Robert H. Selzer

The Role of Carotid Arterial Intima-Media Thickness in Predicting Clinical Coronary Events

Carotid arterial intima-media thickness measured with B-mode ultrasonography is used as a noninvasive end point (that is, an outcome) in epidemiologic studies and clinical trials to gauge progression and regression of atherosclerosis [1-3]. As such, carotid arterial intima-media thickness, expressed as a single measurement (in millimeters) or a rate of change (in millimeters per year), is used as a surrogate end point for atherosclerosis of the coronary artery. However, its relation to coronary events has not been fully explored. It is well established that progression of atherosclerosis of the coronary artery determined by sequential coronary angiography is predictive of coronary events [4-6]. A close histologic relation between carotid and coronary atherosclerosis has been seen in autopsy studies [7], and the two arterial beds share many risk factors that contribute to the progression of atherosclerosis [8, 9]. Furthermore, carotid arterial intima-media thickness has been a good indicator of the presence and extent of coronary artery disease in observational studies [10, 11]. The Cholesterol Lowering Atherosclerosis Study [12] was a clinical arterial imaging trial designed to study the effects of colestipol-niacin therapy on progression of atherosclerosis in the coronary, femoral, and carotid arteries. We have reported that treatment is beneficial for all three arterial beds [3, 13-16]. In addition, long-term follow-up of the study cohort indicated that progression of coronary artery disease was predictive of coronary events [4]. The objectives of this long-term follow-up of the Cholesterol Lowering Atherosclerosis Study cohort are 1) to determine whether carotid arterial intima-media thickness [expressed as a single measurement or as a rate of change] predicts coronary events, 2) to compare the relative prognostic utility of the two carotid arterial intima-media thickness measures; and 3) to compare the relative prognostic contribution of the two carotid arterial intima-media thickness measures with an angiographic measure of coronary artery disease progression and lipid levels. Methods Study Design In the Cholesterol Lowering Atherosclerosis Study, 188 nonsmoking men 40 to 59 years of age who had previously had coronary artery bypass graft surgery were randomly assigned to receive colestipol-niacin therapy plus dietary therapy (target diet, <125 mg of cholesterol per day and 22% of energy as fat, 10% as polyunsaturated fat, and 4% as saturated fat) or placebo plus dietary therapy (target diet, <250 mg of cholesterol per day and 26% of energy as fat, 10% as polyunsaturated fat, and 5% as saturated fat) [12]. In addition to the primary end point provided by coronary angiograms at baseline and after 2 years of treatment, B-mode ultrasonography of the carotid artery was done at baseline and every 6 months during the 2-year treatment period. The cohort for this study consisted of patients who had completed the 2-year treatment period and had evaluable coronary and carotid arterial end points. Baseline and 2-year coronary artery films were processed by quantitative coronary angiography in tandem; frames were matched for orientation and degree of contrast filling [17]. For each evaluable arterial segment, three sequential frames were processed in end diastole. For each coronary lesion, percent diameter stenosis was obtained as the average over the three sequential frames. For each patient, the change in percent diameter stenosis over 2 years was averaged for all evaluable coronary artery lesions. B-mode ultrasonographic images of the carotid artery were obtained with a Diasonics CV400 system with a 7.5-MHz probe (Diasonics, Milpetas, California). Longitudinal views of the far wall of the right distal common carotid artery were recorded with the minimum gain necessary for clear visualization of structures. Common carotid arterial intima-media thickness was measured with an automated computerized edge-detection algorithm [18]. The distance between the echoes arising from the blood-intima interface and the media-adventitia interface was taken as the measure of intima-media thickness. Distal common carotid arterial intima-media thickness was the average of approximately 80 intima-media thickness measurements made over 1 cm. Measurements were made by persons blinded to treatment assignment and the occurrence of clinical coronary events. Follow-up for Coronary Events After completion of the 2-year treatment period, the occurrence of major medical events and information on all medications (including lipid-lowering agents) was determined for all patients by a clinic visit (59% of all follow-ups) or a mailed questionnaire (41%) at annual follow-up points through 30 June 1994. No ascertainment bias was associated with method of follow-up. Coronary events were nonfatal acute myocardial infarction, coronary death, and need for coronary artery revascularization [percutaneous transluminal coronary angioplasty or coronary artery bypass graft surgery] because of recurrence or worsening of angina pectoris. For all patient-reported events, hospital records were obtained for confirmation, and all causes of death were confirmed by hospital records and death certificates. Myocardial infarction was diagnosed by a cardiologist who was blinded to treatment assignment and ultrasonographic and angiographic end point measures. Myocardial infarction was confirmed if two of the following three criteria were substantiated: typical chest pain, positive creatine phosphokinase-MB, and a new Q wave on electrocardiogram. In order to include only events that were clearly related to clinical symptoms, we did not count 1) coronary artery revascularizations that were related to the reading of the 2-year coronary angiogram or 2) silent myocardial infarctions noted on electrocardiograms at annual follow-up examinations as clinical coronary events. Statistical Analysis The two dependent variables were time from completion of the trial to nonfatal myocardial infarction or coronary death and time from completion of the trial to the first coronary event (nonfatal myocardial infarction, coronary death, or coronary artery revascularization). The two independent variables were the absolute carotid arterial intima-media thickness (in millimeters), measured at the end of the 2-year trial, and the annual rate of change in carotid arterial intima-media thickness (in millimeters per year), evaluated over the 2-year trial. The intima-media thickness change rate was computed for each patient by fitting a least-squares regression line relating intima-media thickness measurements to time in the study. The average number of ultrasonographic examinations per patient was 2.8 0.4. The absolute carotid arterial intima-media thickness is a cumulative measure of carotid atherosclerosis, whereas the intima-media thickness change rate represents the speed with which atherosclerosis of the carotid artery is changing. Univariate and multivariate proportional hazards models were used to test for relations (overall and within each treatment group) between the intima-media thickness variables and coronary event rates. Covariates included the baseline value for intima-media thickness (for analyses of intima-media thickness change rates) and treatment group (for analyses of the total sample). Because patients had the option to continue their randomized, blinded treatment in a 2-year extension of the Cholesterol Lowering Atherosclerosis Study, an additional covariate indexed whether a given patient was treated in the 2-year extension period. Likelihood ratio tests for trend in coronary event rates used each intima-media thickness variable as continuous data. Hazard ratios (as estimators of relative risks) and 95% CIs were expressed per SD (0.03 mm/year for the carotid arterial intima-media thickness change rate and 0.13 mm for the absolute carotid arterial intima-media thickness). Absolute carotid arterial intima-media thickness values were categorized by quartiles based on the distribution of the baseline intima-media thickness for all patients; carotid arterial intima-media thickness change rates were categorized by quartiles based on the distribution of changes in the placebo group. Hazard ratios were then computed for each of the upper quartiles relative to the first. Because earlier analyses of the study cohort showed a significant relation between progression of coronary artery disease (assessed by the change in percent diameter stenosis using quantitative coronary angiography) and coronary events [4], we also evaluated the relative prognostic contributions of this angiographic measure of coronary artery disease progression and the ultrasonographic measure of carotid arterial intima-media thickness progression. For the change in percent diameter stenosis, hazard ratios and 95% CIs were expressed per 10% change in percent diameter stenosis. The cutoff of 10% change is double the measurement error for percent diameter stenosis on short-term repeated angiography. The joint prognostic contribution of the carotid artery and coronary artery measures of atherosclerosis with lipid levels that were found to be significantly different between patients with and without coronary events was also evaluated. Values given are the mean SD unless otherwise indicated. Role of the Funding Source The authors were responsible for data collection, data management, statistical analyses, and data interpretation. Research was supported by the National Heart, Lung, and Blood Institute through investigator-initiated grants to Dr. Hodis (RO1-HL-49885) and Dr. Mack (RO3-HL-54532). The funding source had no role in deciding whether the study would be submitted for publication. Results Characteristics of the Cohort at Baseline and after Treatment Of the 188 patients randomly assigned to treatment, 42 (22%) were excluded from the study: Eleven did not have a baseline ultrasonogram, 13 had no ultrasonographic fo

Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial.

Coronary heart disease is the leading cause of death in women, and mortality rates from this disease substantially and steadily increase after menopause (13). Population studies indicate that estrogen reduces the incidence of coronary heart disease in women. Bilateral oophorectomy before natural menopause increases the risk for coronary heart disease (4). This pattern of risk for coronary heart disease suggests that endogenous estrogens, including 17-estradiol, play a cardioprotective role before menopause. More than 40 observational studies have suggested that hormone replacement therapy (HRT) reduces cardiovascular morbidity and mortality in postmenopausal women (5, 6). Most of these studies were conducted in healthy postmenopausal women who used unopposed estrogen replacement therapy (ERT). Although observational studies are important, selection bias is a potential problem, especially when studying HRT, since healthier women tend to use hormones (7). Only randomized, controlled trials can ensure that patients are assigned to treatment in an unbiased manner and can establish the efficacy of HRT for reducing the progression of atherosclerosis and its clinical sequelae. The effect of unopposed ERT on progression of atherosclerosis in healthy postmenopausal women without preexisting cardiovascular disease remains untested in randomized, controlled trials. We report the results of the Estrogen in the Prevention of Atherosclerosis Trial (EPAT), a randomized, double-blind, placebo-controlled trial designed to test whether unopposed micronized 17-estradiol reduces progression of subclinical atherosclerosis in healthy postmenopausal women without preexisting cardiovascular disease. Our primary hypothesis was that unopposed ERT significantly reduces the progression of subclinical atherosclerosis. Methods Study Design Potential participants were prescreened by telephone and seen at three screening visits 2 to 4 weeks apart to collect baseline data and to determine final study eligibility. Women were eligible if they were postmenopausal (serum estradiol level < 73.4 pmol/L [<20 pg/mL]), 45 years of age or older, and had a low-density lipoprotein (LDL) cholesterol level of 3.37 mmol/L or greater ( 130 mg/dL). Women were excluded if breast or gynecologic cancer had been diagnosed in the past 5 years or if these cancers were identified during screening; if they had previously used HRT for more than 10 years or had used HRT within 1 month of the first screening visit; if they had five or more hot flushes daily that interfered with daily activity and precluded randomization, diastolic blood pressure greater than 110 mm Hg, untreated thyroid disease, life-threatening disease with a survival prognosis of less than 5 years, total triglyceride level of 4.52 mmol/L or greater ( 400 mg/dL), high-density lipoprotein (HDL) cholesterol level less than 0.78 mmol/L (<30 mg/dL), or serum creatinine concentration greater than 221 mol/L (>2.5 mg/dL); or if they were current smokers. All women, including those with diabetes mellitus, were included provided that their fasting blood glucose level was less than 11.1 mmol/L (<200 mg/dL). All participants gave written informed consent, and the study protocol was approved by the University of Southern California Institutional Review Board. Packets of study medications were prepared in a blinded manner (to both the clinical staff and participants) before the start of the study. Computer-generated random numbers were used to assign participants to unopposed estradiol or placebo in one of eight strata, defined by LDL cholesterol level (<4.15 mmol/L [<160 mg/dL] or 4.15 mmol/L), previous duration of HRT use (<5 years or 5 years), and diabetes mellitus (yes or no). As a new participant was determined to be eligible for randomization, the next packet in sequence in the appropriate stratum was obtained and recorded. The Data Coordinating Center monitored adherence to sequential assignment of medication packets. The participants, gynecologists, clinical staff, and image analysts were blinded to treatment assignment. The data monitor and data analyst were blinded to treatment assignment until analyses were completed. Participants were followed every month for the first 6 months and every other month thereafter for a total of 2 years. All participants received dietary counseling according to step II American Heart Association dietary recommendations: 200 mg of cholesterol or less per day, 25% of energy as total-fat calories, and 7% of energy as saturated-fat calories. Dietary intake was monitored at each clinic visit by using 3-day dietary booklets (Nutrition Scientific, South Pasadena, California). Participants received lipid-lowering medication (primarily hydroxymethylglutaryl coenzyme A reductase inhibitors) if their LDL cholesterol level exceeded 4.15 mmol/L (160 mg/dL). Vital signs; clinical events; adherence; and use of nonstudy medications, dietary supplements, and nutriceuticals were ascertained at each visit. Carotid artery ultrasonography was performed at baseline (two visits 1 to 3 weeks apart) and every 6 months thereafter. The baseline intimamedia thickness was the average of the two measurements. Pelvic examination (and uterine ultrasonography in participants with a uterus), Papanicolou smear, and mammography were done yearly in all participants. Uterine biopsy was performed if endometrial thickness was 5 mm or more. Adverse clinical symptoms and bleeding were assessed by the study gynecologist, who was blinded to treatment assignment. The primary trial end point was the rate of change in intimamedia thickness of the right distal common carotid artery far wall in computer image processed B-mode ultrasonograms (815). Power calculations indicated that a sample size of 200 (100 participants per treatment group) was needed to detect a treatment effect size (the standardized difference in progression rates between the two treatment groups) of 0.40 or greater with 80% power. Two hundred twenty-two participants (111 per treatment group) were recruited to accommodate the anticipated dropout rate. Assessment of the Progression of Subclinical Atherosclerosis High-resolution B-mode ultrasonograms of the right common carotid artery were obtained by using a 7.5-MHz linear-array transducer attached to a Toshiba SSH 140A ultrasonography system (Toshiba Corp., Tokyo, Japan). The ultrasonographers were blinded to treatment assignment. Participants were placed in a supine position with the head rotated to the left by using a 45-degree head block. The jugular vein and carotid artery were located in the transverse view, with the jugular vein stacked above the carotid artery according to modification of a procedure described by Beach and colleagues (16). The transducer was then rotated 90 degrees around the central line of the transverse image of the stacked jugular vein and carotid artery to obtain a longitudinal image while the stacked position of the vessels was maintained. All images contained anatomic landmarks for reproducing probe angulation, and a hard copy of each participants baseline image was used as a guide for follow-up examinations. For each participant, the depth of field, gain, monitor intensity setting, and other instrumentation settings used at baseline examination were used at all follow-up examinations. These techniques significantly reduce measurement variability (14, 15). All images were recorded with the electrocardiogram tracing on super-VHS video tape. An image analyst who was blinded to treatment assignment measured the intimamedia thickness of the distal common carotid artery far wall with automated computerized edge detection using an in-house software package (Prosound, University of Southern California, Los Angeles, California), as described elsewhere (14, 15). Carotid intimamedia thickness was the average of approximately 70 to 100 individual measurements between the intimalumen and mediaadventitia interfaces along a 1-cm length just distal to the carotid artery bulb. This method standardized the location and the distance over which intimamedia thickness was measured and ensured that the same portion of the arterial wall was measured in each image and compared within and across all participants. Laboratory Measurements Participants fasted for 8 hours before sample collection. Total plasma cholesterol and triglyceride levels were measured by using an enzymatic method of the Standardization Program of the National Centers for Disease Control and Prevention. High-density lipoprotein cholesterol levels were measured after lipoproteins containing apolipoprotein B were precipitated in whole plasma by using heparin manganese chloride. Low-density lipoprotein cholesterol levels were estimated by using the Friedewald equation (17). Serum estradiol and fasting insulin levels were measured by using radioimmunoassay. Fasting serum glucose levels were measured by using the glucose oxidase technique on a Beckman Glucose II analyzer (Beckman Instruments, Brea, California). Hemoglobin A1c levels were measured by using high-performance liquid chromatography (Bio-Rad Diamat, Bio-Rad Corp., Hercules, California). Statistical Analysis We compared demographic and baseline clinical and laboratory values between the estradiol and placebo groups by using a t-test for independent samples for means or a chi-square test for proportions. At each study visit, adherence to study treatment was determined by calculating the percentage pill adherence (number of pills consumed divided by the number that should have been consumed) and by measuring estradiol levels. The average percentage pill adherence (over the entire study and by 6-month study period) and average serum estradiol levels (over the entire study) were compared between treatment groups by using a t-test for independent samples. The preplanned intention-to-treat analysis of the primary study end point, progression of subclinical atherosclerosis (def

Beneficial effects of colestipol-niacin therapy on the common carotid artery. Two- and four-year reduction of intima-media thickness measured by ultrasound.

BackgroundControlled clinical trials have reported treatment effects evaluated with serial imaging in coronary and femoral but not cervical arteries. The Cholesterol Lowering Atherosclerosis Study, a coronary, cervical, and femoral angiographic trial of colestipol plus niacin, included a pilot study of standardized carotid ultrasound imaging. Methods and ResultsSeventy-eight subjects had ultrasound studies at baseline, 2, and 4 years. Twenty-four drug and 22 placebo subjects had carotid ultrasound images at baseline, 2, and 4 years with matching cervical angiograms. Computer image processing was applied to ultrasound images of common carotid (far wall) and cervical angiograms. Computer operators were blind to treatment group. Carotid ultrasound measurements were tested for treatment effects and compared with measurements of atherosclerosis in coronary and cervical angiograms. Drug subjects showed significant progressive reduction in carotid thickness at 2 (P=.OOO1) and 4 years (p=.OOO1); placebo subjects significantly increased wall thickness at 2 and 4 years. Reduced levels of apolipoprotein B and increased levels of high density lipoprotein cholesterol and apolipoprotein C-M were significant predictors of carotid wall thinning. Ultrasound-measured carotid intima-media thickness was correlated at baseline with visually read coronary angiographic stenosis and at 2 years with a robust computer measurement of mild carotid atherosclerosis. ConclusionsCommon carotid intima-media thickening can be reduced by colestipol-niacin treatment. Two-year image-processed carotid ultrasound trials can provide adequate power with 50 subjects per group to test for this treatment effect.

Reduction in Carotid Arterial Wall Thickness Using Lovastatin and Dietary Therapy: A Randomized, Controlled Clinical Trial

Controlled clinical trials to assess the effects of therapy for atherosclerosis have generally used either clinical cardiovascular events or serial arterial imaging as end points. Serial coronary angiographic assessment of lesion change has been the most commonly used end point in arterial imaging trials [1]. Evidence now indicates that high-resolution B-mode ultrasonographic measurement of the combined thickness of the carotid arterial intima-media complex is a reliable end point for lipid-lowering interventional trials [1]. Unlike angiographic imaging procedures that focus on changes in the lumen, noninvasive imaging of the arterial wall 1) directly quantifies the response of early atherosclerotic changes to risk-factor modification, 2) can be done as often as necessary in symptomatic or asymptomatic patients of any age, and 3) carries negligible risk [2]. In addition, the measurement of distal common carotid arterial far wall intima-media thickness (carotid arterial intima-media thickness) by automated computerized edge detection varies less than angiographic measurement of the coronary arteries; therefore, a much smaller sample size is needed to show a therapeutic effect [1, 3-5]. The Cholesterol Lowering Atherosclerosis Study (CLAS), a randomized, placebo-controlled, serial arterial imaging clinical trial [6], was designed to comprehensively survey the effects of colestipol-niacin plus dietary therapy on the progression of atherosclerosis in the coronary [7-9], femoral [10], and carotid arterial beds [3, 4]. That study was the first randomized, controlled clinical trial to provide evidence for a drug-induced reduction in carotid arterial intima-media thickness using B-mode ultrasonographic imaging as an outcome measurement of change in early, preintrusive atherosclerosis (the stage at which atherosclerosis is limited to the arterial wall and does not intrude into the arterial lumen) [3, 4]. The serial ultrasonographic results showed the powerful advantage of modeling sequential change over time [4]. The Monitored Atherosclerosis Regression Study (MARS) was a randomized, double-blind, placebocontrolled, serial arterial imaging clinical trial in which carotid arterial intima-media thickness was measured every 6 months with B-mode ultrasonography. Similar in design to CLAS, MARS was an independent clinical trial that showed that lovastatin plus dietary therapy reduced the progression of lesions of the coronary arteries as determined by both visual assessment of coronary artery change and quantitative coronary angiography [11, 12]. The ultrasonographic methods and findings from CLAS were replicated in a subgroup of 30 patients from MARS who, like the CLAS participants, were nonsmoking men who had had coronary arterial bypass grafts [1]. In this paper, we extend the findings of these studies to the complete cohort of patients from MARS with serial carotid arterial ultrasonographic measurements. We report evidence of benefit from lovastatin plus dietary therapy on early, preintrusive atherosclerosis through the measurement of change in the carotid arterial intima-media thickness in 188 patients evaluated every 6 months for as long as 4 years. We also relate these changes in early atherosclerosis to clinical, lipid, lipoprotein, and apolipoprotein risk factors for atherosclerosis. Methods Design of the Monitored Atherosclerosis Regression Study This study was a randomized, double-blind, placebo-controlled serial coronary angiographic and carotid arterial ultrasonographic imaging clinical trial that has been described previously [12]. Two hundred seventy patients (91% male, smokers and nonsmokers, 37 to 67 years of age) with total serum cholesterol levels between 4.92 and 7.64 mmol/L (190 mg/dL to 295 mg/dL) were randomly assigned to receive either lovastatin, 80 mg/d, or placebo. Two hundred fifteen patients were at the University of Southern California, and 55 were at the University of Wisconsin. The lovastatin group and the placebo group had identical dietary goals: no more than 250 mg of cholesterol per day, 27% of energy as total fat calories, 7% of energy as saturated fat calories, 10% of energy as monounsaturated fat calories, and 10% of energy as polyunsaturated fat calories. All patients had angiographically confirmed coronary artery disease in at least two segments with at least a 50% stenosis. Coronary angiography was done under standardized conditions at baseline and at 2 and 4 years after randomization; the 2-year results have been reported previously [11]. The 215 patients at the University of Southern California also had B-mode carotid ultrasonography, the results of which were used to measure carotid arterial intima-media thickness at baseline and every 6 months throughout the trial. Of these 215 patients, 196 (91%) had angiography at 2 years; 58% of the patients (77 receiving lovastatin and 48 receiving placebo) agreed to participate in an optional, double-blind, 2-year extension of the original randomized trial. An independent External Data and Safety Monitoring Committee recommended discontinuing the 2-year extension because of the observed treatment benefit in the per-patient reduction in stenosis for high-grade lesions as determined by quantitative coronary angiography, and in a panel assessment of overall change in coronary artery lesions [11]. Sixty-nine (32%) of the 215 patients at the University of Southern California had angiography at 4 years. Patients in the lovastatin group who participated in the 2-year extension had on-trial lipid levels, coronary artery end points, and rates of change in carotid arterial intima-media thickness similar to those of the treated patients who chose not to participate in the extension. Patients in the placebo group who chose not to participate in the extension had poorer coronary outcome at 2 years than did the patients who participated (P = 0.02), but both participants and nonparticipants had similar on-trial lipid levels and equivalent rates of change in carotid arterial intima-media thickness (0.02 0.04 mm/y). Lipid, Lipoprotein, and Apolipoprotein Levels Total serum cholesterol and total serum triglyceride levels were measured using an enzymatic method under the Standardization Program of the National Centers for Disease Control and Prevention; patients fasted 8 hours before samples for analysis were collected. High-density lipoprotein (HDL) cholesterol levels were measured after apolipoprotein B-containing lipoproteins were precipitated in whole plasma with heparin manganese chloride. Low-density lipoprotein (LDL) cholesterol levels were estimated using the Friedewald equation [12, 13]. Plasma apolipoprotein A-I, B, C-III, and E levels [14-17] were measured using electroimmunoassay at the Oklahoma Medical Research Foundation. Apolipoprotein C-III levels were measured in whole plasma as well as in heparin manganese supernatants (apolipoprotein C-III-HS) and heparin manganese precipitates (apolipoprotein C-III-HP) as previously described [18]. Apolipoprotein C-III-HS approximates apolipoprotein C-III in HDL, and apolipoprotein C-III-HP approximates apolipoprotein C-III contained in very-low-density lipoprotein (VLDL) plus LDL. Lipid, lipoprotein, and apolipoprotein levels were measured at baseline, and then lipid levels were measured every 2 months and lipoprotein and apolipoprotein levels were measured every 4 months throughout the study. Ultrasonography and Image Analysis The methods for ultrasonography and image analysis for carotid arterial intima-media thickness and their reproducibility have been previously described [3, 5]. B-mode scanning was done with a Diasonics CV400 ultrasound system with a 7.5-MHz probe (Diasonics, Milpitas, California). Longitudinal views of the near wall and the far wall of the right distal common carotid artery were recorded with the minimum gain needed to clearly visualize structures. An image analyst, blinded to treatment assignment, measured the distal common carotid arterial far wall intima-media thickness by automated computerized edge detection using a 386/33 PC computer equipped with a Data Translation DT 2862 image-processing board (Data Translation, Marboro, Massachusetts). The automated computerized edge-finding algorithm results in closely spaced measurements of intima-media thickness, approximately 100 to 120 points/cm, from which the average intima-media thickness is determined. The distance between the echoes arising from the blood-intima interface and from the media-adventitia interface was taken as the measure of the intima-media thickness complex [19]. The computerized edge-detection method has been described previously [5]. Statistical Analysis We compared the clinical measures and lipid, lipoprotein, and apolipoprotein levels at baseline for patients with and those without carotid arterial ultrasonographic end point data. For patients with carotid arterial ultrasonographic end point data, we compared carotid arterial intima-media thickness at baseline, and clinical measures and lipid, lipoprotein, and apolipoprotein levels at baseline and on-trial in the treatment group with those in the placebo group. On-trial levels of these variables were computed as averages of all measurements made during the trial, weighted by the time interval between measurements. Significance testing was done using the Student t-test for independent samples, with the two-sided significance level set at 0.05. For each patient, we fit a least-squares regression line relating carotid arterial intima-media thickness to the time since baseline ultrasonography to estimate the annual rate of progression of carotid arterial intima-media thickness. Thus, the unit of analysis was a patient-specific annualized progression rate of intima-media thickness; mean progression rates were then compared between treatment groups. Because carotid arterial intima-media thickness differed significantly at baseline between the treatment groups, we

Evaluation of computerized edge tracking for quantifying intima-media thickness of the common carotid artery from B-mode ultrasound images

A new method to measure carotid intima-media thickness (IMT) from B-mode ultrasound images was developed that utilizes automatic tracking of the lumen-intima and media-adventitia echoes. Phantom studies and human replicate studies under typical clinical protocols for common carotid IMT measurement were carried out to assist in evaluation of the method. A lucite step wedge phantom was used to show that incorporation of sub-pixel interpolation to locate echo boundaries allowed detection of changes in the echo separation that were 5-10 times smaller than the axial resolution of the ultrasound transducer. For average IMT measured in the distal common carotid artery (CCA) wall in 24 subjects scanned twice within 60 days, mean absolute difference was 0.036 mm with a standard deviation of 0.045 mm. Replicate scans obtained 1 week apart of eight subjects by three sonographers showed the intersonographer variability was 5.4%. In another study of 12 subjects scanned every 4 months for 48 months, the root mean square deviation of the IMT measurements from a linear regression line was 0.030 mm. These data indicate that the method is equally precise over short intervals (60 days) and over long intervals (48 months). The new automated computerized edge tracking method presented in this paper represents an advance for image analysis of B-mode ultrasound images of common carotid IMT with measurement variability substantially reduced (2 to 4 times) compared with currently available manual methods.

Alpha-Tocopherol Supplementation in Healthy Individuals Reduces Low-Density Lipoprotein Oxidation but Not Atherosclerosis The Vitamin E Atherosclerosis Prevention Study (VEAPS)

Background—Epidemiological studies have demonstrated an inverse relationship between vitamin E intake and cardiovascular disease (CVD) risk. In contrast, randomized controlled trials have reported conflicting results as to whether vitamin E supplementation reduces atherosclerosis progression and CVD events. Methods and Results—The study population consisted of men and women ≥40 years old with an LDL cholesterol level ≥3.37 mmol/L (130 mg/dL) and no clinical signs or symptoms of CVD. Eligible participants were randomized to DL-&agr;-tocopherol 400 IU per day or placebo and followed every 3 months for an average of 3 years. The primary trial end point was the rate of change in the common carotid artery far-wall intima-media thickness (IMT) assessed by computer image-processed B-mode ultrasonograms. A mixed effects model using all determinations of IMT was used to test the hypothesis of treatment differences in IMT change rates. Compared with placebo, &agr;-tocopherol supplementation significantly raised plasma vitamin E levels (P <0.0001), reduced circulating oxidized LDL (P =0.03), and reduced LDL oxidative susceptibility (P <0.01). However, vitamin E supplementation did not reduce the progression of IMT over a 3-year period compared with subjects randomized to placebo. Conclusions—The results are consistent with previous randomized controlled trials and extend the null results of vitamin E supplementation to the progression of IMT in healthy men and women at low risk for CVD.

Improved common carotid elasticity and intima-media thickness measurements from computer analysis of sequential ultrasound frames

B-mode ultrasound has gained popularity as a non-invasive method for direct visualization of superficial vessels. With B-mode ultrasound, arterial stiffness can be directly measured since image acquisition of the arterial wall thickness and vessel diameter can be obtained simultaneously in a dynamic fashion throughout the cardiac cycle. Recently, a method was developed to measure carotid arterial diameter and intima-media thickness (IMT) from B-mode images that utilizes computerized edge tracking-multiframe image processing that automatically measures arterial diameter and IMT in multiple sequential frames spanning several cardiac cycles. To evaluate this method, replicate B-mode common carotid artery ultrasound examinations and blood pressure measurements were obtained in 24 subjects 1-2 weeks apart. Approximately 80 sequential frames spanning two cardiac cycles were analyzed from each ultrasound examination to obtain maximum arterial diameter (D(max)), minimum arterial diameter (D(min)), and IMT using a computerized edge detection method. The intraclass correlations of D(max), D(min), and IMT were 0.97-0.99 and the mean absolute difference for these measurements were 0.03-0.11 mm. The coefficient of variation for D(max) and D(min) were 1.28 and 1.18%, respectively. The intraclass correlation for several standard arterial stiffness indices, Petersons elastic modulus, Youngs modulus, arterial distensibility, compliance, and the beta stiffness index ranged between 0.84 and 0.89. Additionally, it was determined that averaging IMT over five frames centered at D(min) reduced single frame IMT measurement variability by 27% (P=0.005) compared with IMT measured from a single frame corresponding to D(min). Comparison of the phasic relationship of D(max) and D(min) measured from the B-mode ultrasound image with the simultaneously recorded electrocardiogram (ECG) signal in the 24 subjects, provided a more accurate method of frame selection for arterial diameter extrema independent of the ECG signal. The method of computerized edge detection-sequential multiframe image processing presented in this paper represents a technological advance for image analysis of B-mode ultrasound images of common carotid arterial dimensions that is highly reproducible and directly applicable to noninvasive imaging of atherosclerosis.

Progression of Coronary Artery Disease Predicts Clinical Coronary Events Long-term Follow-up From the Cholesterol Lowering Atherosclerosis Study

BACKGROUND Progression of coronary artery disease is assumed to be a surrogate end point for clinical coronary events. Because no single method or measure for a coronary angiographic end point is uniformly accepted as optimal, the utility and validity of surrogate end points for predicting clinical coronary events remain unsettled. METHODS AND RESULTS The Cholesterol Lowering Atherosclerosis Study randomized 162 nonsmoking, 40- to 59-year-old men with previous coronary artery bypass graft surgery to colestipol/niacin plus diet or placebo plus diet. Atherosclerosis change on 2-year coronary angiograms was evaluated by a consensus panel and by quantitative coronary angiography (average per-subject change in percent diameter stenosis [%S] and minimum lumen diameter [MLD). With all three end points, the benefit of colestipol/niacin treatment on coronary artery atherosclerosis has been reported. Annual follow-up for an average of 7 years (range, 6.3 months to 10 years) has been carried out on all subjects who completed the 2-year angiogram. Clinical coronary events (need for revascularization, nonfatal acute myocardial infarction, and coronary death) have been documented. Risk of clinical coronary events was positively related to coronary lesion progression for all three surrogate end points (P<.05). New lesion formation in bypass grafts (P=.02) and progression of mild/moderate lesions ( < 50%S) were predictive of clinical coronary events (P<.01). Change in MLD contributed significantly to the prediction of clinical coronary events beyond a model with %S alone (P<.05). CONCLUSIONS In this population of nonsmoking men with previous bypass surgery, both the consensus panel- and quantitative coronary angiography-based end points of coronary artery disease progression predict clinical coronary events. Subjects who demonstrate greater coronary artery lesion progression have an increased risk of future clinical coronary events. Design of shorter, smaller trials of antiatherosclerotic agents is justified.

Intermediate-Density Lipoproteins and Progression of Carotid Arterial Wall Intima-Media Thickness

BACKGROUND Although LDL cholesterol (LDL-C) is generally accepted to be a major risk factor for progression of atherosclerosis, the traditional measurement of LDL-C includes measurement of IDL. Little is known about the relationship between IDL and progression of atherosclerosis. Therefore, we investigated the association of plasma lipoprotein subclasses with progression of preintrusive carotid artery atherosclerosis in the Monitored Atherosclerosis Regression Study (MARS). METHODS AND RESULTS MARS was a randomized, double-blind, placebo-controlled serial arterial imaging trial conducted in subjects 37 to 67 years old with angiographically defined coronary artery disease. Analytical ultracentrifugation was used to determine lipoprotein subclasses, including LDL (Sf 0 to 12), IDL (Sf 12 to 20), VLDL (Sf 20 to 400), and HDL (F1.20 0 to 9) in 188 subjects. Subjects were randomized to a cholesterol-lowering diet plus placebo or lovastatin 80 mg/d. The outcome measure, the annual progression rate of the distal common carotid artery far wall intima-media thickness determined by high resolution B-mode ultrasonography, was determined at baseline and every 6 months on trial. When the major apolipoprotein B-containing lipoproteins were measured independently, IDL (r=.21, P<.005) but not VLDL (r=-.09, P=.24) or LDL (r=.09, P=.26) was associated with the progression of carotid artery intimamedia thickness. CONCLUSIONS These data provide further evidence for the role of triglyceride-rich lipoproteins in the progression of atherosclerosis and support the evidence that indicates that the risk of atherosclerosis attributable to LDL-C may in part be the result of lipoproteins in the IDL fraction (Sf 12 to 20) that is included within the traditional measurements of LDL-C.

Effects of colestipol-niacin therapy on human femoral atherosclerosis.

The 2-year therapy effect on femoral atherosclerosis was evaluated in the Cholesterol Lowering Atherosclerosis Study (CLAS), a randomized, placebo-plus-diet-controlled angiographic trial of colestipol-niacin therapy plus diet in men with previous coronary bypass surgery. Different diet compositions were prescribed to enhance the differential in blood cholesterol responses between the two groups. The annual rate of change in computer-estimated atherosclerosis (CEA), a measure of lumen abnormality, was evaluated between treatment groups. A significant per-segment therapy effect was found in segments with moderately severe atherosclerosis (p less than 0.04) and in proximal segments (p less than 0.02). When segmental CEA measures were combined into a per-patient score using an adaptation of the National Heart, Lung, and Blood Institute scoring procedure, a significant therapy effect was observed (p less than 0.02). Total variance of the annual change rate in CEA was as predicted from pilot studies, but measurement variation was larger. The therapy effect observed in femoral arteries, although significant, was less marked than the strong and consistent benefit previously reported for both native coronary arteries and aortocoronary bypass grafts.