The contribution of childhood obesity to adult carotid intima-media thickness: the Bogalusa Heart Study.

OBJECTIVE: Although obese children are at increased risk for coronary heart disease in later life, it is not clear if the association results from the persistence of childhood obesity into adulthood. We examined the relation of both childhood and adult levels of body mass index (BMI, kg m(-2)) to carotid intima-media thickness (IMT) measured at the (mean) age of 36 years. DESIGN AND SUBJECTS: Prior to the determination of adult IMT, the 1142 participants had been examined 7 (mean) times in the Bogalusa Heart Study. MEASUREMENTS: In addition to BMI, levels of lipids, lipoproteins and blood pressure were measured at each examination. Cumulative levels of each risk factor were based on the areas under the individual growth curves calculated using multilevel models for repeated (BMI) measurements. We then examined the relation of these cumulative levels to adult IMT. RESULTS: Carotid IMT was associated with cumulative levels of BMI in both childhood and adulthood (P<0.001 for each association). Furthermore, the association between childhood BMI and adult IMT persisted, but was reduced, after controlling for adult BMI. Although childhood levels of lipids, lipoproteins and blood pressure were also associated with adult IMT, these associations were not independent of adult levels of these risk factors. CONCLUSIONS: These results emphasize the adverse effects of elevated childhood BMI levels. In addition to the strong tracking of BMI levels from childhood to adulthood, there appears to be a modest, independent effect of childhood BMI on adult IMT. The prevention of childhood obesity should be emphasized.

Correlation of serum IGF-I and IGFBP-1 and -3 to cardiovascular risk indicators and early carotid atherosclerosis in healthy middle-aged men.

OBJECTIVES: IGF-I, IGFBP-1 and IGFBP-3 are putative mediators in cardiovascular disease. The present study examined (i) the correlations of circulating IGF-I, IGFBP-1 and IGFBP-3 to established cardiovascular risk factors and signs of early atherosclerosis as reflected by ultrasound measurement of common carotid intima-media thickness (IMT), and (ii) whether serum concentrations of these analytes are modulated during alimentary lipaemia. DESIGN: Cross-sectional clinical study. PATIENTS: A biobank and clinical database based on 96 healthy Caucasian men, aged 50 years, with an apolipoprotein (apo) E3/E3 genotype, who had originally undergone investigations of postprandial lipoprotein metabolism was used for the study. MEASUREMENTS: Total IGF-I, IGFBP-1 and IGFBP-3 were determined in serum by radioimmunoassay (RIA). Free IGF-I was measured by a commercial two-site immunoradiometric assay (IRMA). RESULTS: In multivariate analyses, fasting serum free IGF-I correlated inversely with IMT and accounted for 5% of the variation in multiple R(2). When fasting serum IGFBP-1 was entered in the models instead of IGF-I, IGFBP-1 correlated positively with IMT and accounted for 6% of the variation in IMT. IGFBP-3 and total IGF-I were unrelated to IMT. There were no associations between free IGF-I and cardiovascular risk factors, whereas IGFBP-1 behaved like a component of the insulin resistance syndrome. Serum free IGF-I increased and IGFBP-1 decreased postprandially. CONCLUSION: The data indicate that serum free IGF-I and IGFBP-1 are implicated in early atherosclerosis.

Physicochemical and histological changes in the arterial wall of nonhuman primates during progression and regression of atherosclerosis.

To identify the temporal changes occurring during progression and regression of atherosclerosis in nonhuman primates, we have studied the physicochemical and histological characteristics of arterial wall lesions during a 30-mo progression period of diet-induced hypercholesterolemia and during a 12-mo period of regression. Three groups of cynomolgous monkeys (Macaca fascicularis) were studied. Control groups were fed a basal chow diet for 18, 24, and 30 mo and were compared with progression groups that were fed a high-cholesterol-containing diet for up to 30 mo. Regression groups were fed a high-cholesterol diet for 18 mo to induce atherosclerosis and then fed monkey chow for up to 12 mo. The progression group monkeys were killed at 6, 12, 18, 24, and 30 mo, and the regression animals were killed at 24 and 30 mo (i.e., after 6 and 12 mo of being fed a noncholesterol-containing chow diet). Histology and morphometry, physical microscopy for cholesterol monohydrate crystals, foam cell and droplet melting points and chemical composition studies were completed on a large number of individual arterial lesions. Control animals had very little cholesterol ester, rare foam cells, and no extracellular cholesterol ester droplets or cholesterol crystals. During progression, the arteries first increased cholesterol ester content to produce high melting (approximately 45 degrees C) foam cell-rich lesions essentially devoid of cholesterol crystals. With time, the number of cholesterol crystals increased so that by 30 mo large numbers were present. Foam cells decreased with time but their melting temperature remained high while that of extracellular droplets fell to approximately 38 degrees C. Between 18 and 30 mo necrosis appeared and worsened. After 6-mo regression, unexpected changes occurred in the lesions. Compared with 24-mo progression, the chemical composition showed a relative increase in free cholesterol, a decrease in cholesterol ester and microscopy revealed large numbers of cholesterol crystals. Concomitantly, foam cells decreased and the melting temperature of both intra- and extracellular cholesterol ester markedly decreased. After 12-mo regression cholesterol decreased, cholesterol crystals and necrosis diminished and collagen appeared increased. Thus, during progression there is initially an increase in the number of foam cells containing very high-melting intracellular cholesterol ester droplets. By 30 mo, cholesterol crystals and necrosis dominate and high-melting foam cells appear only at lesion margins, suggesting that the initial process continues at the lesion edge. The lower melting point of extracellular esters indicates a lipid composition different from intracellular droplets. Thus, the changes observed in these animals generally reflect those predicted for progression of human atherosclerosis. During the initial 6 mo of regression, necrosis remains, the number of foam cell decreases, and cholesterol ester content decreases; however the relative proportion of free cholesterol content increases, and large numbers of cholesterol content are formed. Thus, large and rapid decreases in serum cholesterol concentration to produce regression in fact may result in the precipitation of cholesterol monohydrate and an apparent worsening of the lesions. More prolonged regression (12-mo) tends to return the lipid composition of the artery wall towards normal, partially reduces cholesterol crystals, and results in an improved but scarred intima.

Alimentary lipemia, postprandial triglyceride-rich lipoproteins, and common carotid intima-media thickness in healthy, middle-aged men.

BACKGROUND: Alimentary lipemia has been associated with coronary heart disease and common carotid artery intima-media thickness (IMT). This study was designed to investigate the relations of subclasses of postprandial triglyceride-rich lipoproteins (TRLs) with IMT. METHODS AND RESULTS: Ninety-six healthy 50-year-old men with an apolipoprotein (apo) E3/E3 genotype underwent an oral fat tolerance test and B-mode carotid ultrasound examination. The apo B-48 and apo B-100 contents of each fraction of TRLs were determined as a measure of chylomicron remnant and VLDL particle concentrations. In the fasting state, LDL cholesterol (P<0.05) and basal proinsulin (P<0. 05) were significantly related to IMT, whereas HDL cholesterol, plasma triglycerides, and insulin were not. In the postprandial state, plasma triglycerides at 1 to 4 hours (P<0.01 at 2 hours), total triglyceride area under the curve (AUC) (P<0.05), incremental triglyceride AUC (P<0.01), and the large VLDL (Sf 60 to 400 apo B-100) concentration at 3 hours (P<0.05) were significantly related to IMT. Multivariate analyses showed that plasma triglycerides at 2 hours, LDL cholesterol, and basal proinsulin were consistently and independently related to IMT when cumulative tobacco consumption, alcohol intake, waist-to-hip circumference ratio, and systolic blood pressure were included as confounders. CONCLUSIONS: These results provide further evidence for postprandial triglyceridemia as an independent risk factor for early atherosclerosis and also suggest that the postprandial triglyceridemia is a better predictor of IMT than particle concentrations of individual TRLs.

Carotid plaque associations among hypertensive patients.

OBJECTIVE: To assess the relationship between cardiovascular risk factors and carotid plaque. DESIGN: Hypertensive patients were screened for randomization into the Multicenter Isradipine Diuretic Atherosclerosis Study, a trial intended to determine if blood pressure control by isradipine as compared with hydrochlorothiazide will blunt the progression of carotid plaque (intima plus media thickness, 1.3 to 3.5 mm) in patients with serum cholesterol levels of less than 6.85 mmol/L (265 mg/dL) without insulin-dependent diabetes mellitus or estrogen therapy. Demographics of those who underwent B-mode ultrasound evaluations at common, bifurcation, and internal carotid artery sites to detect plaque were assessed from a southern and a northern site. SETTING: Participants were from ambulatory outpatient clinics associated with medical schools. PATIENTS: The initial screening included 1823 hypertensive volunteer patients who were between 40 and 83 years of age who had a diastolic pressure of 90 to 114 mm Hg (or < 90 mm Hg with treatment). OUTCOME MEASURES: Complete data were collected on the variables of age, cholesterol, cigarette smoking, race, gender, and the presence of carotid plaque in 1126 patients. RESULTS: All variables were significantly associated with carotid plaque (intima plus media thickness, > or = 1.3 mm). The adjusted percentage with plaque was 66.4% +/- 3.4% for blacks and 70.1% +/- 2.3% for whites at the southern site and 42.7% +/- 4.5% for blacks and 61.3% +/- 3.2% for whites at the northern site. The rate of plaque was 75.8% among cigarette smokers, despite a mildly elevated cholesterol level. CONCLUSIONS: Although these 1126 cases do not constitute a random sample of patients, these data suggest that there may be regional differences in racial tendencies toward plaque among blacks.

Pulse wave velocity and morphological changes associated with early atherosclerosis progression in the aortas of cynomolgus monkeys.

To determine the time course of changes in arterial stiffness and corresponding morphology during atherosclerosis progression, we determined pulse wave velocity (PWV) in cynomolgus monkeys fed atherogenic (test) and control diets over an 18-month period. At 6-month intervals, thoracic and abdominal aortic PWVs were determined with a pressure transducer retracted down the aorta in 5 cm increments. Iliac artery PWV was determined from the abdominal aortic pressure to a noninvasive femoral pulse. Groups of individual cardiac cycles, triggered by the ECGs, were sampled on a computer and the velocities (PWV) of the pulse wave fronts were calculated. There was no significant difference between groups until 18 months when test animal PWVs in the thoracic (7.44 +/- 0.83 m X s-1) and abdominal (8.52 +/- 0.67 m X s-1) aorta were significantly greater than those of controls (5.02 +/- 0.51 and 6.24 +/- 0.53 m X s-1, respectively), indicating increased arterial stiffness. There was no change in iliac PWV, 10.96 +/- 0.74 m X s-1 for 18-month test compared with 9.44 +/- 0.89 m X s-1 for controls. Constant infusion of nitroprusside and noradrenaline lowered and raised blood pressure and PWV in all groups, and PWV changes due to drug-induced pressure changes were greater in atherosclerotic than in control arteries. Systolic pressure of 18-month test and pulse pressure of 12- and 18-month test groups were significantly greater than controls under all drug conditions, also indicating increased vessel stiffness. Morphometric evaluation of histological aortic cross sections revealed early, noncomplicated atherosclerosis showing gradual increases in the ratio of intimal to medial cross-sectional area in the thoracic (1.24 +/- 0.30 after 18 months) and abdominal (1.70 +/- 0.42 after 18 months) aortas, compared with control ratios of essentially zero. The fraction of the internal elastic lamina covered with atherosclerotic lesions, and maximal intimal thickness also showed significant increases during the test diet period. These data show that early atherosclerosis resulted in aortic but not iliac stiffening which was detected by increased PWV before development of significant stenotic lesions.

Site-specific atherosclerotic plaques in the carotid arteries of middle-aged women from southern Italy: associations with traditional risk factors and oxidation markers.

BACKGROUND AND PURPOSE: Studies on cardiovascular disease have preferentially involved men because of the lower frequency of the disease in preelderly women. The aim of this analysis was to examine, with the use of a standardized ultrasound protocol, a cohort of women to differentiate early atherosclerotic lesions in different carotid segments in relation to traditional (lipoprotein abnormalities, high blood pressure, cigarette smoking) and nontraditional (oxidation markers) cardiovascular risk factors. METHODS: More than 5000 clinically healthy, middle-aged women (n=5062; age range, 30 to 69 years) living in the area of Naples in southern Italy participated in the Progetto Atena, a population-based study on the etiology of cardiovascular disease and cancer in the female population. A subsample of 310 participants underwent high-resolution B-mode ultrasound to assess intima-media thickness of common carotid artery and carotid bifurcation. RESULTS: Early atherosclerotic plaques (intima-media thickness >1.2 mm) were detected within the common carotid arteries in 37 women, in the carotid bifurcations in 77 women, and in both sites in 91 women. After age adjustment, common carotid plaques were found to be associated with higher systolic blood pressure (143 versus 138 mm Hg; P<0.05) and higher body mass index (29 versus 27 kg/m(2); P<0.01), while lesions at the carotid bifurcations were associated with higher LDL cholesterol (4.3 versus 3.8 mmol/L; P<0.01) and with smoking habit. Multivariate odds ratios for the presence of common carotid plaques were related to antibodies against oxidized LDL (odds ratio, 2.72; 95% CI, 1.46 to 5.07), and those for plaques at the bifurcation were related to lipid peroxides (odds ratio, 1.90; 95% CI, 1.04 to 3.47), and both relationships were independent of age, LDL cholesterol concentrations, body mass index, smoking habit, and systolic blood pressure. CONCLUSIONS: In a cohort of clinically healthy, middle-aged women, we found a site-specific association of traditional risk factors and oxidation markers with early atherosclerotic lesions in arterial segments differing in geometry, shear stress, extracellular matrix composition, and cell type populations.

Relationship of intraabdominal fat as measured by magnetic resonance imaging to postprandial lipemia in middle-aged subjects.

Adipose distribution has been associated with coronary artery disease and its risk factors. We previously described an association between postprandial triglyceride response (pptg response) to a standard high-fat meal and extracranial carotid atherosclerosis. This study was designed to evaluate the association between intraabdominal fat and pptg response. Twenty-nine subjects were recalled for determination of intraabdominal fat by magnetic resonance imaging (MRI). Fat was quantified according to an inversion recovery protocol previously validated and the cross-sectional area of intraabdominal fat at the umbilicus was analyzed as an independent variable. We observed a strong independent correlation between intraabdominal fat and pptg response to a fatty meal (r = 0.521, P < 0.05). Baseline triglyceride was also independently correlated with postprandial triglycerides (r = 0.631, P < 0.05). In univariate analysis, intraabdominal fat was correlated with age, sex, body mass index (BMI), waist-to-hip ratio (WHR), and dietary saturated fatty acids. The association with age and BMI persisted in multivariate analyses.

Correlation of noninvasive arterial compliance with anatomic pathology of atherosclerotic nonhuman primates.

Fifteen cynomolgus monkeys were fed a control (n = 3) or cholesterol-containing diet (n = 12) for 26 months. An impedance plethysmograph and a calibrated volume plethysmograph were used to determine femoral arterial volume change, delta V, from femoral arteries. Abdominal aorta pulse pressure was measured directly. The ratio of delta V to pulse pressure, delta P, defined femoral artery compliance. At necropsy, sections of pressure fixed common iliac, external iliac, femoral and carotid arteries were obtained for measurements. The site of the largest atherosclerotic lesion was chosen for histologic measurement. The percentage intima in arterial tissue (PIAT) was determined at the site of the largest atherosclerotic lesions in iliac arteries and averaged. Peak compliance was inversely correlated with the PIAT (Pearson correlation -0.39, P less than 0.10, n = 21) which improved to r = -0.52, P less than 0.01 (n = 27) when the PIAT also included the carotid atherosclerosis. The correlation coefficients were comparable to those obtained for total plasma cholesterol concentration, and direct systolic and diastolic blood pressure. Peak compliance and alpha-cholesterol concentrations provided the best multiple linear regression fit for the prediction of PIAT.

Reduction in tissue LDL accumulation during coronary artery regression in cynomolgus macaques.

The aim of this study was to determine whether the amount of LDL that had accumulated in the coronary arteries of cynomolgus monkeys during an 18-month period on a hypercholesterolemic (H) diet was reduced during subsequent periods of 6 and 12 months on a normolipemic (N) diet. This was performed by assessing the accumulation of LDL in the left anterior descending (LAD) branch of the left coronary artery within an area 4 mm from its origin, since this region contained the largest lesions in the LAD. LDL accumulation was estimated by measuring the percent cross-sectional area of artery occupied by reaction product depicting apo B by an immunoperoxidase procedure. The following reduction in mean (+/- SD) percent cross-sectional area occupied by reaction product was found in 8 animals on the progression diet (group I), 7 animals on the 6-month regression diet (group II), and 9 animals on the 12-month regression diet (group III), respectively: 21.7 +/- 4.7, 6.9 +/- 5.5, and 2.3 +/- 1.3. Differences between group I and either group II or III were statistically significant (using the Wilcoxon signed-ranks test). In group I, LDL was localized primarily in the necrotic core and around pools of foam cells. In groups II and III fewer foam cells and smaller pools of extracellular debris were qualitatively evident, and LDL was localized closer to the lumen and along collagen fibers. These results suggest that lowering of the plasma LDL level following termination of a hypercholesterolemic diet also induces a decrease in the LDL content in coronary artery lesions, even without significant reductions in lesion size, and that this decrease might be responsible for the decrease in foam cells.

Effect of heat shock proteins on survival of isolated aortic cells from normal and atherosclerotic cynomolgus macaques.

Alterations in the level and distribution of arterial heat shock proteins (HSPs) have been demonstrated during atherogenesis. The significance of these changes within the developing and dying plaque, however, is not understood. To examine a potential protective effect of HSPs on arterial cells, enzymatically isolated cells from normal and diet-induced atherosclerotic aortas of cynomolgus macaques were stressed for 20 h with and without added 72/73 kDa heat shock proteins (HSP-72/73), over a range of temperatures and dosages. Cells were analyzed for changes in viability and lysosomal membrane integrity. The responses of cells from normal and diseased aortas for all test regimens were similar. Viability and lysosomal membrane integrity of untreated cells were correlated (r = 0.85), and both factors declined with increasing thermal stress (P less than 0.0005 and P less than 0.004, respectively). Exogenous HSP-72/73 increased cell viability after stress at a minimum concentration of 10 micrograms/ml (P less than 0.05) but was not concentration dependent. Response to different temperatures showed exogenous HSP-72/73 increased cell survival at all temperatures, with the greatest effect at 37 degrees C (P less than 0.01). In contrast, HSP-72/73 did not have an effect on lysosomal membrane integrity for the test period studied. The results demonstrate exogenous HSP-72/73 increases arterial cell survival, suggesting these proteins are associated with a protective mechanism in normal and diseased arteries.

The human carotid atherosclerotic plaque stimulates angiogenesis on the chick chorioallantoic membrane.

The chick chorioallantoic membrane was used to determine whether the carotid atherosclerotic plaque stimulates angiogenesis. Carotid endarterectomy specimens (1 mm3) with fibromuscular plaque (n = 8) and complicated plaque (n = 11) were implanted on the membrane on day nine of incubation and the response evaluated on day 11. Following fixation in situ with 10% formalin the angiogenic response was evaluated by: (1) examining whole membrane mounts, (2) quantitatively from a vascular density index and (3) from a histological study. Unmanipulated chorioallantoic membrane (n = 11) and plaque boiled prior to implantation (n = 6) served as controls. The vascularity of whole mounts of both fibromuscular and complicated plaque was greater than the controls. Vessel density of the membrane was estimated by counting the number of vessels intersecting four concentric circles (144.5 mm total circumference) placed on the formalin fixed membrane. The vascular density index due to the fibromuscular plaque (390.6 +/- 8.3) and complicated plaque (391.0 +/- 14.9) were similar (P greater than 0.9) but were significantly greater (P less than 0.001) than the unmanipulated membrane (327.9 +/- 5.6) or after treatment with the boiled plaque (283.8 +/- 15.6). Transforming growth factor beta 1 confirmed the validity of the experimental model to study angiogenesis. The histology of the chorioallantoic membrane due to either type of plaque was similar. Numerous vessels surrounded the plaque, and intraplaque vessels containing nucleated chick erythrocytes were observed. Although scattered vessels surrounded the boiled plaque, intraplaque vessels were not observed. This study demonstrates that the atherosclerotic plaque has angiogenic properties that may account for the increase in vasa vasorum that is associated with the plaque.

Time course of diet-exacerbated carotid artery atherogenesis in the White Carneau pigeon.

The carotid arteries of White Carneau pigeons fed an atherogenic diet developed fatty streaks, proliferative and atheromatous lesions. The carotid bifurcation had accelerated lesion development when compared to either the proximal internal carotid or the dorsal carotid artery. After 4 weeks of being fed an atherogenic diet, the bifurcation region of all birds showed some lesion involvement. Lesions at the bifurcation initially involved the medial and lateral walls; flow dividers became involved slightly later, with the anterior flow divider consistently developing thicker lesions than the posterior flow divider. Lesions progressed in terms of length of circumference, mean thickness, cross-sectional area, and percent lumen stenosis as the time fed the atherogenic diet increased.20

Magnitude of alimentary lipemia is related to intima-media thickness of the common carotid artery in middle-aged men.

Fat intake leads to generation of potentially atherogenic triglyceride-rich lipoproteins (TRL). To investigate the relationship between early atherosclerotic changes and accumulation of hepatic and intestinal TRL after oral fat intake, an estimate of the intima-media thickness (IMT) was made using ultrasound of the common carotid artery, and postprandial TRL was quantified during a standardized oral fat tolerance test in 30 healthy normo- and hypertriglyceridemic middle-aged men. At base line the expected positive association between the LDL cholesterol level and the IMT of the common carotid artery was observed (r = 0.53, P<0.01). In addition, postprandial plasma triglycerides, in particular those measured late (6 h) after intake of the test meal, correlated positively with the IMT (r = 0.44, P<0.05). Of note, this latter correlation was independent of both the LDL cholesterol and the fasting plasma triglyceride concentrations. In a multivariate analysis, 39% of the total variability for the common carotid IMT were explained by age, LDL cholesterol and the postprandial triglyceride level. In univariate analysis, few statistically significant relations were found between common carotid IMT and postprandial levels of chylomicron remnants, VLDL and VLDL remnants of different particle size, the latter determined by specific measurements of ApoB-48 and ApoB-100 in subfractions of TRL. Therefore, in healthy middle-aged men, elevated postprandial triglyceride levels might identify a metabolic state related to early atherosclerosis.

Apolipoprotein E polymorphism and carotid artery intima-media thickness in a random sample of middle-aged men.

Genetic polymorphism of apolipoprotein E (apoE) is an important factor in the development of coronary artery disease but the results concerning apoE genotype and carotid artery atherosclerosis remain controversial. We investigated a random sample of 189 Finnish middle aged men (mean age 54 years, range 50-59) to assess the role of apoE in the process of carotid atherosclerosis. Intima-media thickness (IMT) of the carotid artery wall was measured at three standardised segments (common carotid artery, bifurcation and internal carotid artery) by B-mode ultrasonography. Overall mean IMT value was also calculated. The carriers of E3/2 (n=20) genotype had significantly lower (P<0.01) total cholesterol and LDL cholesterol concentrations than carriers of E3/3 genotype (n=109) or the E4 allele (n=60). ApoE polymorphism was associated with common carotid artery IMT (P=0.034) when adjusted for age and body-mass index (model 1). The carriers of E3/2 had on average 9% (95% CI 0.8-16%, P=0.028) lower common carotid IMT values than the carriers of E3/3. After further adjustment with LDL and HDL cholesterol, systolic blood pressure, lipoprotein (a), apolipoprotein B and pack-years of smoking (model 2) the association was not statistically significant. The overall mean IMT varied significantly with apoE genotype (P=0.03 for model 1 and P=0.07 for model 2), and it was also lowest in the carriers of E3/2 genotype. This suggests that apoE E3/2 genotype is a protective factor in the development of carotid artery atherosclerosis in randomly selected middle-aged men. The favourable effect might be mediated at least partly by the lowering effect of E3/2 genotype on serum cholesterol.

Correlates of carotid artery stiffness in young adults: The Bogalusa Heart Study.

Decreased arterial elasticity, an independent risk factor for cardiovascular (C-V) disease, is associated with C-V risk factors in middle-aged and older individuals. However, information is limited in this regard in young adults. This aspect was examined in a community-based sample of 516 black and white subjects aged 25-38 years (71% white, 39% male). The common carotid artery elasticity was measured from M-mode ultrasonography as Peterson's elastic modulus (Ep) and relative wall thickness-adjusted Young's elastic modulus (YEM). Blacks and males had higher Ep (P < 0.05); males had higher YEM (P < 0.0001); and blacks had higher wall thickness (P < 0.01). For the entire sample adjusted for race and gender both Ep and YEM correlated significantly (P < 0.05-0.0001) with age, BMI, waist, systolic and diastolic blood pressures, heart rate, product of heart rate and pulse pressure, triglycerides, total cholesterol to HDL cholesterol ratio, insulin and glucose. In a multivariate regression model that included hemodynamic variables, systolic blood pressure, product of heart rate and pulse pressure, age, triglycerides, BMI, and male gender (for YEM only) were independent correlates of Ep (R2 = 0.38) and YEM (R2 = 0.25). When the hemodynamic variables were excluded from the model, age, triglycerides, BMI, black race (Ep only), male gender, parental history of hypertension, HDL cholesterol (inverse association), and insulin (marginal significance) remained independent correlates of Ep (R2 = 0.20) and YEM (R2 = 16). Both Ep and YEM increased (P for trend P < 0.0001) with increasing number of independent continuous risk factors (defined as values above or below the age, race, and gender-specific extreme quintiles) that were retained in the regression models. The observed increasing arterial stiffness (or decreased elasticity) with increasing number of risk factors related to insulin resistance syndrome in free-living, asymptomatic young adults has important implications for prevention.

Influence of dietary fats and an oral contraceptive on plasma lipids, high density lipoproteins, gallstones, and atherosclerosis in african green monkeys.

Twenty-nine African green monkeys were fed diets for 22 months containing 0.79 mg cholesterol/kcal and 40% of calories as either safflower oil or butter with or without the addition of an estrogen- and progestin-containing oral contraceptive. Plasma cholesterol concentrations ranged from 199 to 250 mg/dl. Animals consuming the safflower oil diet had plasma cholesterol concentrations that averaged 61 mg/dl lower than those consuming butter. At least 72% of this lowering was due to a reduction in low density lipoproteins. Triglyceride concentrations were also slightly lower in animals consuming the safflower oil diet. The oral contraceptive lowered total plasma cholesterol concentrations in both diet groups by an average of 41 mg/dl with 54% of this lowering (22 mg/dl) due to a reduction in high density lipoprotein cholesterol. This effect occurred only during the 3 weeks while the contraceptive was being administered and was not apparent 1 week after stopping the drug. Animals consuming safflower oil had bile that was more lithogenic and had more gallstones than did those consuming butter. Addition of the oral contraceptive caused a slight increase in bile lithogenicity, but this increase was not statistically significant. There was no significant interaction between the oral contraceptive and either of the diets to exacerbate cholelithiasis. At the plasma cholesterol concentrations achieved only minimal amounts of atherosclerosis developed and there were no indications of differences due to diet or oral contraceptive in the extent of atherosclerosis.

Detection and monitoring of asymptomatic atherosclerosis in clinical trials.

Methods are currently available to noninvasively detect and evaluate asymptomatic atherosclerosis in the carotid artery, and provide a unique opportunity to monitor the effect of medical intervention during the early stages of atherosclerotic progression. When using high-resolution B-mode ultrasound to monitor lesion change over time, it is the reproducibility of measurements at the arterial wall and lumen that defines the confidence of establishing rates of disease progression. Previous studies have demonstrated that, in a research environment using standardized protocols for scanning and interpretation, the absolute difference between blinded replicate measurements of arterial wall thicknesses at sites of lesion is less than 0.2 mm. The Multicenter Isradipine Diuretic Atherosclerosis Study will use high-resolution B-mode ultrasound to determine the effect of isradipine and hydrochlorothiazide on the rate of progression of carotid artery atherosclerosis in hypertensive subjects. Methods for scanning and interpretation of arterial wall thickenings are presented.

Pravastatin reduces carotid intima-media thickness progression in an asymptomatic hypercholesterolemic mediterranean population: the Carotid Atherosclerosis Italian Ultrasound Study.

PURPOSE: The Carotid Atherosclerosis Italian Ultrasound Study (CAIUS) was performed to test the effects of lipid lowering on the progression of carotid intima-media thickness (IMT) in 305 asymptomatic patients from a Mediterranean country. PATIENTS AND METHODS: Eligibility included hypercholesterolemia (baseline means: low-density lipoprotein [LDL] = 4.68 mmol/L, high-density lipoprotein [HDL] = 1.37 mmol/L), and at least one 1.3 < IMT < 3.5 mm in the carotid arteries. Patients (mean age 55 years, 53% male) were assigned to pravastatin (40 mg/day, n = 151) or placebo (n not equal to 154). Ultrasound imaging was used to quantify IMT at baseline, and semiannually thereafter for up to 3 years. The mean of the 12 maximum IMTs (MMaxIMT), was calculated for each patient visit, and used to determine each patient's longitudinal progression slope. The intention-to-treat group difference in the MMaxIMT progression was chosen a priori as the primary end point. RESULTS: Five serious cardiovascular events (1 fatal myocardial infarction), and 7 drop-outs for cancer were registered. In the pravastatin group, LDL decreased -0.22 after 3 months versus -0.01 in the placebo group, and remained substantially unchanged afterward (-0.23 versus +0.01 at 36 months, respectively). Progression of the MMaxIMT was 0.009 +/- 0.0027 versus -0.0043 +/- 0.0028 mm/year (mean +/- SE, P < 0.0007) in the placebo and pravastatin groups, respectively. IMT progression slopes diverged after 6 months of treatment. CONCLUSIONS: Pravastatin stops the progression of carotid IMT in asymptomatic, moderately hypercholesterolemic men and women. This finding extends the beneficial effects of cholesterol lowering to the primary prevention of atherosclerosis in a population with relatively low cardiovascular event rates, and suggests that this benefit is mediated by specific morphological effects on early stages of plaque development.

Baseline reproducibility of B-mode ultrasonic measurement of carotid artery intima-media thickness: the European Lacidipine Study on Atherosclerosis (ELSA).

BACKGROUND AND OBJECTIVE: The European Lacidipine Study of Atherosclerosis (ELSA) is a prospective, randomized, double-blind, multi-national interventional trial to determine the effect of four-year treatment using the calcium antagonist lacidipine versus the beta-blocker atenolol on the progression of carotid atherosclerosis in 2259 asymptomatic hypertensive patients. B-mode ultrasound is used to measure the primary and secondary endpoints including the mean maximum intima-media thickness (IMT) of the carotid bifurcations and the common carotid arteries (CBM(max)), the mean maximum IMT of 12 standard carotid sites (M(max)) and the overall maximum IMT (T(max)). This paper reports the cross-sectional reproducibility of ultrasound measurements at baseline. METHOD: To evaluate measurement reliability, each patient is scanned twice at baseline and again at four annual visits, with 80% of the replicate scans performed by the same sonographer and 20% by a different sonographer; 50% of the replicate scans are read by the same reader and the other 50% by different readers. RESULTS: The overall coefficient of reliability (R) was 0.859 for CBM(max), 0.872 for M(max) and 0.794 for T(max). The reliability for CBM(max) was stable during the 1 3/4-year baseline period (R = 0.848 to 0.953) and was uniform among the 23 field centres (R = 0.798 to 0.926). Intra- and inter-reader reliability were 0.915 and 0.872 respectively, and intra-sonographer reliability was 0.866. CONCLUSION: The results demonstrate that by implementing standardized protocols and strict quality control procedures, highly reliable ultrasonic measurements of carotid artery IMT can be achieved in large multi-national trials.