Arcangelo Iannuzzi

Association of Obesity and Central Fat Distribution With Carotid Artery Wall Thickening in Middle-Aged Women

Background and Purpose— The association between obesity and atherosclerotic disease is controversial. In the present analysis, we evaluated whether common carotid intima-media thickness (IMT) and area, 2 markers of preclinical atherosclerosis, were increased in obese subjects. Methods— More than 5000 middle-aged women (n=5062; age, 30 to 69 years) living in the area of Naples, Southern Italy, were recruited for a prospective, currently ongoing study on the etiology of cardiovascular disease and cancer in the female population (the Progetto ATENA study). A subsample of 310 participants underwent high-resolution B-mode ultrasound examination, and the IMTs, intima-media areas, and lumen diameters of common carotid arteries were measured with a semiautomated computerized program. Subjects were divided into 3 groups on the basis of the recently published obesity guidelines for body mass index (BMI), a marker of general obesity, and tertiles of waist-to-hip ratio (WHR), a marker of regional obesity. Results— Women with a BMI ≥30 kg/m2 showed higher systolic and diastolic blood pressures, triglycerides, and fasting glucose and insulin, as well as lower high-density lipoprotein concentrations, than subjects with lower BMI. A gradual increase in common carotid IMT and intima-media area was observed when lean women (0.94±0.01 mm and 19.8±0.5 mm2, respectively) were compared with overweight (0.98±0.01 mm and 21.0±0.4 mm2) and obese (1.02±0.02 mm and 22.6±0.8 mm2, P <0.005 for linear trend) individuals. Similarly, women in the highest tertile of WHR (>0.85) had adverse risk factor profiles and thicker carotid intima-media complex than those in the first 2 tertiles (P <0.01 and P <0.05 for IMT and intima-media area, respectively). In multivariate analyses, BMI and WHR were significant predictors of carotid wall thickness, independently of other traditional and nontraditional cardiovascular risk factors (age, blood pressure, lipid abnormalities, fasting insulin). Conclusions— The present results indicate a graded and independent association between general and abdominal obesity—reflected by high BMI and WHR—and carotid artery wall thickening in a population of middle-aged women.

Hemodynamic changes in the peripheral circulation after repeat low density lipoprotein apheresis in familial hypercholesterolemia.

Repeat low density lipoprotein (LDL) apheresis and blood flow determinations in the forearm and leg were performed in 10 patients (age range, 13-49 years; four male, six female) with familial hypercholesterolemia (eight homozygous, two heterozygous). To perform LDL apheresis, plasma was first separated by a polysulphone hollow fiber filter; then, LDL was selectively removed from plasma by dextran sulphate cellulose beads packed in columns. Blood flows in the forearm and leg were determined at rest and during a reactive hyperemia test (peak flow). This test was performed noninvasively by a strain-gauge plethysmograph with semicontinuous registration of arterial blood flow variables before the first apheresis and 3 weeks after the last of six procedures for apheresis. Resting arterial blood flows in the forearm and leg were slightly increased after repeat LDL apheresis (p less than 0.05). Peak blood flow in the leg significantly increased (+34%, p less than 0.01). No change in peak blood flow in the forearm was observed. Systolic blood pressures were slightly but significantly reduced (p less than 0.05); forearm peripheral resistances were also reduced (p less than 0.05). Flow response was not related to LDL receptor status. Blood and plasma viscosities were determined before and 7 days after the last apheresis. Blood viscosity was significantly reduced after LDL apheresis at shear rates of 11.25-450 sec-1. Plasma viscosity did not change.

A paraoxonase gene polymorphism, PON 1 (55), as an independent risk factor for increased carotid intima-media thickness in middle-aged women.

Paraoxonase (PON) gene polymorphisms have been proposed as genetic markers of risk for cardiovascular disease (CVD). Sporadic results suggest they are correlated with intima-media thickness (IMT), an indicator of preclinical atherosclerotic disease. We have investigated whether polymorphisms PON 1 (M/L) 55, (Q/R) 192, PON 2 (S/C) 311 are related to site-specific carotid plaques in 310 middle-aged women. Subjects were also investigated for physical and biochemical parameters including oxidative markers to evaluate their effect on development of atherosclerotic plaques (IMT>1.2 mm) identified by high resolution B-mode ultrasound. We demonstrate that PON 1 (LL+ML) 55 is associated with plaques both at the bifurcation (OR=2.40; 95% CI 1.00-5.90) and at the common carotid artery (OR=2.75; 95% CI 1.01-7.50), and to the total number of plaques at any site (P<0.05). This polymorphism is an independent parameter with respect to other variables that are significantly associated with plaques, i.e. systolic blood pressure (OR=2.06; 95% CI 1.11-3.81) and oxidized low-density lipoprotein (LDL) antibodies (OR=1.96; 95% CI 1.05-3.69) in cases of common carotid plaques, and lipid peroxides (OR=1.86; 95% CI 1.00-3.50) in cases of bifurcation plaques. In conclusion, PON 1 (LL+ML) 55 but not PON 1 (Q/R) 192 or PON 2 (S/C) 311, appears to be an independent risk factor for increased carotid IMT in middle-aged women.

Premature carotid atherosclerosis: does it occur in both familial hypercholesterolemia and homocystinuria? Ultrasound assessment of arterial intima-media thickness and blood flow velocity.

Background and Purpose Homocystinuria due to cystathio-nine β-synthase deficiency and familial hypercholesterolemia are inherited disorders of metabolism that are associated with premature development of cardiovascular disease. This study addresses the possibility that different patterns of carotid wall damage and cerebral blood flow hemodynamics are present in these two metabolic diseases. Methods Twelve patients with homocystinuria due to cys-tathionine β-synthase deficiency (mean age, 24 years), 10 patients with homozygous familial hypercholesterolemia (mean age, 26 years), and 11 healthy control subjects (mean age, 26 years) underwent a vascular examination by noninvasive methods. B-mode ultrasound imaging was used to obtain measurements of intima-media thickness of common carotid, bifurcation, and internal carotid arteries as an index of atherosclerosis. Cerebral blood flow velocity was estimated from vascular examination of the middle cerebral artery by transcranial Doppler. Systolic, diastolic, and mean velocities were measured. Pulsatility index, a possible indicator of vascular resistance in the cerebral circulation, was also calculated. Results Mean maximum intima-media thickness was 1.4 mm in patients with familial hypercholesterolemia, 0.6 mm in patients with homocystinuria, and 0.6 mm in control subjects. The difference between hypercholesterolemic and homocystinuric patients or control subjects was statistically significant (p<.001). Diastolic blood flow velocities were significantly reduced in the middle cerebral arteries of hypercholesterolemic patients compared with homocystinuric patients or control subjects (P<.05), whereas systolic or mean velocities did not differ. The pulsatUity index, a possible indicator of vascular resistance in the cerebral circulation, was significantly higher in hypercholesterolemic patients compared with homocystinuric patients or healthy control subjects (P<.01). A direct relation was demonstrated between pulsatility index of the middle cerebral artery and mean maximum intima-media thickness of carotid arteries on the same side (P<.001). Conclusions Familial hypercholesterolemia is responsible for diffuse and focal thickening of carotid arteries and possibly also for hyperlipidemic endothelial dysfunction extending to small resistance arteries and leading to a disturbed cerebral blood flow. Patients with homocystinuria due to homozygosis for cystathionine β-synthase deficiency seldom have plaques in their carotid arteries. They are similar to healthy control subjects with regard to both intima-media thickness and blood flow velocity in the middle cerebral artery. Therefore, it is unlikely that typical atherosclerotic lesions precede thrombotic events in homocystinuria. However, it is possible that arterial dilatations caused by medial damage lead to thrombosis in homocystinuric patients.

Comparison of two diets of varying glycemic index on carotid subclinical atherosclerosis in obese children

Childhood obesity is associated with an increased carotid intima-media thickness (IMT) and stiffness. Increased carotid wall thickening and rigidity are considered markers of subclinical atherosclerosis. The aim of the present study was to test the effect of two hypocaloric diets of varying glycemic index on weight loss and markers of subclinical atherosclerosis in obese children. Seventy consecutive obese children attending the Outpatient Weight Clinic of the Department of Pediatrics were invited to participate in an intensive dietary protocol. Twenty-six accepted and were randomly assigned to two different groups: the first group followed a hypocaloric low-glycemic index diet and the second a hypocaloric high-glycemic index diet. Anthropometric measures and biochemical tests were performed in all children. Quantitative B-mode ultrasound scans were used to measure intima-media thickness (IMT) and diameters of the common carotid artery. Considering both groups together, at 6 months, body mass index decreased from 28.3 ± 3.1 to 25.8 ± 3.3 kg/m2, systolic blood pressure from 119 ± 12 to 110 ± 11 mmHg (P< 0.001), diastolic blood pressure from 78 ± 8 to 74 ± 7 mmHg (P< 0.001), IMT from 0.48 ± 0.05 to 0.43 ± 0.07 mm (P< 0.001), stiffness from 3.57 ± 1.04 to 2.98 ± 0.94 mm (P = 0.002), and high-sensitivity C-reactive protein from 1.5 ± 0.9 (values log transformed) to 0.4 ± 1.1 (P < 0.001). No differences were detectable in fasting serum triglycerides, total cholesterol, and high-density lipoprotein cholesterol. Insulin resistance (calculated by the HOmeostatic Model Assessment index [HOMA] score) significantly reduced only in the low-glycemic-index diet group (P < 0.04). In conclusion, this study confirms a benefit of hypocaloric diets on carotid IMT and stiffness in obese children and demonstrates, for the first time, an amelioration of insulin sensitivity in obese children after a low-glycemic index diet. These results justify the advice to obese children to follow a low-glycemic index diet in order to improve their cardiometabolic profile.

Cerebral blood flow velocity and systemic vascular resistance after acute reduction of low-density lipoprotein in familial hypercholesterolemia.

Background and Purpose Low-density lipoprotein apheresis is currently used for the treatment of familial hypercholesterolemia, an inherited disorder of metabolism associated with premature development of cardiovascular disease. We wanted to evaluate cerebral blood flow velocity, cardiac output, and systemic vascular resistance in patients with familial hypercholesterolemia before and after low-density lipoprotein apheresis. Methods Ten patients (age range, 14 to 46 years; 4 males, 6 females) with familial hypercholesterolemia (8 homozygotes, 2 heterozygotes) and 10 healthy control subjects of comparable age and sex distribution participated in the study. Low-density lipoprotein apheresis by dextran sulfate was performed in 8 patients (7 homozygotes, 1 heterozygote). Six patients (4 homozygotes, 2 heterozygotes) underwent a procedure of extracorporeal erythrocyte filtration with the same extracorporeal volume as for low-density lipoprotein apheresis, but with the exclusion of the passage of plasma through the dextran sulfate column. Cerebral blood flow velocity (transcranial Doppler), cardiac output, and systemic vascular resistance (electric bioimpedance cardiography) were determined by noninvasive techniques before and 1 day and 7 days after low-density lipoprotein apheresis or extracorporeal erythrocyte filtration. Plasma and blood viscosities were measured at the same time. Results Before apheresis, mean and diastolic cerebral flow velocities were abnormally low in hypercholesterolemic patients (P<01 and P<02 vs healthy control subjects, respectively). After apheresis, low-density lipoprotein cholesterol was lowered by 40% to 60% from baseline, and cerebral blood flow velocities (mean, systolic, and diastolic velocities) were increased (P<01). Cardiac output, systemic vascular resistance, and viscosity values were not significantly modified. Extracorporeal erythrocyte nitration (without passage of plasma through the dextran sulfate column) did not modify serum lipids, hemodynamic parameters, or viscosity values. Conclusions Low-density lipoprotein apheresis produces potentially useful hemodynamic effects. They are not adequately explained by changes in blood viscosity alone and might reflect a restoration of endothelium-mediated vasodilation, which is inhibited by high concentrations of low-density lipoprotein.

Metabolic changes after a hypocaloric, low-glycemic-index diet in obese children

Background: A low glycemic index (LGI) diet has been proposed as a treatment for obesity in adults; few studies have evaluated LGI diets in obese children. Aim: The purpose of the study was to compare the effects of two diets, with similar energy intakes, but different glycemic indexes in a pediatric outpatient setting. Subjects and methods: A parallel-group, randomized controlled trial was conducted, and 22 obese outpatient children with a body mass index (BMI) Z-score >2 (11 females and 11 males, BMI 28.9±2.9 kg/m2) were included in the study. Patients were randomly allocated to a hypocaloric LGI (GI: 60), or to a hypocaloric high glycemic index (HGI) diet (GI: 90). The LGI and HGI diets were almost equivalent for macronutrient composition. Anthropometric and biochemical parameters were measured at baseline and after 6 months. Results: In both groups there were significant decreases in BMI, BMI Z-score, blood pressure, and high-sensitivity C-reactive protein. Only LGI diets produced a significant decrease in waist circumference and homeostasis model assessment. Analysis of variance demonstrated that the BMI Z-score decrease from baseline values was significantly greater after the LGI diet than after the HGI diet [−0.20 (95% confidence interval (CI) −0.29 to −0.10) vs −0.34 (95%CI −0.43 to −0.24)], mean difference between groups −0.14 (95%CI −0.27 to −0.01), p<0.05). Changes in triglyceride concentrations were significantly lower in LGI as compared to HGI diet (p<0.05). Conclusions: This study demonstrates that a hypocaloric LGI diet has beneficial metabolic effects in comparison to a hypocaloric HGI diet in obese children.

Carotid artery wall hypertrophy in children with metabolic syndrome

Preclinical vascular changes (increased stiffness and/or wall thickness) have been observed in children with known metabolic risk factors. Aim of the present study was to evaluate different carotid parameters, representative of vascular health, in children with and without metabolic syndrome (MS). We studied 38 children with MS (mean age 9.6±2.6 years; range 6–14 years) and 45 healthy age-matched subjects. Children who met three or more of the following criteria qualified as having the MS: fasting glucose >110 mg dl−1, fasting triglyceride concentration >100 mg dl−1, fasting high-density lipoprotein cholesterol concentration <50 mg dl−1 for females or <45 mg dl−1 for the males, waist circumference >75th percentile for age and gender and systolic or diastolic blood pressure >90th percentile for age, gender and height. Carotid B-mode ultrasound examinations were performed and intima–media thickness and diameters were measured in all subjects. Arterial geometry was further characterized by calculation of carotid cross-sectional area. Carotid intima–media thickness and lumen diameters were increased in children with MS as compared to children without MS. Moreover, carotid cross-sectional area was significantly higher in the group of children with MS 9.83±1.86 mm2 [mean±s.d.] compared with the control group: 7.77±1.72 mm2, P<0.001, even after adjustment for age, gender and height. Carotid hypertrophy is already detectable in children with MS. High-resolution B-mode ultrasound could provide a valuable tool for the cardiovascular risk stratification of children.

Association between small dense LDL and early atherosclerosis in a sample of menopausal women

The association between small dense LDL particles and early atherosclerosis has been evaluated in a sample of middle-aged women. We analysed the relation between sd-LDL and common carotid intima media thickness in 228 menopausal women. LDL separation was performed by Lipoprint System: 7 LDL subfractions were obtained, mean LDL size and LDL score (% of sd-LDL) were calculated. Multivariate analysis showed a significant association between IMT (≥ 1.30 mm) and mean LDL size after controlling for age (OR 7.80; 95% CI 1.47-41.39; p = 0.016 for mean LDL particle size). IMT remained significantly related to mean LDL particle size after controlling for age and Apo B. In a subsequent multivariate analysis, after controlling for age, IMT (≥ 1.30 mm) was significantly related to LDL score (OR 12.15; 95% CI 1.29-114.36; p = 0.029 for LDL score), or age and Apo B (OR 10.13; 95% CI 1.07-95.71; p = 0.043 for LDL score). Our results suggest an association between sd-LDL and IMT, independently of age and Apo B. This data may indicate that sd-LDL are markers of early carotid atherosclerosis, and suggest that measurement of sd-LDL-C gives useful information in the risk assessment for atherosclerotic disease in menopausal women.

Cardiovascular Effects of Ketanserin, A New Antiserotonergic Agent in the Treatment of Arterial Hypertension

Ketanserin, an investigational, antiserotonergic agent, at a dose of 40 mg bid was given to 18 patients with mild to moderate primary hypertension in a randomized, double‐blind, crossover study, with 100‐mg metoprolol bid for four weeks each. The following parameters were evaluated: blood pressure, heart rate, cardiac workload (product of systolic blood pressure and heart rate during bicycle exercise), systolic time intervals, and peripheral blood flow (by strain‐gauge plethysmography). Significant reductions in diastolic and concomitant slight decreases in systolic blood pressure without changes in heart rate were observed during ketanserin treatment; cardiac oxygen demands during exercise test did not change, however. Pre‐ejection period and left ventricular ejection time were unchanged, while significant increase in rest flow to the lower limbs and decrease in peripheral resistance were demonstrated by strain‐gauge plethysmography. The results indicate that ketanserin has vasodilating properties and hypotensive activity that may be useful in the management of patients with essential hypertension.