes in hamster cremaster muscle capillaries. We subsequently assessed sublingual microvascular glycocalyx thickness in 24 healthy men using orthogonal polarization spectral imaging. In parallel, systemic glycocalyx volume (using a previously published tracer dilution technique) as well as cardiovascular risk profiles were assessed. Estimates of microvascular glycocalyx dimension from the transient erythrocyte widening correlated well with the size of the erythrocyte-endothelium gap (r = 0.63). Measurements in humans were reproducible (0.58 +/- 0.16 and 0.53 +/- 0.15 microm, coefficient of variance 15 +/- 5%). In univariate analysis, microvascular glycocalyx thickness significantly correlated with systemic glycocalyx volume (r = 0.45), fasting plasma glucose (r = 0.43), and high-density lipoprotein-cholesterol (r = 0.40) and correlated negatively with low-density lipoprotein-cholesterol (r = -0.41) as well as body mass index (r = -0.45) (all P < 0.05). In conclusion, the dimension of the endothelial glycocalyx can be measured reproducibly in humans and is related to cardiovascular risk factors. It remains to be tested whether glycocalyx dimension can be used as an early marker of vascular damage and whether therapies aimed at glycocalyx repair can protect the vasculature against pathogenic challenges.

Early impairment of large artery structure and function in type I diabetes mellitus.

Diabetes mellitus is associated with an increased incidence of atherosclerosis. How early functional and structural alterations of large arteries that may preceded atherosclerosis occur in the course of this disease has, however, never been conclusively documented. We evaluated arterial wall distensibility in the radial artery, common carotid artery and abdominal aorta in 133 patients (aged 35.4 +/- 0.9 years, means +/- SEM) with Type I (insulin-dependent) diabetes mellitus and no macrovascular complications. Arterial distensibility was derived from continuous measurements of arterial diameter through echotracking techniques and use of either the Langewouters (radial artery) or the Reneman (carotid artery and aorta) formula. The same echotracking techniques enabled us to obtain radial artery and carotid artery wall thickness. Data were compared with those from 70 age-matched normotensive control subjects. In diabetic patients arterial distensibility was consistently less (p < 0.01) than in control subjects, the reduction averaging 26%, 14% and 25% for the radial artery, carotid artery and aorta, respectively. This was accompanied by an increase (p < 0.01) in both radial and carotid artery wall thickness. The changes were more pronounced in patients with microalbuminuria, retinopathy or neuropathy or both. They were evident also in those without microvascular complications. This was the case also when subjects in whom diabetes was associated with hypertension (n = 30) were excluded from data analysis. Carotid and aortic wall abnormalities showed a relation with the duration of disease and blood pressure whereas radial artery abnormalities showed a relation with glycated haemoglobin. Type I diabetes is characterised by diffuse arterial wall stiffening and thickening which progress with the severity of the disease but can clearly be seen also in the absence of any diabetic-related complication. This suggests that in diabetes stiffening and thickening are an early marker of vascular damage.