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Unlabelled: An association between fatty liver and carotid atherosclerosis has been established; however, it is not clear whether this relationship is a consequence of shared conventional risk factors or whether it is determined by specific circulating factors originating from liver or adipose tissue. To identify the factors possibly linking fatty liver and atherosclerosis, we assessed, in 1,012 subjects free of confounding diseases (e.g., hypertension, diabetes, cardiovascular diseases, and dyslipidemia) and metabolic syndrome, the relationship between the presence of early plaques at carotid bifurcation and fatty liver index (FLI; a validated surrogate marker of fatty liver), as well as the associations between carotid plaque presence and established atherosclerotic risk factors, family history of cardiovascular disease (FH-CVD) or diabetes, insulin sensitivity, serum liver enzymes, adipokines, fatty free acids, and high-sensitivity C-reactive protein (hsCRP). A total of 55 of 1,012 subjects (5.4%) had small plaque at carotid bifurcation. Subjects with plaque were older and had higher prevalence of FLI ≥60 and FH-CVD, higher blood pressure, plasma low-density lipoprotein cholesterol, glucose, gamma-glutamyltransferase (GGT), and hsCRP, as compared to subjects without plaques (P < 0.05). In a logistic regression model, adjusted for sex, liver transaminase, and alcohol consumption, the independent predictors of plaque presence were age (P < 0.0005), FLI ≥60 (P < 0.0005), and current smoking (P < 0.05). When FLI in the model was replaced by variables used in its equation (e.g., body mass index, waist circumference, plasma triglycerides, and GGT), the independent determinants of plaque presence were age (P < 0.001), GGT (P = 0.001), and current smoking (P < 0.05)., Conclusions: Our cross-sectional study suggests that subjects with FLI ≥60 are at higher risk of atherosclerotic lesions, independently of established risk factors, and that serum GGT may represent a link between fatty liver and the development of early atherosclerosis., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Background: Carotid intima-media thickness (IMT), indices of large artery stiffness and measures of endothelium function may be used as markers of early atherosclerosis in type 1 diabetes mellitus (T1DM). The aim of the present study was to compare the indices of large artery structure and function as well as endothelial function and regenerating capacity between adolescents with T1DM and healthy control of similar age. In addition, the associations of different vascular measures with endothelial progenitor cells (EPCs), glyco-metabolic control and serum levels of advanced glycation endproducts (AGEs), soluble receptors for AGEs (sRAGE) and adiponectin were evaluated., Methods: Sixteen uncomplicated young T1DM patients (mean age 18 ± 2 years, history of disease 11 ± 5 years, HbA1c 7.7 ± 1.1%) and 26 controls (mean age 19 ± 2 years) were studied. A radiofrequency-based ultrasound system (Esaote MyLab 70) was used to measure carotid IMT and wave speed (WS, index of local stiffness), applanation tonometry (PulsePen) was applied to obtain central pulse pressure (PP) and augmentation index (AIx), and carotid-femoral pulse wave velocity (PWV, Complior) was used as index of aortic stiffness. Peripheral endothelium-dependent vasodilation was determined as reactive hyperemia index (RHI, EndoPAT). Circulating EPCs, glycometabolic profile, AGEs (autofluorescence method), sRAGE and adiponectin were also measured., Results: After adjusting for age, sex and blood pressure, T1DM adolescents had significantly higher carotid IMT (456 ± 7 vs. 395 ± 63 μm, p < 0.005), carotid WS (p < 0.005), PWV (p = 0.01), AIx (p < 0.0001) and central PP (p < 0.01) and lower EPCs (p = 0.02) as compared to controls. RHI was reduced only in diabetic patients with HbA1c ≥7.5% (p < 0.05). In the overall population, EPCs were an independent determinant of carotid IMT (together with adiponectin), while fasting plasma glucose was an independent determinant of carotid WS, AIx and central PP., Conclusions: Our findings suggest that young subjects with relatively long-lasting T1DM have a generalized preclinical involvement of large artery structure and function, as well as a blunted endothelium regenerating capacity. Hyperglycemia and suboptimal chronic glycemic control seem to deteriorate the functional arterial characteristics, such as large arteries stiffness, wave reflection and peripheral endothelium-dependent vasodilation, whereas an impaired endothelium regenerating capacity and adiponectin levels seem to influence arterial structure.

Objective: Fasting insulin concentrations are often used as a surrogate measure of insulin resistance. We investigated the relative contributions of fasting insulin and insulin resistance to cardiometabolic risk and preclinical atherosclerosis., Design and Methods: The Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) cohort consists of 1326 European non-diabetic, overall healthy men and women aged 30-60 years. We performed standard oral glucose tolerance tests and hyperinsulinemic euglycemic clamps. As a general measure of cardiovascular risk, we assessed the prevalence of the metabolic syndrome in 1177 participants. Carotid artery intima media thickness (IMT) was measured by ultrasound to assess preclinical atherosclerosis., Results: Fasting insulin was correlated with all elements of the metabolic syndrome. Insulin sensitivity (M/I) was correlated with most elements. The odds ratio for the metabolic syndrome of those in the highest quartile of fasting insulin compared with those in the lower quartiles was 5.4 (95% confidence interval (CI) 2.8-10.3, adjusted for insulin sensitivity) in men and 5.1 (2.6-9.9) in women. The odds ratio for metabolic syndrome of those with insulin sensitivity in the lowest quartile of the cohort compared with those in the higher quartiles was 2.4 (95% CI 1.3-4.7, adjusted for fasting insulin) in men and 1.6 (0.8-3.1) in women. Carotid IMT was only statistically significantly associated with fasting insulin in both men and women., Conclusions: Fasting insulin, a simple and practical measure, may be a stronger and independent contributor to cardiometabolic risk and atherosclerosis in a healthy population than hyperinsulinemic euglycemic clamp-derived insulin sensitivity.

Unlabelled: Patients with fatty liver (FL) disease have a high risk of developing diabetes and cardiovascular diseases. The aim was to evaluate the association between FL, insulin resistance (IR), coronary heart disease (CHD) risk, and early atherosclerosis in a large European population (RISC Study). In 1,307 nondiabetic subjects (age 30-60 years) recruited at 19 centers, we evaluated liver enzymes, lipids, insulin sensitivity (by euglycemic-hyperinsulinemic clamp), glucose tolerance (by 75 g oral glucose tolerance test), carotid atherosclerosis as intima media thickness (IMT), CHD risk by the Framingham Heart study prediction score, and physical activity (by accelerometer). The presence of FL was estimated using the fatty liver index (FLI; >60, likelihood >78% presence FL; FLI <20 likelihood >91% absence of FL). Subjects were divided into three groups: G1: FLI <20 (n = 608); G3: FLI >60 (n = 234), G2: intermediate group (n = 465). Compared to G1, G3 included more men (70% versus 24%) and people with impaired glucose tolerance (23% versus 5%). IMT increased with FLI (G3 = 0.64 +/- 0.08 versus G1 = 0.58 +/- 0.08 mm, P < 0.0001). FLI was associated with increased CHD risk (r = 0.48), low-density lipoprotein cholesterol (r = 0.33), alanine aminotransferase (r = 0.48), aspartate aminotransferase (r = 0.25), systolic blood pressure (r = 0.39) and IMT (r = 0.30), and reduced insulin sensitivity (r = -0.43), high-density lipoprotein cholesterol (r = -0.50), adiponectin (r = -0.42), and physical activity (r = -0.16, all P < 0.0001). The correlations hold also in multivariate analysis after adjusting for age, gender, and recruiting center., Conclusion: In middle-age nondiabetic subjects, increased IMT, CHD risk, and reduced insulin sensitivity are associated with high values of FLI.

Context: An independent association between obesity and preclinical carotid atherosclerosis has been demonstrated, however, the pathophysiological links were not clearly established. Body composition (BC) influences systemic hemodynamics and may participate in the remodeling of common carotid artery (CCA), independently of risk factors., Objective: This study evaluated the association between CCA structure and BC in a large population of healthy subjects., Design: This was a cross-sectional study., Settings: The study was conducted at 19 European centers., Subjects: The study included 627 healthy subjects (252 men, age 30-60 yr, body mass index 17-40 kg/m2)., Main Outcome Measures: CCA luminal diameter and intima-media thickness were measured on digitized ultrasound images. Acoustic properties of CCA wall were evaluated by digital densitometric analysis and described in terms of mean gray level. BC was assessed by electrical bioimpedance. Insulin sensitivity (euglycemic hyperinsulinemic clamp) and plasma adiponectin levels were measured. Associations between CCA structure, age, BC, and metabolic and atherosclerotic risk factors were analyzed by multivariate regression models., Results: Independent factors affecting CCA diameter were fat-free mass and waist girth (standardized r = 0.44 and 0.12; P < 0.01 and < 0.0001; R2 = 0.35); independent correlates of intima-media thickness were age, CCA diameter, systolic blood pressure, and low-density lipoprotein-cholesterol (standardized r = 0.39, 0.25, 0.10, and 0.14; P < 0.005-0.0001; R2 = 0.40). The mean gray level of carotid wall was independently associated with age and waist girth (standardized r = 0.23 and 0.12; P < 0.0001 and = 0.001; R2 = 0.30)., Conclusions: Findings of this cross-sectional study suggest that BC modulates CCA diameter, and may induce adaptive changes in carotid wall thickness, independently of metabolic and atherosclerotic factors. Central adiposity modifies the acoustic properties of carotid wall.

Context: Adiponectin inhibits protein synthesis in cardiac myocytes, thereby opposing the effect of cardiac workload and trophic factors (in particular, insulin) on left ventricular (LV) mass and wall thickness (WT)., Objective: We tested whether adiponectin and its isoforms are related to LV mass, WT, and function independently of metabolic factors., Design: This was a cross-sectional study., Subjects: The study included 77 healthy volunteers (42 men) aged 30-59 yr with normal LV structure and function., Main Outcome Measures: Insulin response and insulin sensitivity were assessed by oral glucose tolerance test and euglycemic hyperinsulinemic clamp. LV mass, WT, stroke work, chamber function, and myocardial longitudinal function were evaluated by standard Doppler echocardiography and tissue Doppler imaging. Total and molecular isoforms of adiponectin were measured in plasma., Results: By multivariate analysis, independent factors affecting LV mass were sex, body mass index, stroke work, and current smoking (R(2) = 0.66). Independent correlates of LV WT were age, stroke work, and plasma adiponectin (standardized r = 0.28, 0.41, and -0.26, P at least < 0.005, R(2) = 0.48). LV longitudinal late diastolic velocity was independently related to age, body mass index, and adiponectin (standardized r = 0.20, 0.26, -0.33, P at least < 0.05, R(2) = 0.30). High-molecular-weight adiponectin (47% of total), but not lower molecular-weight isoforms, insulin sensitivity, or other metabolic factors, was inversely and independently related to WT (standardized r = -0.27, P < 0.01) and myocardial longitudinal late diastolic velocity (standardized r = -0.28, P < 0.05)., Conclusion: In healthy subjects, circulating total and high-molecular-weight adiponectin are related to LV WT and diastolic function, independently of age and metabolic factors.

Objective: The purpose of this study was to test whether carotid intima-media thickness (IMT) is already increased in normotensive subjects who progress to hypertension (confirmed prehypertensives) independently of known determinants of vessel wall thickness., Methods and Results: Common carotid artery (CCA) far-wall IMT was measured (B-mode ultrasound) in 1536 subjects from the population-based Mexico City Diabetes Study at baseline and 3.5 years later. In the 136 confirmed prehypertensives, CCA-IMT (720 [253] microm, median[interquartile range]) was intermediate between normotensives (615 [140] microm) and hypertensives (725 [215] microm). After multiadjusting for gender, age, BMI, blood pressure, total cholesterol, antihypertensive therapy, and diabetes, converter status was independently associated with a higher CCA-IMT (+93+/-14 microm). At follow-up, CCA-IMT increased by 35 [180] microm. Gender, age, blood pressure, and presence of diabetes, but not the converter status, were significant independent predictors of CCA-IMT progression. In a model adjusting for gender, age, blood pressure (level, status and treatment), diabetes status, total and HDL-cholesterol, the G variant of the 45T/G polymorphism of the adiponectin gene was associated with a hazard ratio of 1.45 (95% CI: 1.04 to 2.01) of a baseline CCA-IMT in the top quintile., Conclusions: In confirmed prehypertensives, CCA-IMT is increased independently of blood pressure and known determinants of wall thickness, but short-term CCA-IMT progression is not accelerated.

Objective: To assess the relationship between insulin resistance and baroreflex gain (BRS) in the context of the metabolic syndrome., Design: Observational population study., Patients: We studied the healthy population of a small Mediterranean island (Linosa, about 0.5 square miles, 450 inhabitants) where genetic, psychosocial and behavioral bias is likely to be minimal for historical and social reasons., Measures: Baroreflex gain (BRS, by the frequency domain alpha index) and indices of autonomic regulation of the sino-atrial (SA) node derived from spectral analysis of RR interval variability were obtained, together with metabolic and behavioral indicators in the 144 participating subjects (age range 20-82 years). Carotid artery thickness (CCA) was also obtained with computer-aided ultrasound techniques. Insulin resistance was estimated by the homeostasis model assessment (HOMA), and subjects divided in tertiles accordingly., Results: BRS appeared to be reduced progressively with increasing levels of HOMA (respectively, 21.0 +/- 2.6, 17.7 +/- 1.7, 15.7 +/- 1.9 ms/mmHg, P < 0.03), while spectral indices of autonomic SA regulation appeared to be only insignificantly affected. Conversely, CCA was significantly increased with increasing HOMA (P < 0.024). Furthermore, BRS appeared to be significantly correlated with various elements of the metabolic syndrome, with CCA and abdominal obesity showing the strongest link., Conclusions: In an otherwise healthy population, BRS, but not spectrally derived indices of SA node autonomic regulation, are progressively reduced with increasing severity of insulin resistance, possibly as a consequence of attendant carotid artery thickening.

In many hypertensive patients, left ventricular pump function is normal at rest but abnormal during exercise. Myocardial dysfunction or altered left ventricular loading may be responsible for this finding. To verify the hypothesis of impaired myocardial functional reserve in the hypertensive heart, we assessed the response of stress-adjusted midwall shortening to graded, low-dose dobutamine infusion in hypertensive subjects with normal midwall shortening at rest. Sixty-five subjects (45 never treated hypertensive subjects and 20 normotensive volunteers comparable for age) received dobutamine at 1, 2, 3, 4, and 5 microg x kg(-1) x min(-1) for 5-minute steps; within this range of infusion rates, heart rate and systemic blood pressure were stable. Two-dimensional, M-mode, and Doppler echocardiography were performed at baseline and at the end of each step. In normotensive controls, midwall shortening increased from baseline during 2 microg x kg(-1) x min(-1) dobutamine by an average of 16+/-4.5% (P<0.01); a value of 2 standard deviations below this mean response was taken as the lower limit of normal. In the hypertensive subjects, 24 had a normal midwall shortening response to dobutamine at this dose (group I) and 21 had a subnormal response (group II). Whereas blood pressure and left ventricular mass were similar in group II and group I, the former had greater relative wall thickness (P<0.01) than the latter. beta-adrenergic stimulation by very-low-dose dobutamine unmasks subtle impairment of myocardial functional reserve in hypertensive subjects with normal myocardial performance at rest. This alteration seems to be related mainly to increase in left ventricular relative wall thickness.

Background and Purpose: It has been proved that symptomatic patients with severe carotid stenosis benefit from endarterectomy. Currently used methods for quantitation of the severity of carotid stenosis have limitations, and the impact of endarterectomy on the operated region of carotid artery remains unknown. The purpose of this study was to examine the accuracy of a 3-D ultrasound system for quantitation of stenotic lesions and to evaluate changes in regional vessel volume and cross-sectional area after carotid endarterectomy., Methods: We studied 14 patients with both carotid angiography and 3-D ultrasound. Of 13 patients who underwent surgery, 12 were reexamined with 3-D ultrasound after surgery. The length and volume of 20 randomly selected plaques were measured from 3-D data sets. The severity of stenosis was quantified by 3-D ultrasound using both a diameter method and an area method on cross-sectional views at the most stenotic site; the results were then compared with those from carotid angiography. The segmental vessel volume and average cross-sectional area of the operated artery both before and after endarterectomy were measured from 3-D ultrasound data., Results: Good correlation was obtained between 3-D ultrasound and carotid angiography in quantitative analysis of carotid stenosis (SEE=12.4%, r=0.76, and mean difference=7.0+/-12.3% with the diameter method; SEE=10.5%, r=0.82, and mean difference=1.8+/-10.5% with the area method by 3-D ultrasound). 3-D ultrasound had excellent reproducibility and small intraobserver and interobserver variability in plaque length and volume measurements. No significant changes in segmental vessel volume and average cross-sectional area of the operated artery were observed after surgery in patients with suture closure. However, a significant increase in segmental vessel volume was obtained in patients with polyfluorethylene patches applied to the surgical opening of the artery., Conclusions: 3-D ultrasound can be used for both qualitative and quantitative analysis of plaques in the carotid artery and to detect and quantify significant carotid stenosis. Its volumetric potential has important clinical implications in serial follow-up studies for observing the progression or regression of stenotic lesions and for evaluating the outcome of interventional procedures such as endarterectomy or stent placement.

The purpose of this study was to detect myocardial perfusion defects as a result of coronary occlusion and myocardial reperfusion after thrombolysis with intravenous (i.v.) administration of the echo contrast agent BR1 (Bracco Research, Switzerland), which consists of microbubbles (median diameter 2.5 microm) containing sulfur exafluoride in a phospholipidic shell. To generate a coronary thrombosis, a copper coil was advanced into the left circumflex coronary artery in eight anesthetized dogs with opened chest cavities. Coronary occlusion occurred 18 +/- 10 minutes after the insertion of the coil and was documented both by an electromagnetic flow meter (as zero blood flow) and by radiolabeled microspheres (as myocardial perfusion defect). After 2 hours of occlusion, streptokinase was infused i.v.; reperfusion was documented by both the flow-meter and microspheres. Left ventricular cavity enhancement was apparent after all contrast injections. Peak cavity intensity did not increase with dose and was not affected by signal processing (suggesting signal saturation), whereas the duration of contrast effect significantly increased with the dose (from 26 +/- 16 to 147 +/- 74 seconds). Myocardial contrast intensity also increased after contrast (from 15 +/- 12 to 21 +/- 18 gray level/pixel, p < 0.001). Contrast echo detected myocardial perfusion defects (corresponding to 17% +/- 11% of LV cross-sectional area) in all the injections performed during coronary occlusion and detected myocardial reperfusion with a sensitivity of 50% versus microspheres. The extent of perfusion defects by contrast echo showed a good correlation with microspheres (r = 0.73). Myocardial reperfusion was not detected by changes in heart rate, aortic pressure, pulmonary arterial pressure, cardiac output, left ventricular fractional area change, or wall-motion score index. Hemodynamic parameters were not affected by contrast injections. Thus, the i.v. administration of BR1 allows us to accurately detect myocardial perfusion defects during coronary occlusion and, to a lesser extent, myocardial reperfusion after thrombolysis.