Search

Background: Activation of the renin-angiotensin-aldosterone system and oxidative modification of LDL cholesterol play important roles in atherosclerosis. The Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and vitamin E (SECURE), a substudy of the Heart Outcomes Prevention Evaluation (HOPE) trial, was a prospective, double-blind, 3x2 factorial design trial that evaluated the effects of long-term treatment with the angiotensin-converting enzyme inhibitor ramipril and vitamin E on atherosclerosis progression in high-risk patients., Methods and Results: A total of 732 patients >/=55 years of age who had vascular disease or diabetes and at least one other risk factor and who did not have heart failure or a low left ventricular ejection fraction were randomly assigned to receive ramipril 2.5 mg/d or 10 mg/d and vitamin E (RRR-alpha-tocopheryl acetate) 400 IU/d or their matching placebos. Average follow-up was 4.5 years. Atherosclerosis progression was evaluated by B-mode carotid ultrasound. The progression slope of the mean maximum carotid intimal medial thickness was 0.0217 mm/year in the placebo group, 0.0180 mm/year in the ramipril 2.5 mg/d group, and 0.0137 mm/year in the ramipril 10 mg/d group (P=0.033). There were no differences in atherosclerosis progression rates between patients on vitamin E and those on placebo., Conclusions: Long-term treatment with ramipril had a beneficial effect on atherosclerosis progression. Vitamin E had a neutral effect on atherosclerosis progression.

Our objective was to describe the relationship of arterial stiffness and hypertension in a large, population-based sample of men and women. Hypertension-related increases in arterial stiffness may reflect the distending pressure and/or structural alterations in the artery. Included were 10,712 participants, ages 45 to 64 years, of the Atherosclerosis Risk in Communities Study, free of prevalent cardiovascular disease. Hypertension was classified as systolic or diastolic blood pressure (BP) > or =140/90 mm Hg, respectively, or the current use of antihypertensive medications. Common carotid arterial diameter change was measured using B-mode ultrasound and an electronic device that utilized radio frequency signals to track the motion of the arterial walls. Using statistical models to control for diastolic BP and pulse pressure, arterial diameter change was calculated separately in normotensive/ nonmedicated and medicated hypertensives. Hypertension was associated with a smaller adjusted diameter change (ie, greater stiffness) in comparison to optimal blood pressure (BP < 120/80 mm Hg): normotensive/nonmedicated men, 0.33 versus 0.43 mm (P < 0.001); medicated men, 0.34 versus 0.42 mm (P < 0.001); normotensive/ nonmedicated women, 0.34 versus 0.40 mm (P < 0.001), and medicated women, 0.33 versus 0.40 mm (P < 0.001). The relationship between pulse pressure and diameter change (ie, the slope of pulse pressure and diameter change) did not differ between hypertensives and normotensives. These cross-sectional data suggest that hypertension is associated with carotid arterial stiffness; however, these differences in the calculated stiffness appear to be the effect of distending pressure rather than structural changes in the carotid artery.

Arterial stiffness is emerging as an important risk marker for cardiovascular disease. Ultrasound-based measurements of arterial stiffness are in use by several large epidemiological studies. The reliability of ultrasonic measurements of arterial stiffness was assessed as part of one of these, the Atherosclerosis Risk in Communities (ARIC) study. ARIC, a prospective, four-center epidemiological study, used B-mode ultrasound with an electronic tracking device to measure arterial stiffness of the carotid artery. Oscillometric blood pressure measures were obtained before and after the arterial wall tracking. Measurement variability was estimated in 36 volunteers who were scanned at three visits conducted at 7- to 14-day intervals. Between- and within-person components of variation were estimated for arterial diameter and blood-pressure measurements. The correlation (R) between repeated measurements for pulse pressure, the percent change in arterial diameter (strain), and the percent and absolute change in the arterial area were 0.69, 0.67, 0.66 and 0.81, respectively. The R for the stress-strain elastic modulus (Ep), arterial distensibility, and arterial compliance were 0.66, 0.67, and 0.77, respectively. The R for the pressure-adjusted diameter change (i.e., diameter change adjusted for diastolic and pulse pressures) was 0.75. In summary, the ultrasonic measurements of arterial stiffness employed in the ARIC study demonstrate excellent short-term repeatability, demonstrating their utility in field settings.

Background and Purpose: A low HDL cholesterol (HDL-C) frequently occurs in conjunction with a desirable LDL cholesterol (LDL-C) and is a risk factor for coronary heart disease (CHD). Additionally, the presence of carotid atherosclerosis is a strong and independent predictor of morbidity and mortality in patients with CHD. This article describes the prevalence and correlates of sonographically detected carotid atherosclerosis in men with low levels of HDL-C and CHD but without elevated levels of LDL-C or total cholesterol., Methods: High-resolution B-mode ultrasonography was used to quantify intima-media wall thickness (IMT) in the common and internal carotid arteries and at the carotid artery bifurcation in 202 randomly selected male veterans with CHD and low levels of HDL-C who are participating in the VA HDL Intervention Trial. Ultrasonographic measurement of carotid artery wall stiffness was determined in a subset of 94 of these individuals., Results: The mean maximum and single greatest carotid artery IMT measurements were 1.41 and 2.58 mm, respectively. The prevalence of ultrasound-detected carotid atherosclerosis as defined by a mean maximum IMT > or = 1.3 mm was 58.9% and by single maximum IMT > or = 1.5 mm was 87.1%. IMT was associated with increased age, lower extremity arterial disease, systolic blood pressure, and ultrasonographically measured carotid artery stiffness., Conclusions: Men with low levels of HDL-C and CHD but without elevated LDL-C or total cholesterol have a very high prevalence of ultrasound-detected carotid artery atherosclerosis.

Atherosclerotic cardiovascular disease remains a major cause of mortality and morbidity in most developed countries. Experimental and clinical evidence suggests that angiotensin-converting enzyme inhibitors and vitamin E therapy may retard the atherosclerotic process; however, definitive proof in humans is lacking. The Study to Evaluate Carotid Ultrasound Changes in Patients Treated with Ramipril and Vitamin E (SECURE) is designed to assess the effects of ramipril--an angiotensin-converting enzyme inhibitor, at 2 doses: 2.5 mg daily (which has little effect on lowering blood pressure) and 10 mg daily--and the antioxidant vitamin E, 400 IU daily, on atherosclerosis progression in 732 patients using a factorial 3 x 2 study design. High-risk patients with a documented history of significant cardiovascular disease or with diabetes and additional risk factors were enrolled and will be followed for 4 years. The extent and progression of atherosclerosis are assessed noninvasively by B-mode carotid ultrasonography. The SECURE trial is a substudy of the larger Heart Outcomes Prevention Evaluation (HOPE) study of 9,541 high-risk patients evaluating the effects of ramipril and vitamin E on major cardiovascular events (cardiovascular death, myocardial infarction, and stroke). The 2 studies are complementary. Whereas HOPE is expected to provide information on major clinical outcomes, SECURE will shed light on the mechanisms by which these effects may be mediated.

Background and Purpose: Serial ultrasonic B-mode measurements of intimal-medial thickness (IMT) of the carotid artery are commonly used as surrogates for describing atherosclerosis progression. This report describes the longitudinal reliability of IMT measurement during a multicenter clinical trial, quantifies the error attributable to differences among readers, and discusses how studies can be efficiently designed., Methods: Serial B-mode measurements of carotid IMT from the 3-year Asymptomatic Carotid Artery Progression Study (ACAPS; formerly Asymptomatic Carotid Artery Plaque Study) were used to estimate the contributions to longitudinal measurement error of systematic reader effects, nonvisualization, and nonsystematic error and to describe the distribution of "true" progression rates that underlie the observed data. Variance components were estimated from random-effects models fitted to outcome measures formed by averaging IMTs from different sets of carotid artery walls. These were used to contrast the relative efficiency of study designs., Results: Of the total variance of measured IMT, 11% was attributable to systematic differences among readers. Nonvisualization contributed less than 7%. Thus, the predominant source of error was unaccounted for (ie, random error or "noise," which in our analyses included any drift, nonlinearity, and sonographer differences). For studies with measurement protocols similar to ACAPS, follow-up times of 2 years or more are desirable for describing the mean progression rates of cohorts, and of 6 years or more for categorizing progression within individuals. In 3-year studies, sample sizes as low as 237 provide 90% statistical power for detecting risk factors that have correlations with IMT progression of .50 or greater., Conclusions: The ACAPS measurement protocol provided highly reliable serial IMT data. Moderate-sized multicenter studies using B-mode outcomes are feasible.

A randomly selected subset of 100 pairs of baseline and 36-month follow-up carotid B-mode ultrasound examinations from the 919 patients participating in the Asymptomatic Carotid Artery Progression Study (ACAPS) were subjected to a blinded rereading at the conclusion of the trial to assess temporal bias in the measurement of carotid artery intimal-medial thickness (IMT). The original measurements of the primary outcome variable and five secondary outcome variables at baseline and 36 months, respectively, and the 3-year change in each of these variables, were compared with those obtained from the rereadings. For the primary outcome variable, the mean value of 12 IMT measurements obtained from predefined carotid segments, the mean difference (original-rereading) and the 95% confidence interval which resulted from the rereadings were -0.005 (-0.033, 0.023) mm at baseline and -0.009 (-0.031, 0.013) mm at 36 months. The difference in the 3-year change was -0.004 (-0.038, 0.028) mm. The 95% confidence interval for the mean difference between the rereadings and the original readings for the baseline and the 36-month follow-up examinations included zero for all of the six outcome variables as was also the case for the 3-year change in each variable. The magnitude of the mean differences for these 18 variables ranged from 0.004 to 0.034 mm. Intraclass correlation coefficients between the original readings and rereadings ranged from 0.56 to 0.87 with the 3-year changes in outcome variables tending to have lower correlations and the 36-month examinations higher correlations. The carotid IMT measurement process, when combined with uniform reader training, certification and monitoring of reading performance throughout the course of the study, can avoid the temporal bias observed in other studies.

The Atherosclerosis Risk in Communities (ARIC) study is a multicenter, long-term epidemiologic study that uses B-mode ultrasound primarily to measure carotid arterial intima-media wall thickness. To assess the reliability of the measurement process of this application of B-mode technology to population-based research, 36 volunteers from four centers were scanned at three visits, 7-14 days apart. Estimates of the components of variation in the B-mode measurements of artery wall thickness from between-person, between-sonographer, within-sonographer, between-reader and within-reader variation are presented, along with estimates of the correlation R between measures made at repeat visits by different sonographers and read by different readers. The estimates of R for mean intima-media thickness are 0.69, 0.60, 0.54 and 0.66 for the carotid bifurcation, internal carotid, common carotid, and three-segment overall carotid mean, respectively. When these are adjusted to account for differences in between-person variance between the ancillary study and the main ARIC study, the estimated site-specific reliability coefficients appropriate to the ARIC study population are 0.77, 0.73 and 0.70 for mean carotid far-wall intima-media thickness at the carotid bifurcation and the internal and common carotid arteries.

Background and Purpose: B-mode ultrasound imaging affords the opportunity to quantify both intimal-medial thickness (IMT) and lumen diameter of extracranial carotid arteries in ambulatory populations. Since the relation of IMT to lumen diameter may be complex, we asked whether cardiovascular disease risk factors (previously shown to be associated with greater arterial IMT) are related to smaller lumen diameters., Methods: We used B-mode ultrasound to quantify lumen diameter, interadventitial diameter, and IMT of the extracranial carotid arteries and assessed the relationship of these measures to body mass index, smoking, low-density lipoprotein (LDL) and high-density lipoprotein cholesterol, hypertension, and diabetes in 6088 male and 7493 female participants in the Atherosclerosis Risk in Communities (ARIC) cohort., Results: Smoking, hypertension, and LDL cholesterol were consistently related to greater IMT in the common and internal carotid arteries of men and women, as has been previously reported. In the internal carotid artery, smoking, hypertension, and LDL cholesterol were consistently related to smaller lumens. In the common carotid artery, body mass index, smoking, and hypertension were related to significantly larger, and LDL cholesterol to smaller, lumens. Thus, only LDL cholesterol was consistently associated with smaller lumens in both the common and internal carotid arteries., Conclusions: Risk factors relate positively to IMT in both the common and internal carotid arteries and inversely with lumen diameter in the internal carotid artery, in parallel with their relation to clinical events. However, their association with lumen diameters of the common carotid artery in population-based samples is more complex, and in some cases adverse levels of risk factors may be associated with larger lumens.

Background and Purpose: This study was done to assess the relationship between prevalent cardiovascular disease and arterial wall thickness in middle-aged US adults., Methods: The association of preexisting coronary heart disease, cerebrovascular disease, and peripheral vascular disease with carotid and popliteal intimal-medial thickness (IMT) (measured by B-mode ultrasound) was assessed in 13,870 black and white men and women, aged 45 to 64, during the Atherosclerosis Risk in Communities (ARIC) Study baseline examination (1987 through 1989). Prevalent disease was determined according to both participant self-report and measurements at the baseline examination (including electrocardiogram, fasting blood glucose, and medication use)., Results: Across four race and gender strata, mean carotid far wall IMT was consistently greater in participants with prevalent clinical cardiovascular disease than in disease-free subjects. Similarly, the prevalence of cardiovascular disease was consistently greater in participants with progressively thicker IMT. The greatest differences in carotid IMT associated with prevalent disease were observed for reported symptomatic peripheral vascular disease (0.09 to 0.22 mm greater IMT in the four race-gender groups)., Conclusions: These data document the substantially greater arterial wall thickness observed in middle-aged adults with prevalent cardiovascular disease. Both carotid and popliteal arterial IMT were related to clinically manifest cardiovascular disease affecting distant vascular beds, such as the cerebral, peripheral, and coronary artery vascular beds.

This review discusses the quality control of equipment and technician performance in long term, multicentre trials using ultrasound detection and quantification of atherosclerosis. Examples on how such quality control measures could be implemented are given. Based on our own experience and that of other groups we suggest the following items as being important when planning for quality control in this type of study. 1. Write down the specifications demanded with regard to the ultrasound equipment and reading stations. 2. Compare the commercially available equipment on those characteristics by means of in-vitro and/or in-vivo testing. 3. Select the most suitable equipment for all centres and check it before shipping. 4. Sign a full maintenance agreement for all centres. 5. Evaluate the ultrasound devices and reading stations regularly during the study using phantoms. 6. Train sonographer and readers thoroughly before the start of the study. Certify those who successfully complete the training programme and demonstrate proficiency in scanning or reading. 7. Determine each sonographer's/reader's variability before and repeatedly during the study. Give feedback on performance to the sonographer/reader. 8. Create a regular retraining programme for all sonographers/readers and extend for those with poor performance. 9. Feed all the above information to a Data Quality Control Committee, having the ultimate responsibility for the quality control in the study.

Background: HMG CoA reductase inhibitors (or statins), a new class of lipid-lowering compounds, have raised expectations for more widespread use than that of the older lipid-lowering drugs. Not only are they more effective in lowering LDL cholesterol, but they are better tolerated as well. No data exist concerning the effect of statins on early carotid atherosclerosis and clinical events in men and women who have moderately elevated LDL cholesterol levels but are free of symptomatic cardiovascular disease., Methods and Results: Lovastatin (20 to 40 mg/d) or its placebo was evaluated in a double-blind, randomized clinical trial with factorial design along with warfarin (1 mg/d) or its placebo. This report is limited to the lovastatin component of the trial. Daily aspirin (81 mg/d) was recommended for everyone. Enrollment included 919 asymptomatic men and women, 40 to 79 years old, with early carotid atherosclerosis as defined by B-mode ultrasonography and LDL cholesterol between the 60th and 90th percentiles. The 3-year change in mean maximum intimal-medial thickness (IMT) in 12 walls of the carotid arteries was the primary outcome; change in single maximum IMT and incidence of major cardiovascular events were secondary outcomes. LDL cholesterol fell 28%, from 156.6 mg/dL at baseline to 113.1 mg/dL at 6 months (P < .0001), in the lovastatin groups and was largely unchanged in the lovastatin-placebo groups. Among participants not on warfarin, regression of the mean maximum IMT was seen after 12 months in the lovastatin group compared with the placebo group; the 3-year difference was statistically significant (P = .001). A larger favorable effect of lovastatin was observed for the change in single maximum IMT but was not statistically significant (P = .12). Five lovastatin-treated participants suffered major cardiovascular events--coronary heart disease mortality, nonfatal myocardial infarction, or stroke--versus 14 in the lovastatin-placebo groups (P = .04). One lovastatin-treated participant died, compared with eight on lovastatin-placebo (P = .02)., Conclusions: In men and women with moderately elevated LDL cholesterol, lovastatin reverses progression of IMT in the carotid arteries and appears to reduce the risk of major cardiovascular events and mortality. Results from ongoing large-scale clinical trials may further establish the clinical benefit of statins.

Background and Purpose: Measurements of intimal-medial thickness (IMT) of the carotid artery by B-mode ultrasonography are widely used as markers of atherosclerosis. This report describes empirical features of these measurements to characterize their distribution within arterial wall segments, to explore their potential as study outcome measures, and to examine their links with traditional risk factors for cardiovascular disease., Methods: Sequential transverse measurements of IMT in the carotid arteries were made in 899 participants from the Asymptomatic Carotid Artery Progression Study (ACAPS) at baseline. Data from 17 intrasegment sites in each of 12 arterial wall segments were used to describe patterns of thickness and visualization and to characterize cross-sectional area, severity, and roughness/irregularity by the intrasegment averages, maxima, and SDs of IMT, respectively., Results: Serial correlations of IMT measurements indicated localized and diffuse features of disease. The spatial distribution of IMT had two dominant features: overall mass and mass relative to roughness. The validity of these features was demonstrated by their correlation to known risk factors for carotid atherosclerosis: body mass index, age, high-density lipoprotein cholesterol, systolic blood pressure, smoking, and sex., Conclusions: Both the mean and maxima of intrasegment measurements appear to be good candidates for use in clinical studies. B-mode ultrasonography has validity for the description of IMT roughness and shape. Both of these features are linked to cardiovascular risk factors, which supports the multifaceted nature of atherosclerosis.

Background and Purpose: B-mode ultrasound is a widely used technique for the clinical and epidemiological assessment of carotid atherosclerosis. This article describes the relation between arterial intimal-medial thickness (IMT) at different sites within the extracranial carotid artery., Methods: IMT was measured by B-mode real-time ultrasound as an index of atherosclerotic involvement in the extracranial carotid arteries as part of the population-based Atherosclerosis Risk in Communities (ARIC) study. The relation between IMT at different sites was described by correlation coefficients and percentile regression techniques based on between 4034 and 9386 pairs of measurements (variation in sample size depending on the paired sites)., Results: Increased IMT at one site was associated with increased IMT at other sites. The correlation between right and left IMT at the same anatomic location in the carotid artery ranged from .34 to .49; the correlation at different anatomic locations in the carotid artery on the same side ranged from .25 to .43. The distribution of IMT, described by the percentiles of IMT at the inference site as a function of IMT at the index site, showed constricted percentiles of IMT at the inference site for small IMT at the index site and an increase in the spread of percentiles with increasing IMT., Conclusions: Although increased carotid IMT at one site is positively associated with thickened walls at other carotid sites, the ability to accurately predict wall thickness at a site given the wall thickness at other sites is modest. The general association between sites supports the systemic nature of atherosclerosis, while the lack of tight agreement between sites supports the focal nature of the atherosclerotic process.

Background and Purpose: The relation between arterial wall (intimal-medial) thickness and lumen narrowing is complex and has previously been studied predominantly at autopsy. B-mode ultrasound affords the opportunity to visualize both wall and lumen of the extracranial carotid arteries in vivo. Several studies have quantified the relation of various independent variables to wall thickness of carotid arteries in population-based samples, but the relation of age and wall thickness to interadventitial and lumen diameter has not previously been investigated in these samples., Methods: We used B-mode ultrasound to quantify the relation of arterial lumen diameter to age, arterial wall thickness, and arterial size (interadventitial diameter) of the extracranial carotid artery in 13,711 members of the Atherosclerosis Risk in Communities (ARIC) cohort., Results: Men had greater interadventitial diameters, thicker walls, and wider lumens than women. Wall thicknesses of the common carotid artery were greater by 21% in men and 22% in women aged 60 to 64 years compared with those aged 45 to 49 years (P < .001). However, lumen diameters were also greater in older individuals because interadventitial diameters were greater. Wall thickness of the internal carotid artery was also associated positively with age, but the lumen diameter of the internal carotid artery was smaller in older individuals. Diameters of the carotid artery segments also differed in their relation to arterial wall thickening. The lumen of the internal carotid artery was uniformly progressively narrower with increasing wall thickness. For the common carotid artery greater wall thickness bore only a small correlation with narrower lumen diameter for thickening of the arterial wall up to 1.2 mm, but the association was more marked for the range of thicknesses between 1.2 mm and 2.5 mm., Conclusions: When arterial enlargement accompanies increased wall thickness, less lumen constriction results than expected. Quantification of these complex relations in vivo may provide new insight into the pathogenesis of symptoms related to vascular disease. Narrowing of the internal carotid artery lumen associated with thicker walls is consistent with the observation that stenosis develops in this region and often leads to symptoms.

Background and Purpose: B-mode ultrasound is a widely used technique for the clinical and epidemiological assessment of carotid atherosclerosis. This article provides a description of the distribution of carotid atherosclerosis in the general population., Methods: Intimal-medial arterial wall thickness was measured by B-mode real-time ultrasound as an index of atherosclerotic involvement in the extracranial carotid arteries as part of the population-based Atherosclerosis Risk in Communities (ARIC) study. The distribution was described by race-sex strata, in which 759 to 4952 individuals were imaged depending on strata and location in the carotid system., Results: Median wall thickness ranged between 0.5 and 1 mm at all ages; fewer than 5% of ARIC participants had values exceeding 2 mm. Individuals tended to have a larger wall thickness in the carotid bifurcation than in the common carotid artery. Internal carotid artery values were more variable, with higher proportions of both large and small wall thicknesses than in the common carotid. The proportion of individuals with a large wall thickness was greatest at the bifurcation and smallest at the common carotid artery. Men had uniformly larger wall thickness than women. Cross-sectional analysis suggests that age-related increases in wall thickness average approximately 0.015 mm/y in women and 0.018 mm/y in men in the carotid bifurcation, 0.010 mm/y for women and 0.014 mm/y for men in the internal carotid artery, and 0.010 mm/y in both sexes in the common carotid artery., Conclusions: Estimates provided for wall thickness percentiles can serve as "nomograms" by age, race, and sex.

Background: The association between coronary heart disease and lesions of the coronary arteries has led to investigations of different interventions on atherosclerotic change. Currently, B-mode ultrasound of the peripheral arterial vessels, rather than arteriography of the coronary arteries, provides the most accurate evaluation of atherosclerotic disease extent in the patient., Methods and Results: When measuring the effect of risk factor modification on atherosclerotic change, it is important to select appropriate methods and end points for quantifying disease and evaluating subsequent change. Measurements must be valid, precise, and reliable and require appropriate a priori definitions of end points and their change. Consistent methodology within studies is crucial. Multiple measurements and data reduction methods can increase the efficiency of comparisons and merit careful consideration. Missing data arising from nonvisualization of sites complicate analyses. Identifying both covariates of atherosclerotic change and possible confounding interventions require monitoring biochemical, physiological, and/or clinical variables and making inferences from these., Conclusions: To strengthen the rationale for use of B-mode ultrasonography in assessing the natural history of atherosclerosis, four methodological issues must be addressed: evaluation of primary end points using composite and/or individual measurements of atherosclerotic assessment from the carotid arteries, evaluation of new methodology that may allow assessment of the anatomy of specific lesions and/or their potential for rupture, development of methods making complementary use of both angiographic measurements of lumen diameter and ultrasound assessment of the arterial wall, and concrete demonstration of a direct link between increasing intimal-medial thickness and subsequent clinical events. The use of a continuous variable (intimal-medial thickness) in ultrasound studies offers cost/benefit advantages; this methodology continues to evolve.

Background and Purpose: To determine the effect of a lipid-lowering agent and/or a low-dose antithrombotic agent on the progression of early-stage carotid atherosclerosis, noninvasive B-mode ultrasound was used to measure intimal-medial thickness in asymptomatic individuals with moderately elevated lipids as part of the ongoing multicenter Asymptomatic Carotid Artery Plaque Study., Methods: Uniform ultrasonic scanning and reading protocols were implemented to obtain maximum intimal-medial thickness measurements in 12 standard segments in patients having a small to moderate wall thickness (1.5-3.5 mm) in at least one of the carotid arteries. Paired B-mode image recordings on 858 patients, performed 1 month apart and read at a core laboratory (each pair by the same reader), determined both within-sonographer (W, n = 405) and between-sonographer (B, n = 453) reproducibility., Results: The primary end point (mean +/- SD), defined in each individual as the mean value of the 12 maximum intimal-medial thickness measurements, was 1.31 +/- 0.21 mm (W) and 1.32 +/- 0.22 (B) at the time of the second examination. The mean difference in the primary end point (exam 2-exam 1) was -0.01 +/- 0.13 mm (W) and 0.00 +/- 0.15 mm (B). The Pearson correlation coefficients were 0.79 (W) and 0.75 (B). In 90% of the patients, the absolute difference in the primary end point was less than 0.22 mm (W) and less than 0.24 mm (B). Variability of the secondary end point, defined as the single largest intimal-medial thickness measurement in a patient, was between three and four times larger than the variability for the primary end point. Differences in sonographer performance between clinical centers were very small., Conclusions: The results demonstrate that standardized noninvasive ultrasonic techniques yield highly reproducible measures of carotid intimal-medial thickness, which can serve as a measure of carotid atherosclerosis in clinical trials that monitor small rates of lesion progression.

We noninvasively measured changes in average aortic stiffness in 79 cynomolgus monkeys being fed cholesterol progression, regression, and control diets by measuring pulse wave velocity (PWV) in 260 experiments during a 30-month period. Every 6 months, a group of monkeys was studied with invasive aortic PWV techniques and with ultrasonically determined pressure-strain elastic modulus (Ep) of the carotid artery, and then the group was killed so that morphometric evaluation of atherosclerosis severity could be made. After 6 months of a cholesterol progression diet, PWV decreased slightly from 6.2 +/- 0.1 to 5.7 +/- 0.1 m/sec, followed by an approximate linear increase to 8.8 +/- 1.2 m/sec after 30 months on the diet. The corresponding ratio of intimal (plaque) area to medial area (IA/MA) measured on perfusion-fixed cross-sections of the abdominal and thoracic aortas increased from 0.16 +/- 0.07 at 6 months to 1.23 +/- 0.22 at 30 months. Monkeys in the regression groups were fed the cholesterol progression diet for 18 months, followed by a chow diet for 6 or 12 months. In the first 6 months of the cholesterol regression diet, PWV continued to increase from 7.0 +/- 0.2 to 8.1 +/- 0.4 m/sec, and IA/MA was 1.24 +/- 0.18. However, after 12 months of the cholesterol regression diet, PWV decreased to 6.8 +/- 0.4 m/sec, and IA/MA was 0.90 +/- 0.18. The variability of the data demonstrates that PWV is not a simple function of atherosclerosis severity, and the best simple correlation was r = 0.69 (r2 = 0.48) between PWV and intimal area. However, multiple regression analysis of aortic PWV, systolic (SP) and diastolic (DP) blood pressures, and total plasma cholesterol concentration (TPC), all of which can be measured with minimally invasive techniques, improved the prediction of the IA/MA ratio through the following equation: IA/MA = 0.127 PWV-0.039 DP+0.023SP+0.0003TPC-0.292 (r = 0.81, r2 = 0.66). These data suggest that arterial stiffness in combination with minimally invasive parameters can be used to predict the severity of diffuse asymptomatic atherosclerosis in monkeys. However, more widespread application of these data to humans is uncertain because of biological variability and differences between animal models and human subjects.