Carotid intimal-medial thickness is related to cardiovascular risk factors measured from childhood through middle age: The Muscatine Study.

BACKGROUND: Higher carotid intimal-medial thickness (IMT) is associated with cardiovascular risk factors and is predictive of coronary artery disease and stroke in older adults. Carotid IMT was measured in young and middle-aged adults to determine its relationship with risk factors measured (1) in childhood, (2) currently, and (3) as a "load" from childhood to adulthood. METHODS AND RESULTS: Carotid ultrasound studies were performed in 346 men and 379 women aged 33 to 42 years who were representative of a cohort followed since childhood and who live in Muscatine, Iowa. The mean of the measurements of maximal carotid IMT at 12 locations was determined for each subject. A medical questionnaire was completed, and measurements of anthropometric characteristics and risk factors were obtained. The mean maximum carotid IMT was 0.79+/-0.12 mm for men and 0.72+/-0.10 mm for women. On the basis of multivariable analysis, the significant current predictors of IMT were age and LDL cholesterol in both sexes and diastolic blood pressure in women. Total cholesterol was a significant childhood predictor in both sexes, while childhood body mass index was significant only in women. For men, LDL cholesterol, HDL cholesterol, and diastolic blood pressure were predictive of carotid IMT in a risk factor load model, whereas in women, LDL cholesterol, body mass index, and triglycerides were predictive. CONCLUSIONS: Higher carotid IMT in young and middle-aged adults is associated with childhood and current cardiovascular risk factors, as well as risk factor load.

Individual and combined effects of estrogen/progestin therapy and lovastatin on lipids and flow-mediated vasodilation in postmenopausal women with coronary artery disease.

OBJECTIVES: We sought to examine the individual and combined effects of estrogen/progestin therapy versus lovastatin on lipids and flow-mediated vasodilation in postmenopausal women with heart disease. BACKGROUND: Little information is available regarding the relative benefits of estrogen replacement therapy versus reductase inhibitors and the potential utility of their combination as lipid-lowering therapy for postmenopausal women. METHODS: We conducted a randomized, double-blind, crossover trial in 24 postmenopausal women, each of whom received the following drug regimens during three consecutive six-week treatment periods: 1) hormone replacement (oral dose of 0.625 mg/day conjugated equine estrogens and 2.5 mg/day medroxyprogesterone acetate); 2) 20 mg lovastatin/day and 3) hormone replacement plus lovastatin. RESULTS: Total and low density lipoprotein (LDL) cholesterol were significantly lowered and high density lipoprotein (HDL) cholesterol was significantly increased by all three regimens compared with baseline (p < 0.05). Lovastatin was more effective than estrogen/progestin in reducing LDL (p < 0.001), but estrogen/progestin was slightly more effective in increasing HDL. The hormone replacement and lovastatin regimen blocked the estrogen-associated increase in triglycerides. Hormone replacement (alone and with lovastatin) resulted in increases in brachial artery flow-mediated vasodilator capacity (p = 0.01 for both regimens) and the area under the curve (p = 0.016 and p = 0.005, respectively) compared with baseline. Percent dilation was greatest after the hormone replacement regimen, whereas the area under the curve was greatest after hormone replacement plus lovastatin (69% improvement vs. baseline). CONCLUSIONS: In postmenopausal women with coronary disease and hyperlipidemia, conjugated equine estrogen produced significant improvements in lipids and vasodilator responses despite the concurrent administration of low dose medroxyprogesterone acetate. Low dose lovastatin produced greater reductions in LDL, but less dramatic improvements in vasodilator responses. Estrogen/progestin plus lovastatin may provide additional benefits via a greater reduction in the LDL/HDL ratio and attenuation of estrogen-associated hypertriglyceridemia. More information is needed about the safety and efficacy of such combinations of hormone replacement and reductase inhibitor therapy.

Estrogen replacement and brachial artery flow-mediated vasodilation in older women.

It remains unclear whether estrogen therapy (with or without progestin) improves endothelial function in older postmenopausal women with or at risk for coronary heart disease. To address this issue, we analyzed brachial artery flow-mediated vasodilation in the Cardiovascular Health Study, a longitudinal study of cardiovascular risk factors in subjects over 65 years of age. At the tenth annual Cardiovascular Health Study examination, 1662 women returned for follow-up. Eighteen percent (n=291) were current users of estrogen replacement, most of whom (75.9%, n=221) took unopposed estrogen. Brachial artery ultrasound examinations measuring vasodilation in response to a flow stimulus (hyperemia) were performed on 1636 women. There were no statistical differences in brachial flow-mediated vasodilator responses between users and nonusers, even after adjustment for potential confounders. Absence of an effect was most notable in women over 80 years old and in those with established cardiovascular disease. However, among women without clinical or subclinical cardiovascular disease or its risk factors, there was a significant association between hormone replacement therapy use and flow-mediated vasodilator responses (P=0.01). Among older postmenopausal women, favorable vascular effects of estrogen may be limited to those who have not yet developed atherosclerotic vascular disease. These data emphasize the importance of ongoing efforts to determine the role of hormone replacement therapy for primary prevention of cardiovascular disease.

Arterial stiffness and the development of hypertension. The ARIC study.

Decreased elasticity in large and medium-sized arteries has been postulated to be associated with cardiovascular diseases. We prospectively examined the relation between arterial elasticity and the development of hypertension over 6 years of follow-up in a cohort of 6992 normotensive men and women aged 45 to 64 years at baseline from the biracial, population-based Atherosclerosis Risk in Communities (ARIC) Study. Arterial elasticity was measured from high-resolution B-mode ultrasound examination of the left common carotid artery as adjusted arterial diameter change (in micrometers, simultaneously adjusted for diastolic blood pressure, pulse pressure, pulse pressure squared, diastolic arterial diameter, and height), Peterson's elastic modulus (in kilopascals), Young's elastic modulus (in kilopascals), and beta stiffness index. Incident hypertension (n=551) was defined as systolic blood pressure >/=160 mm Hg, diastolic blood pressure >/=95 mm Hg, or the use of antihypertensive medication at a follow-up examination conducted every 3 years. The age-, ethnicity-, center-, gender-, education-, smoking-, heart rate-, and obesity-adjusted means (SE) of baseline adjusted arterial diameter change, Peterson's elastic modulus, Young's elastic modulus, and beta stiffness index were 397 (5), 148 (2.0), 787 (12.7), and 11.43 (0.16), respectively, in persons who developed hypertension during follow-up, in contrast to 407 (1), 124 (0.6), 681 (3.7), and 10.34 (0.05), respectively, for persons who did not. The similarly adjusted cumulative incident rates of hypertension from the highest to the lowest quartiles of arterial elasticity were 6.7%, 8.0%, 7.3%, and 9.6%, respectively, when measured by adjusted arterial diameter change (P<0.01). One standard deviation decrease in arterial elasticity was associated with 15% greater risk of hypertension, independent of established risk factors for hypertension and the level of baseline blood pressure. These results suggest that lower arterial elasticity is related to the development of hypertension.

Enteric coating of fenoprofen calcium reduces gastrointestinal microbleeding.

The effects of plain and enteric-coated fenoprofen calcium (Nalfon, Dista, Indianapolis, Ind.) on gastrointestinal microbleeding were studied in 32 normal male volunteers in a randomized, open-label, parallel trial at two inpatient research facilities. A 1-week placebo (baseline) period preceded 2 weeks of fenoprofen therapy (enteric coated or plain, 600 mg q.i.d.). Fecal blood loss was measured by 51Cr-tagged erythrocyte assay and averaged over days 4 to 7 (baseline) and 11 to 14 and 18 to 21 (active therapy). At one center gastrointestinal irritation was evaluated endoscopically before and after active therapy. Endoscopy showed both formulations to cause mucosal damage not evident by subject-reported symptoms. Four of the 16 subjects developed asymptomatic duodenal ulcers. Mean daily fecal blood loss was significantly lower (P = 0.03) with enteric-coated (mean +/- SD, 1.104 +/- 0.961 ml/day) than with plain fenoprofen calcium (mean +/- SD, 1.686 +/- 0.858 ml/day), suggesting that tolerance of fenoprofen can be improved with administration in an enteric-coated form.

Evaluation of coronary risk factors in patients with heterozygous familial hypercholesterolemia.

Age at onset of clinically manifested coronary artery disease (CAD) varies widely among patients with familial hypercholesterolemia (FH). A number of factors in addition to high low-density lipoprotein cholesterol (LDL) have been suggested as predictors of risk among patients with FH, but a comprehensive examination of their utility is lacking. We therefore measured plasma lipids, carotid intima-medial thickness, and a variety of coronary risk factors in 262 patients with FH > or = 30 years old (68 of whom had premature CAD). Age (p < 0.0001) and gender were the most important determinants of premature CAD risk, with men having 5.64 times the risk of women (p < 0.0001). In addition, cigarette smoking (odds ratio [OR] 2.71, p = 0.026), smaller LDL as determined by the LDL cholesterol/LDL apolipoprotein B ratio (OR 2.60, p = 0.014), and white blood cell count (p = 0.014) were also statistically significant risk factors. Lipoprotein(a) and the presence of xanthoma were associated with risk only in very early coronary cases. After correction for age, carotid intima-media thickness was not associated with CAD risk. Insulin, fibrinogen, homocysteine, plasma C-reactive protein, and the angiotensin-converting enzyme insertion/deletion polymorphism were unrelated to risk in this cohort. These results provide little justification for extensive investigation of risk factors among patients with FH, at least for the risk factors examined here. Rather, the inherent high LDL cholesterol of these patients should be the focus of preventive efforts. The novel finding of increased risk with smaller LDL may prove useful but needs further confirmation.

Study design and baseline characteristics of the study to evaluate carotid ultrasound changes in patients treated with ramipril and vitamin E: SECURE.

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.

Assessment of temporal bias in longitudinal measurements of carotid intimal-medial thickness in the Asymptomatic Carotid Artery Progression Study (ACAPS). ACAPS Research Group.

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.

Variability in B-mode ultrasound measurements in the atherosclerosis risk in communities (ARIC) study.

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.

Variation of common carotid artery elasticity with intimal-medial thickness: the ARIC Study. Atherosclerosis Risk in Communities.

The Atherosclerosis Risk in Communities (ARIC) study is a prospective investigation of the etiology and natural history of atherosclerosis and cardiovascular disease in four U.S. communities. The purpose of this work is to investigate the relationship between common carotid artery elasticity and intimal-medial thickness (IMT) in the four race-gender groups represented in the ARIC cohort. Noninvasive ultrasonic methods were used to measure IMT and the [systolic minus diastolic] diameter change (DC) of the left common carotid artery in 10,920 black and white, men and women between the ages of 45 and 64 y. The relationship between DC and IMT and IMT2 was examined after adjustment of DC for age, height, diastolic diameter, diastolic blood pressure and linear and quadratic terms for pulse pressure. This adjusted value of DC was used as an index of elasticity of the common carotid artery in the ARIC cohort with larger values of adjusted DC implying a more elastic vessel. The general behavior of adjusted DC with increasing IMT was observed to be qualitatively similar in all four race-gender groups. Adjusted DC remained nearly constant or increased slightly for values of IMT between approximately 0.4 and 0.8 mm, up to approximately the 90th percentile of IMT, and then decreased above the 90th percentile of IMT. Common carotid artery elasticity, defined as adjusted DC, varies with increasing IMT in the ARIC cohort in a manner consistent with results from previous studies in animals and human subjects addressing the variation of several elasticity indices with atherosclerotic involvement and risk factor exposure in the aorta, and brachial and radial arteries. Our results suggest that thicker common carotid artery walls in middle-aged U.S. populations are no stiffer than thinner walls, except for the thickest 10% of arteries. Since the distal common carotid artery frequently contains atheromatous plaques in this population, the lack of change in stiffness, indeed, the reduction in stiffness per unit thickness, may reflect the various stages of early common carotid atherosclerosis most often found in this population. These are characterized more by destruction of arterial wall structural elements than by changes such as widespread or circumferential sclerosis, which would strengthen and stiffen the artery.

Detection of early atherosclerosis in M. fascicularis with transcutaneous ultrasonic measurement of the elastic properties of the common carotid artery.

The elastic properties of 22 common carotid arteries from 13 male cynomolgus monkeys (M. fascicularis) that were fed either a high cholesterol (test) diet or a standard monkey chow (control) diet for 18 months were measured noninvasively with 5 MHz ultrasound. A B-mode image of the artery was obtained with a 32-element linear array transducer, and a single line of video ultrasonic information was selected for tracking the echoes from the adventitial side of the near wall to the lumen-intima interface of the far wall. This technique measured lumen diameter plus anterior wall thickness. The diastolic diameter (Dd) (mean +/- SEM) of the test arteries was slightly larger than controls (2.9 +/- 0.1 vs 2.5 +/- 0.1 mm), whereas the fractional diameter change from diastole to systole (DeltaD/Dd, where DeltaD = diameter change) was slightly less (0.062 +/- 0.010 vs 0.082 +/- 0.011). Direct subclavian artery pulse pressure (DeltaP) in the test animals (63 +/- 4 mm Hg) was significantly greater than in the controls (41 +/- 2 mm Hg), whereas there was no difference in diastolic pressure (85 +/- 3 vs 81 +/- 2), respectively. The pressure-strain elastic modulus Ep = (DeltaP/DeltaD) Dd was significantly greater in the test monkeys (182 +/- 33 kPa) than in the controls (73 +/- 9 kPa). Morphometric analysis of atherosclerosis revealed more connective tissue and intra- and extracellular lipids in the test arteries than in the controls. Based on the average of three cross-sections equally spaced along each common carotid artery, the intimal area and the maximal intimal thickness averaged 0.89 +/- 0.16 mm2 and 0.26 +/- 0.04 mm for the test monkeys compared to negligible intimae from the controls. Medial area also was significantly greater in the test monkeys (0.71 +/- 0.03 mm2) compared to controls (0.57 +/- 0.04 mm2). Percentage stenosis defined as intimal area/IEL area, where IEL area is that within the internal elastic lamina, showed the test arteries to have 30 +/- 5% stenosis compared to 0% for the controls. However, dilatation appeared to compensate for any loss in lumen area due to intimal thickening. In this study, significant carotid artery stiffening associated with diet-induced atherosclerosis is demonstrated. This noninvasive technique may be useful in pediatrics and in preventive medicine for the detection of arterial stiffening associated with early progressive atherosclerotic lesions.

The Maryland experience and a practical proposal to expand existing models in ambulatory primary care.

Two unique models for caring for the uninsured and underinsured are operating in Maryland. The first is a group practice, primary care model with a unique ambulatory Medicare waiver that has had a positive impact on patients and physicians. The second is a financial model--an all-payer prospective rate-setting system for all critical care inpatient hospitals that, during a 13-year period from 1977 through 1989, has saved the citizens of the state approximately $5.361 billion, has allowed hospitals to provide $1.657 billion of charity care and bad debts, and has earned $517 million in net profits. The reasons for the success of each of the models are discussed and form the basis for a practical and politically feasible proposal: merge the best aspects of each model into an ambulatory primary care-based model financed through an all-payer prospective charge system.

A simple optical method for observing medical ultrasound pulse characteristics in vitro.

An optical method is described for studying the spatial and temporal characteristics of broad-band ultrasonic pulses propagating in transparent media. The simplicity of the approach suggests its consideration as a method for calibration and comparison of the transmitted pulse characteristics of medical ultrasound systems.

An approach to the noninvasive periodic assessment of arterial elasticity in the young.

The detailed variation of the lumen diameter of common carotid arteries throughout the cardiac cycle was noninvasively measured using a pulse-echo ultrasonic technique in a population of 100 free-living, unrelated, human subjects between the ages of 6 and 25 years. The fractional diameter change (mean +/- SEM) during the cardiac cycle in the 50 male subjects (0.122 +/- 0.004) was found to be significantly (P less than 0.001) greater than the corresponding diameter change in the 50 female subjects (0.106 +/- 0.003). The pressure-strain elastic modulus, Ep, for the carotid arteries was also computed for these subjects by dividing the blood pulse pressure measured in the brachial artery by the fractional diameter change of the carotid. The male elastic modulus (67 +/- 3 kPa) was not significantly (P approximately 0.17) different from the female elastic modulus (62 +/- 2 kPa). Subject age and systolic blood pressure were able to explain approximately one-third of the variability in Ep. Reproductibility studies clearly demonstrated that only a small fraction of the remaining variability could be attributed to experimental technique or intrasubject variability. The results suggest that studies can now be safely performed on young human subjects to assess the effects of a variety of developmental, behavioral, and environmental factors on arterial elasticity. Such results could help to establish an important data base on arterial mechanics which might help in evaluating health promotion recommendations to societies.

Anatomic correlates of aortic pulse wave velocity and carotid artery elasticity during atherosclerosis progression and regression in monkeys.

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.

Ultrasonic measurement of the elastic modulus of the common carotid artery. The Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND AND PURPOSE: The Atherosclerosis Risk in Communities Study is a prospective investigation of the etiology and natural history of atherosclerosis and the etiology of clinical disease in four US communities. METHODS: Noninvasive ultrasonic methods were used to determine mean wall thickness (WT), radius (R), and circumferential arterial strain (CAS) in the left common carotid artery of 3,321 white male and female study participants between the ages of 45 and 64 years. The mean and standard deviation of Young's elastic modulus (Y) in 5-year age groups were determined for each sex by combining the ultrasonic data with concurrent noninvasive measurements of pulse pressure (PP) in the right brachial artery using the equation Y = (R/WT) x (PP/CAS). RESULTS: Significant (p = 0.0001) age group differences in Y were observed in both sexes, with the mean value increasing from 701 kPa in women and 771 kPa in men in the 45-49-year-old age group to 965 and 983 kPa, respectively, in the 60-64-year-old age group. Significant (p = 0.0001) age group differences were also observed for WT, the WT/R ratio, PP, CAS, and the PP/CAS ratio in both sexes. A sex difference in Y was detected (male greater than female, p = 0.0006) only in the 45-49-year-old age group. Significant (p less than 0.0001) sex differences were found, with men having a greater lumen diameter calculated as 2 x (R - WT), a greater WT, and a greater 2R in all age groups. The WT/R ratio did not differ in both sexes in all age groups. CONCLUSIONS: Knowledge of the arterial wall elastic modulus and the parameters required for its determination can provide important insight into structural changes occurring within the arterial wall with age and sex, and possibly with the onset of very early arterial disease.

Quality control in ultrasound studies on atherosclerosis.

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.

Spatial distribution of carotid intimal-medial thickness as measured by B-mode ultrasonography.

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.

Decreased arterial elasticity associated with cardiovascular disease risk factors in the young. Bogalusa Heart Study.

Noninvasive ultrasonic examinations were performed in 1984 on a biracial sample of 109 10- to 17-year-old adolescents to determine whether elastic properties of the carotid arteries are associated with cardiovascular disease risk factors in the young. The subjects examined were in either the upper (high risk) or lower (low risk) race-, sex-, and age-specific tertile for both serum total cholesterol (TC) and systolic blood pressure (SBP) during a 1981-82 community survey. The pressure-strain elastic modulus (Ep), a measure of stiffness, for the carotid arteries was calculated by dividing the pulse pressure by the fractional diameter increase in the carotid artery during the cardiac cycle, as measured by ultrasonic techniques. Repeat studies on 20 randomly selected subjects demonstrated high reproducibility of the elasticity measurements (intraclass correlation coefficient = 0.84). The mean Ep in the high risk group was 5.1 kPa higher than in the low risk group, after controlling for race, sex, and age (one-sided p value = 0.03). Furthermore, a positive parental history of myocardial infarction was related to increased Ep levels (p less than 0.05), independently of race, sex, age, TC, and SBP. The results indicate that ultrasonic techniques can detect functional differences in the carotid arteries of children and adolescents that are associated with the risk of cardiovascular disease as adults.

Reliability of longitudinal ultrasonographic measurements of carotid intimal-medial thicknesses. Asymptomatic Carotid Artery Progression Study Research Group.

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.