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Data suggest that estrogen-containing hormone therapy is associated with beneficial effects with regard to cardiovascular disease when the therapy is initiated temporally close to menopause but not when it is initiated later. However, the hypothesis that the cardiovascular effects of postmenopausal hormone therapy vary with the timing of therapy initiation (the hormone-timing hypothesis) has not been tested.A total of 643 healthy postmenopausal women were stratified according to time since menopause (6 years [early postmenopause] or ≥10 years [late postmenopause]) and were randomly assigned to receive either oral 17β-estradiol (1 mg per day, plus progesterone [45 mg] vaginal gel administered sequentially [i.e., once daily for 10 days of each 30-day cycle] for women with a uterus) or placebo (plus sequential placebo vaginal gel for women with a uterus). The primary outcome was the rate of change in carotid-artery intima-media thickness (CIMT), which was measured every 6 months. Secondary outcomes included an assessment of coronary atherosclerosis by cardiac computed tomography (CT), which was performed when participants completed the randomly assigned regimen.After a median of 5 years, the effect of estradiol, with or without progesterone, on CIMT progression differed between the early and late postmenopause strata (P=0.007 for the interaction). Among women who were less than 6 years past menopause at the time of randomization, the mean CIMT increased by 0.0078 mm per year in the placebo group versus 0.0044 mm per year in the estradiol group (P=0.008). Among women who were 10 or more years past menopause at the time of randomization, the rates of CIMT progression in the placebo and estradiol groups were similar (0.0088 and 0.0100 mm per year, respectively; P=0.29). CT measures of coronary-artery calcium, total stenosis, and plaque did not differ significantly between the placebo group and the estradiol group in either postmenopause stratum.Oral estradiol therapy was associated with less progression of subclinical atherosclerosis (measured as CIMT) than was placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause. Estradiol had no significant effect on cardiac CT measures of atherosclerosis in either postmenopause stratum. (Funded by the National Institute on Aging, National Institutes of Health; ELITE ClinicalTrials.gov number, NCT00114517.).

Background Adults infected with HIV have increased atherosclerosis potentially associated with both HIV and non‐ HIV associated factors. We characterized risk factors for atherosclerosis as measured by noninvasive vascular imaging. Methods and Results We used B‐mode ultrasound to examine levels and correlates of echogenicity and vessel wall thickness of the carotid artery intima‐media complex in 1282 HIV ‐infected and 510 HIV ‐uninfected women of the Women's Interagency HIV Study. Levels of gray scale median ( GSM , a measure of echogenicity) did not vary between HIV infection groups. In both groups, smokers had increased GSM , whereas age, diabetes, elevated blood pressure, and high BMI were associated with lower (rather than higher) GSM . Each of these non‐lipid CVD risk factors, especially age and blood pressure, was also associated with higher levels of carotid artery intima‐media thickness ( cIMT ). Higher serum triglyceride levels were associated with lower GSM in both HIV ‐infected and HIV ‐uninfected groups. Additional lipid risk factors for low GSM including high LDL cholesterol and low HDL cholesterol levels were identified in HIV uninfected but not in HIV infected women. In contrast to findings for GSM , among the lipid parameters only LDL cholesterol level had an association with cIMT , which was observed only in the HIV uninfected group. Conclusions Lipid and non‐lipid risk factor associations with echolucency of the carotid artery and the thickness of the common carotid artery intima‐media layer suggest that these measures capture different aspects of atherosclerosis.

We investigated whether change in coronary artery atherosclerosis as measured by quantitative coronary angiography is related to cardiovascular event risk. Although many studies have demonstrated the effectiveness of statins in decreasing atherosclerotic progression and cardiovascular event risk, a relation between coronary atherosclerotic progression and event risk has not been documented in clinical trials that have evaluated statin therapy. The Monitored Atherosclerosis Regression Study (MARS) was a randomized, double-blind, placebo-controlled trial designed to test whether lovastatin would decrease coronary atherosclerotic progression as measured by quantitative coronary angiography. We followed 173 subjects in the MARS who had minimum luminal diameter and percent diameter stenosis measured at the beginning and end of a 2-year intervention. Postintervention follow-up events over a mean period of 9.4 years were reported by subjects and verified by medical records. Two-year percent stenosis and minimum luminal diameter changes were tested in relation to clinical event risk in multivariate Cox's regression models. Events ascertained were (1) coronary death and myocardial infarction, (2) coronary death, myocardial infarction, coronary artery bypass grafting, and percutaneous transluminal coronary angioplasty, and (3) any cardiovascular event. Increased percent stenosis was associated with significantly increased hazard ratios (HRs) in all event categories (category 1 HR 1.55 per SD percent stenosis, p

In postmenopausal women with coronary artery disease, conjugated equine estrogen with or without continuous administration of medroxyprogesterone acetate has failed to slow the progression of atherosclerosis. Whether 17beta-estradiol (the endogenous estrogen molecule) alone or administered sequentially with medroxyprogesterone acetate can slow the progression of atherosclerosis is unknown.We conducted a double-blind, placebo-controlled trial in 226 postmenopausal women (mean age, 63.5 years) who had at least one coronary-artery lesion. Participants were randomly assigned to usual care (control group), estrogen therapy with micronized 17beta-estradiol alone (estrogen group), or 17beta-estradiol plus sequentially administered medroxyprogesterone acetate (estrogen-progestin group). In all patients the low-density lipoprotein (LDL) cholesterol level was reduced to a target of less than 130 mg per deciliter. The primary outcome was the average per-participant change between base-line and follow-up coronary angiograms in the percent stenosis measured by quantitative coronary angiography.After a median of 3.3 years of follow-up, the mean (+/-SE) change in the percent stenosis in the 169 participants who had a pair of matched angiograms was 1.89+/-0.78 percentage points in the control group, 2.18+/-0.76 in the estrogen group, and 1.24+/-0.80 in the estrogen-progestin group (P=0.66 for the comparison among the three groups). The mean difference in the percent stenosis between the estrogen group and the control group was 0.29 percentage point (95 percent confidence interval, -1.88 to 2.46), and the mean difference between the estrogen-progestin group and the control group was -0.65 (95 percent confidence interval, -2.87 to 1.57).In older postmenopausal women with established coronary-artery atherosclerosis, 17beta-estradiol either alone or with sequentially administered medroxyprogesterone acetate had no significant effect on the progression of atherosclerosis.

Few studies have examined the correlation between change in carotid artery intima-media thickness (IMT) and change in coronary artery disease. In the Cholesterol Lowering Atherosclerosis Study, current nonsmoking men with coronary artery disease were randomized to colestipol-niacin or placebo. Among 133 subjects with baseline and on-trial coronary angiography and carotid ultrasonography, colestipol-niacin treatment significantly reduced progression of atherosclerosis by both end point measures (2-year average change in percent diameter stenosis by coronary angiography and rate of change in carotid IMT). Significant correlations between change in common carotid artery IMT and quantitative coronary angiographic measures of change were evident over all coronary artery lesions, and in mild:moderate (B 50% diameter stenosis), but not severe (] 50% diameter stenosis) coronary artery lesions. In mild:moderate lesions, correlations with change in common carotid IMT were: percent diameter stenosis (r0.28, P0.002), minimum lumen diameter (r 0.28, P 0.002), and vessel edge roughness (r0.25, P0.003). While measures obtained by carotid ultrasonography and coronary angiography are correlated, they each assess different aspects of atherosclerosis change. © 2000 Elsevier Science Ireland Ltd. All rights reserved.

Background Although assessment of progression of atherosclerosis by quantitative coronary angiography (QCA) is used as a surrogate for coronary events, no validation study has compared the several QCA measures used. Methods and Results The Cholesterol Lowering Atherosclerosis Study was a clinical trial testing the efficacy of colestipol-niacin on the progression of coronary atherosclerosis. Baseline/2-year coronary angiograms were obtained on 156 men with prior coronary artery bypass graft surgery. Changes in percent diameter stenosis and minimum lumen diameter (both measured in coronary lesions and segments) and coronary segment measures of average diameter, percent involvement, and vessel edge roughness were measured by QCA. Coronary events ascertained over 12 years of follow-up included myocardial infarction (MI), coronary death, and coronary artery revascularizations. Proportional hazards models evaluated the relation between QCA change measures and coronary events. Changes in percent diameter stenosis and minimum lumen diameter of coronary artery lesions were significantly related to the risk of MI/coronary death. All QCA measures were significantly related to the risk of any coronary event. Relative risks for each QCA measure were of similar magnitude when estimated separately within each treatment group. Change in minimum lumen diameter of lesions was the only measure independently associated with the risk of coronary events. Conclusions All QCA measures of progression of coronary artery disease were related to all coronary events (including revascularizations). Only QCA measures of lesion progression were related to MI/coronary death. QCA measures of lesion change may be better surrogate end points for "hard" coronary events than measures of change in coronary segments. (Am Heart J 2000;139:993-9.)

Common carotid artery (CCA) intima-media thickness (IMT) from B-mode ultrasound is a widely used measure of early atherosclerosis. This study evaluated within- and between-sonographer reproducibility of automated edge-tracking IMT using a low-cost mobile scanner. B-mode images of the left and right CCA were acquired on two occasions (interval of 2–14 days) by two sonographers for 38 subjects, aged 31–75 y. Reproduciblity error was measured as the mean absolute difference (MAD ± SEM) and the standard deviation of differences (SDΔ) between repeated measurements. Within-sonographer (MAD = 0.027 ± 0.006 mm; SDΔ = 0.044 mm) and between-sonographer errors (MAD = 0.041 ± 0.008 mm; SDΔ = 0.064) in IMT (mean = 0.74, SD = 0.14) of a single artery were small compared to those of other protocols. Combined averaging across both body positions and arteries reduced intersonographer MAD by 47% (MAD = 0.022 ± 0.003 mm; SDΔ = 0.029 mm). These data demonstrate that the proposed IMT protocol reduces reproducibility error by more than 50% relative to several protocols used in other major studies.

Background There is accumulating experimental, epidemiological, and clinical evidence of an association between antioxidant vitamin intake and reduced risk of coronary heart disease. Using data from the Cholesterol Lowering Atherosclerosis Study (CLAS), we explored the association of self-selected supplementary antioxidant vitamin intake on the rate of progression of early preintrusive atherosclerosis. Methods and Results CLAS was an arterial imaging trial in which nonsmoking 40- to 59-year-old men with previous coronary artery bypass graft surgery were randomized to colestipol/niacin plus diet or placebo plus diet. The rate of progression of early preintrusive atherosclerosis was determined in 146 subjects using high-resolution B-mode ultrasound quantification of the distal common carotid artery far wall intima-media thickness (IMT). From the nutritional supplement database, 22 subjects had an on-trial average supplementary vitamin E intake of ≥100 IU per day (high users) and 29 subjects had an average on-trial supplementary vitamin C intake of ≥250 mg per day (high users). Within the placebo group, less carotid IMT progression was found for high supplementary vitamin E users when compared with low vitamin E users (0.008 versus 0.023 mm/y, P =.03). No effect of vitamin E within the drug group was found. No effect of vitamin C within the drug or placebo group was found. Conclusions Supplementary vitamin E intake appears to be effective in reducing the progression of atherosclerosis in subjects not treated with lipid-lowering drugs while the process is still confined to the arterial wall (early preintrusive atherosclerosis).

Background Local coronary artery enlargement to compensate for atherosclerotic plaques preserves the vessel lumen. The extent to which coronary segments remote from progressing lesions enlarge is unknown. This is clinically relevant since compensatory enlargement may be important in determining whether clinical complications result from progression of coronary artery disease (CAD). Additionally, compensatory change has implications for quantitative coronary angiographic (QCA) trials, since the effect of progression on diameter means may be mitigated by compensatory changes in remote coronary segments when QCA change is averaged over all lesions. Methods and Results Serial QCA data from 78 subjects in the Monitored Atherosclerosis Regression Study were used to demonstrate compensatory changes in coronary segments remote from progressing or regressing lesions. Coronary segments were first classified as progressing (regressing) if percent diameter stenosis (PS) increased or decreased by >10 with a concurrent decrease or increase in minimum lumen diameter (MLD) of either >0.32 mm or >10% of the normal baseline reference diameter (DNORM). Segments not meeting these criteria were labeled stenosis stable. Stenosis-stable segments opposite progressing lesions showed increases in MLD ( P =.0006), DNORM ( P =.001), and average diameter ( P =.001). On-trial apolipoprotein (apo) B, apo C-III, and blood pressure levels inversely correlated with these compensatory changes. Conclusions Lesion progression in one coronary segment is associated with significant increases in segmental diameter of remote parts of the coronary tree. We hypothesize these increases to be vascular compensatory changes in response to progression of CAD. Vascular compensatory change is enhanced by LDL cholesterol and triglyceride-rich lipoprotein reduction and appears to be part of the treatment effect itself.

The Cholesterol Lowering Atherosclerosis Study, a randomized angiographic clinical trial, demonstrated the beneficial effect of niacin/colestipol plus diet therapy on coronary atherosclerosis. Outcome was determined by panel-based estimates (viewed in both still and cine modes) of percent stenosis severity and change in native artery and bypass graft lesions. Computer-based quantitative coronary angiography (QCA) was also used to measure lesion and bypass graft stenosis severity and change in individual frames closely matched in orientation, opacification, and cardiac phase. Both methods jointly evaluated 350 nonoccluded lesions. The correlation between QCA and panel estimates of lesion size was 0.70 (p less than 0.0001) and for change in lesion size was 0.28 (p = 0.002). Agreement between the two methods in classifying lesion changes (i.e., regression, unchanged, or progression) occurred for 60% (210 of 350) of the lesions kappa +/- SEM = 0.20 +/- 0.05, p less than 0.001). The panel identified 442 nonoccluded lesions for which QCA stenosis measurements could not be obtained. Lesions not measurable by QCA included those with stenosis greater than 85% that could not be reliably edge tracked, segments with diffuse or ecstatic disease that had no reliable reference diameter, and segments for which matched frames could not be located. Seventy-nine lesions, the majority between 21% and 40% stenosis, were identified and measured by QCA but were not identified by the panel. This comparison study demonstrates the need to consider available angiographic measurement methods in relation to the goals of their use.

Background and Purpose— Although plasma total homocysteine (tHcy) levels are associated with cardiovascular disease, it remains unclear whether homocysteine is a cause or a marker of atherosclerotic vascular disease. We determined whether reduction of tHcy levels with B vitamin supplementation reduces subclinical atherosclerosis progression. Methods— In this double-blind clinical trial, 506 participants 40 to 89 years of age with an initial tHcy >8.5 μmol/L without diabetes and cardiovascular disease were randomized to high-dose B vitamin supplementation (5 mg folic acid+0.4 mg vitamin B 12 +50 mg vitamin B 6 ) or matching placebo for 3.1 years. Subclinical atherosclerosis progression across 3 vascular beds was assessed using high-resolution B-mode ultrasonography to measure carotid artery intima media thickness (primary outcome) and multidetector spiral CT to measure aortic and coronary artery calcium (secondary outcome). Results— Although the overall carotid artery intima media thickness progression rate was lower with B vitamin supplementation than with placebo, statistically significant between-group differences were not found ( P =0.31). However, among subjects with baseline tHcy ≥9.1 μmol/L, those randomized to B vitamin supplementation had a statistically significant lower average rate of carotid artery intima media thickness progression compared with placebo ( P =0.02); among subjects with a baseline tHcy Conclusion— High-dose B vitamin supplementation significantly reduces progression of early-stage subclinical atherosclerosis (carotid artery intima media thickness) in well-nourished healthy B vitamin “replete” individuals at low risk for cardiovascular disease with a fasting tHcy ≥9.1 μmol/L.

Background Although active smoking acutely increases arterial stiffness, the association between arterial stiffness and chronic exposure to environmental tobacco smoke (ETS) has not been evaluated. We used baseline data from the Vitamin E Atherosclerosis Prevention Study to evaluate the association between ETS exposure and arterial stiffness among 227 healthy adult nonsmokers. Methods B-mode ultrasonograms of the common carotid artery were used to compute the carotid arterial wall stiffness index beta. Beta was compared by the number of sources and daily hours of ETS exposure. Results The carotid stiffness index beta was positively associated with age, body mass index (BMI), fasting glucose, and common carotid artery intima-media thickness (IMT). In the total sample, beta was not related to the number of ETS exposure sources. The carotid stiffness index beta increased with number of sources and daily hours of ETS in subjects with BMI ≥ 27.1 kg/m 2 and IMT ≥ 0.707 mm. The association was not apparent in subjects with lower BMI or IMT (for number of ETS sources, interaction P values = 0.006 and 0.01, respectively). For number of ETS sources, but not hours of exposure, positive associations were apparent among females (but not males) and among subjects ≥55 years old (but not younger subjects). Conclusions These data indicate that arterial stiffness is adversely associated with ETS in a dose-dependent manner among individuals with higher BMI and greater carotid artery IMT.

The end-diastole is the optimum portion of the cardiac cycle for computerized analysis of coronary angiograms, since vessel movement is minimal and the vessels are relatively straight. Since it is frequently not possible to find suitable end-diastolic frames, the authors initiated a study to determine the penalty in precision that is incurred when other than end-diastolic frames are processed. Computer measurements of average and minimum diameter were made for every frame of two complete cardiac cycles in angiograms of 20 subjects who had received bypass grafts. To estimate the effects of phase on the measurement, six sampling schemes were defined: beginning systole, end-diastole, mid-diastole, anywhere in diastole, anywhere in systole, and anywhere in the cardiac cycle. Two frames were selected for each scheme and the mean and standard deviation (SD) computed. Frames for the last three schemes above were randomly selected 50 times and the results averaged. The SD of average diameter is half that of the minimum diameter and relatively independent of cardiac phase. The SD of the minimum diameter is lowest for end-diastole, but an approximately 25% penalty in variability is paid when sampling elsewhere. >

A method is under development to measure carotid artery lesions from a computer-generated 3-D ultrasound image. 3-D images are generated from multiple B-mode ultrasound images with known spatial coordinates derived from a magnetic spatial locating device attached to the ultrasound transducer. For each image, the position of the transducer in six coordinates (x, y, z, azimuth elevation, and roll) is recorded and used to position each B-mode picture element in its proper spatial position in a 3-D memory array. After all B-mode images have been assembled in the memory, the 3-D image is filtered and resampled to produce a new series of parallel-plane 2-D images, from which arterial boundaries can be determined using edge-tracking methods. The method is described, and sample 3-D images are shown. >

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-α-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, α-tocopherol supplementation significantly raised plasma vitamin E levels ( P P =0.03), and reduced LDL oxidative susceptibility ( P 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.

Background Although observational studies suggest that estrogen replacement therapy (ERT) reduces cardiovascular morbidity and mortality in postmenopausal women, use of unopposed ERT for prevention of coronary heart disease in healthy postmenopausal women remains untested. Objective To determine the effects of unopposed ERT on the progression of subclinical atherosclerosis in healthy postmenopausal women without preexisting cardiovascular disease. Design Randomized, double-blind, placebo-controlled trial. Setting University-based clinic. Patients 222 postmenopausal women 45 years of age or older without preexisting cardiovascular disease and with low-density lipoprotein cholesterol levels of 3.37 mmol/L or greater (>/=130 mg/dL). Intervention Unopposed micronized 17beta-estradiol (1 mg/d) or placebo. All women received dietary counseling. Women received lipid-lowering medication if their low-density lipoprotein cholesterol level exceeded 4.15 mmol/L (160 mg/dL). Measurements The rate of change in intima-media thickness of the right distal common carotid artery far wall in computer image processed B-mode ultrasonograms obtained at baseline and every 6 months during the 2-year trial. Results In a multivariable mixed-effects model, among women who had at least one follow-up measurement of carotid intima-media thickness (n = 199), the average rate of progression of subclinical atherosclerosis was lower in those taking unopposed estradiol than in those taking placebo (-0.0017 mm/y vs. 0.0036 mm/y); the placebo-estradiol difference between average progression rates was 0.0053 mm/y (95% CI, 0.0001 to 0.0105 mm/y) (P = 0.046). Among women who did not receive lipid-lowering medication (n = 77), the placebo-estradiol difference between average rates of progression was 0.0147 mm/y (CI, 0.0055 to 0.0240) (P = 0.002). Average rates of progression did not differ between estradiol and placebo recipients who took lipid-lowering medication (n = 122) (P > 0.2). Conclusions Overall, the average rate of progression of subclinical atherosclerosis was slower in healthy postmenopausal women taking unopposed ERT with 17beta-estradiol than in women taking placebo. Reduction in the progression of subclinical atherosclerosis was seen in women who did not take lipid-lowering medication but not in those who took these medications.

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 (Dmax), minimum arterial diameter (Dmin), and IMT using a computerized edge detection method. The intraclass correlations of Dmax, Dmin, 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 Dmax and Dmin were 1.28 and 1.18%, respectively. The intraclass correlation for several standard arterial stiffness indices, Peterson’s elastic modulus, Young’s 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 Dmin reduced single frame IMT measurement variability by 27% (P0.005) compared with IMT measured from a single frame corresponding to Dmin. Comparison of the phasic relationship of Dmax and Dmin 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. © 2001 Elsevier Science Ireland Ltd. All rights reserved.

Carotid arterial intima-media thickness is used as a noninvasive surrogate end point to measure progression of atherosclerosis, but its relation to coronary events has not been fully explored.To determine whether carotid arterial intima-media thickness predicts coronary events.Long-term follow-up (average, 8.8 years) of a previously assembled cohort of persons who completed the 2-year Cholesterol Lowering Atherosclerosis Study, a randomized arterial imaging trial designed to study the effects of lipid lowering on progression of atherosclerosis.University-based ultrasonography laboratory.146 men 40 to 59 years of age who had previously had coronary artery bypass graft surgery.Preintrusive atherosclerosis in the common carotid artery was evaluated every 6 months with B-mode ultrasonography, and intrusive atherosclerosis in the coronary arteries was evaluated at baseline and at 2 years with quantitative coronary angiography. After the trial, the incidences of coronary events (nonfatal acute myocardial infarction, coronary death, and coronary artery revascularization) were documented.For each 0.03-mm increase per year in carotid arterial intima-media thickness, the relative risk for nonfatal myocardial infarction or coronary death was 2.2 (95% CI, 1.4 to 3.6) and the relative risk for any coronary event was 3.1 (CI, 2.1 to 4.5) (P0.001). Absolute intima-media thickness was also related to risk for clinical coronary events (P0.02). Absolute thickness and progression in thickness predicted risk for coronary events beyond that predicted by coronary arterial measures of atherosclerosis and lipid measurements (P0.001).Noninvasive B-mode ultrasonographic measurement of progression of intima-media thickness in the distal common carotid artery is a useful surrogate end point for clinical coronary events.

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 (S f 0 to 12), IDL (S f 12 to 20), VLDL (S f 20 to 400), and HDL (F 1.20 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 r =−.09, P =.24) or LDL ( r =.09, P =.26) was associated with the progression of carotid artery intima-media 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 (S f 12 to 20) that is included within the traditional measurements of LDL-C.

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 P =.02) and progression of mild/moderate lesions (P P 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.

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.

A standardized acquisition methodology assists operators to accurately replicate high resolution B-mode ultrasound images obtained over several spaced-apart examinations utilizing a split-screen display in which the arterial ultrasound image from an earlier examination is displayed on one side of the screen while a real-time “live” ultrasound image from a current examination is displayed next to the earlier image on the opposite side of the screen. By viewing both images, whether simultaneously or alternately, while manually adjusting the ultrasound transducer, an operator is able to bring into view the real-time image that best matches a selected image from the earlier ultrasound examination. Utilizing this methodology, dynamic material properties of arterial structures, such as IMT and diameter, are measured in a standard region over successive image frames. Each frame of the sequence has its echo edge boundaries automatically determined by using the immediately prior frame's true echo edge coordinates as initial boundary conditions. Computerized echo edge recognition and tracking over multiple successive image frames enhances measurement of arterial diameter and IMT and allows for improved vascular dimension measurements, including vascular stiffness and IMT determinations.

The Cholesterol Lowering Atherosclerosis Study has reported significant reduction of coronary artery disease and of carotid arterial intima-media thickness (IMT) at 2 and 4 years with colestipol/niacin therapy. We now report on treatment effects on carotid IMT at 6 months and 1 year. One hundred eighty-eight nonsmoking men, aged 40 to 59 years, with prior coronary artery bypass graft surgery were randomized to colestipol/niacin plus diet therapy or placebo plus diet therapy. Computerized image processing of carotid ultrasound films was used to measure IMT in the right common carotid artery. Treatment group comparisons were made at 6 months and 1 year (46 and 33 subjects, respectively, with baseline and 6-month or 1-year ultrasound measures). The time course of the treatment effect on carotid IMT was estimated using the complete sample of 78 subjects with baseline and on-trial data. No significant treatment group differences on carotid IMT were found at 6 months. At 1 year, the treated group showed significant reduction of carotid IMT (P = .01 between groups). The placebo group showed continuing progression of IMT during the 4-year study period (estimated progression rate, 0.018 mm/y). The treated group showed reduction of IMT during the first 3 years and a plateau during the remainder of the study. Reduction of carotid IMT was found with aggressive lipid-lowering therapy. Ultrasound measures of IMT offer a noninvasive and precise measure of early carotid atherosclerosis that will decrease sample size requirements, potentially decrease dropout rates, and widen the study population of antiatherosclerotic clinical trials.

BACKGROUND Controlled 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 RESULTS Seventy-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 = .0001) and 4 years (P = .0001); 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-III 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. CONCLUSIONS Common 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.

CLAS, a placebo controlled trial of Colestipol/Niacin therapy in men with previous coronary artery bypass surgery, obtained 188 baseline, 162 two year and 103 four year angiograms. Human panel readers evaluated all films with treatment assignment and film order masked. All lesions in native arteries and grafts were identified, assigned percent stenosis estimates, lesion change estimates and an overall change score. In a 50% random sample, all processable segments have been computer evaluated with multiple lesion and segment based algorithms derived by the USC-Caltech/JPL method. Among nonocclusive lesions, 350 were evaluated for percent stenosis by panel and computer methods with correlation between the two methods of 0.70 p < 0.0001). Four hundred forty-two lesions (principally more severe) could only be evaluated by humans. Seventy-nine early lesions could be evaluated only by computer. Seven hundred thirty-one native coronary segments were analyzed by QCA including 302 segments without discrete lesions in addition to the 429 segments with discrete lesions that were compared with the panel evaluation. After accounting for baseline effects, position relative to grafts and within subject correlation, significant therapy effects were demonstrated by computer measures of both stenosis and vessel edge roughness. These data confirm that computer analsis of angiograms can reduce subject numbers compared to human panel reading and offer different endpoint measures.

BACKGROUND The Cholesterol Lowering Atherosclerosis Study has demonstrated beneficial effect of colestipol/niacin on coronary atherosclerosis using a panel-determined global coronary change score. We now report treatment group comparisons using quantitative coronary angiographic (QCA) measures from all processable segments in 85 of 162 randomly selected baseline/2-year film pairs. METHODS AND RESULTS Treatment benefit was established for percent stenosis for either continuous or categorical analyses with regression established regardless of the per-patient scoring procedure. In addition, treatment benefit favoring regression was established in some cases for roughness and for percent involvement, a longitudinal estimate of the percent of coronary surface involved by raised lesions. Benefit on minimum diameter was directly related to whether the segment was proximal to a graft insertion and hemodynamically related to the bypass graft. QCA correlates of panel-determined progression were increases in percent stenosis and numbers of occluded lesions in native arteries and the number of progressing lesions in bypass grafts. CONCLUSIONS These results demonstrate that a variety of computer measures can be used as end points in coronary angiographic therapy trials, but change in percent stenosis correlates best with visual panel assessments and best reflects the treatment benefit; when treatment effect sizes are moderate to large, the required sample size of coronary angiographic trials can be reduced when QCA is used.

Using a 1-page bar-coded food frequency questionnaire, the food habits of 996 adults who participated in diet screening at the annual meetings of the American Heart Association (1989) and the American College of Cardiology (1990) were analyzed for sex, age and regional differences. Estimated nutrient intakes were also compared with those from the Department of Agriculture's 1985 and 1986 Continuing Survey of Food Intake of Individuals. The average diet reported in this study satisfied National Cholesterol Education Program guidelines for cholesterol intake, but was higher than that recommended for total and saturated fats. In addition, dietary fat intake was influenced by sex, age and geographic region. Reduction in total and saturated fat intake was confined to men greater than 35 years of age; intake of these nutrients was highest among young, Mid-western women. These results suggest the need for diet intervention programs, targeted specifically to young adults with additional consideration given to regional variation. Repeated surveys of cardiac care givers might be used as an early indicator of the nationwide effectiveness of dietary intervention programs.

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.

There are two ways to test therapy for atherosclerosis in man: trials which measure cardiovascular death rates and trials that measure the rate of change in atherosclerotic lesions. Mortality-based trials require large study groups and relatively long periods of observation. Lesion tracking trials require fewer study subjects and shorter periods of observation, but are dependent on valid reliable assessment of lesion changes. To date, coronary angiography has been the major endpoint measure used in lesion trials. This review covers factors which influence the performance of angiography.

Clinical studies of atherosclerosis that require quantitative estimates of lesion change from images have moved strongly in the direction of automated techniques in the last five years. Angiogram analysis is the most widely used approach with more than 10 research groups reporting development of computer methods to assess coronary lesion change from cineangiograms (1–10) and at least two groups reporting methods for femoral angiogram analysis (11,12). Computer-aided lesion assessment from B-mode ultrasound has also been developed and used clinically in the U.S. Multicenter Ultrasound Assessment Program (13). Other imaging methods such as magnetic resonance imaging (14) and nuclear imaging (15) have the potential to be used in clinical studies of lesion change but are still under development and have not been tested.

High resolution B-mode ultrasound images of the common carotid artery are obtained with an ultrasound transducer using a standardized methodology. Subjects are supine with the head counter-rotated 45 degrees using a head pillow. The jugular vein and carotid artery are located and positioned in a vertical stacked orientation. The transducer is rotated 90 degrees around the centerline of the transverse image of the stacked structure to obtain a longitudinal image while maintaining the vessels in a stacked position. A computerized methodology assists operators to accurately replicate images obtained over several spaced-apart examinations. The methodology utilizes a split-screen display in which the arterial ultrasound image from an earlier examination is displayed on one side of the screen while a real-time “live” ultrasound image from a current examination is displayed next to the earlier image on the opposite side of the screen. By viewing both images, whether simultaneously or alternately, while manually adjusting the ultrasound transducer, an operator is able to bring into view the real-time image that best matches a selected image from the earlier ultrasound examination. Utilizing this methodology, measurement of vascular dimensions such as carotid arterial IMT and diameter, the coefficient of variation is substantially reduced to values approximating from about 1.0% to about 1.25%. All images contain anatomical landmarks for reproducing probe angulation, including visualization of the carotid bulb, stacking of the jugular vein above the carotid artery, and initial instrumentation settings, used at a baseline measurement are maintained during all follow-up examinations.

A standardized acquisition methodology assists operators to accurately replicate high resolution B-mode ultrasound images obtained over several spaced-apart examinations. The methodology utilizes a split-screen display in which the arterial ultrasound image from an earlier examination is displayed on one side of the screen while a real-time “live” ultrasound image from a current examination is displayed next to the earlier image on the opposite side of the screen. A computerized echo edge recognition and tracking methodology automatically identifies ultrasound echo boundaries of the intima-media complex and automatically extracts IMT and arterial dimension measurements, without introducing human measurement error. Measurement accuracy is enhanced by use of sub-pixel resolution for echo edge boundary definition. Utilizing this methodology, measurement of vascular dimensions, such as carotid arterial IMT and diameter, the coefficient of variation is substantially reduced to values approximating from about 1.0% to about 1.25%. Dynamic material properties of arterial structures are measured in a standardized region in accordance with a standardized methodology in order to promote measurement repeatability.

The rate of change of femoral atherosclerosis has been determined in 25 treated hyperlipoproteinemic patients. There were 13 Type II patients and 12 Type IV patients. Serial angiograms had been performed at an interval averaging 13 months. Film densities were analyzed by digigal image processing to yield a computer estimate of atherosclerosis (CEA). Serial measurements of CEA on each patient were used to determine atherosclerosis percent change per month in that patient. CEA percent change per month was significantly correlated ;ith triglyceride and cholesterol level. Lower lipid levels were associated with more rapid regression. When hyperlipoproteinemic types were considered separately, significant single correlates were confined to Type IV. Triglyceride level and CEA/age significantly predicted atherosclerosis change rate and accounted for 72% of the variability observed in Type IV patients.

Atherosclerosis has been studied by femoral angiography in men with myocardial infarction. Smoking history recorded at entry was the strongest variable asssociated with degree of atherosclerosis at the first angiogram. This correlation was significant at the 1% level in two out of three femoral segments. Fifty-four men had two angiograms; 28 of these men had one additional angiogram. Two variables recorded in the interval between angiograms were significantly correlated with atherosclerosis change in one femoral segment; α-lipoprotein level determined by electrophoresis (a negative correlation, p < 0.01) and maximum systolic blood pressure occurring during an exercise tolerance test (a positive correlation, p < 0.01). An estimate of angiographic atherosclerosis assessment error has been obtained (S.D. = 8.28; in a scale of 1–128) and used to calculate sample size for future clinical trials which employ this endpoint. Testing the effect of therapy on lesion change with angiography requires fewer study subjects observed for a shorter period than is necessary to test a commensurate effect on atherosclerosis-related morbidity or mortality rates. For example, an angiographic study with design features comparable to those of the Coronary Drug Project could require a 1-yr observation period and 132 subjects per test group.

This system allows for efficient use of professional time and immediate availability of nutrient analysis for use in counseling.

Documentation of nutrition counseling effectiveness is essential to reinforce its value in an era of escalating health care costs. Counseling effectiveness can be determined definitively only if dietary assessment is made both before and after intervention. Unfortunately, methods currently available have drawbacks that limit feasibility of routine use. A directly computer-readable Quantitative Food Frequency Analysis method, which eliminates the need for manual data entry, has been developed and instituted at the University of Southern California School of Medicine, Los Angeles, for outpatient counseling. A 1-hour interview, focusing upon "usual" intake, is conducted using pictorial menus for food items. Feedback is available to the patient and health care team immediately. The data base is derived from the National Heart, Lung, and Blood Institute Food Table; the intake of 61 nutrients, including 23 fatty acids, is computed. The computer printout consists of four components: a summary; an alert for foods high in fat, cholesterol, sucrose, alcohol, and/or sodium; a listing of all foods consumed by frequency, accompanied by their nutrient contribution to daily intake; and a bar graph relating current nutrient intake to recommended levels. This document serves as a counseling tool and can support claims for third-party payment.

The application of digital image processing techniques to medical problems has been under development at the Jet Propulsion Laboratory, California Institute of Technology, since 1966. The initial research concentrated on medical X-ray films and include (1) image restoration, i.e., using digital techniques to retrieve information partially lost in the imaging system which generated the pictures, (2) image enhancement to emphasize features or remove useless data, and (3) image mensuration to provide more quantitative measurements and analyses than are available through visual inspection techniques. From the initial concern with X-ray image processing, this research in image processing as applied to biomedicine has been expanded to include a system for the automated analysis of images from light and electron microscopes. The Automated Light Microscope System (ALMS), around which the chromosome analysis system has been developed, allows direct scanning of specimen images into a computer for subsequent analysis. The applications of digital image processing to biomedicine at the Jet Propulsion Laboratory encompass 15 separate research projects. The areas selected for discussion in this paper give some indication of the types of picture analysis that are being performed. The current trend in biomedical image processing is toward more human interaction in the research setting.

Femoral angiograms were made in 21 cadavers under conditions which simulated clinical films. Then these arteries were excised, laid open, and color photographed along side of corresponding casts of the arterial lumen. Twenty-seven segments, 5 cm long, were classified as exemplary of normal vessel, uncomplicated stenosis, or hemorrhagic ulceration. The corresponding angiogram images of these arterial segments were digitized and processed to yield outlines of the vessel edges, and from these, computer measures were developed which described how these outlines deviated from ideal ones. Six of these measures were selected by means of stepwise discriminant analysis to distinguish the type of disease along the 27 exemplary segments, and 96% were correctly classified. Computer processing of angiograms shows promise for discriminating the nature of atherosclerotic lesions.

Comparison of coronary atherosclerosis change in a pilot angiographic study of retrospectively matched smokers and controls indicates more rapid progression in smokers. The findings indicate the feasibility of small-scale angiographic trials of treatment designed to ameliorate arterial damage in atherosclerotic smokers who cannot quit.

SummaryRaised aortic atheromas can be quantitated by densitometer-computer analysis of edge irregularity on angiographic shadows. Combined measurement of edge irregularity and variation in cross-sectional density provides an angiographic index indicative of local cholesterol concentration in aorta walls and atheromas.

There are currently more than ten research groups, including ours at JPL and USC, that are developing computer methods to quantify atherosclerosis from cineangiograms. There are variations in equipment and algorithms employed by the various groups but results in terms of accuracy and precision have been roughly similar. In the past six months, we have been investigating several sources of measurement variability that have received relatively little attention, but which we believe could cause significant errors if ignored. For example, we have observed substantial variability in the measurement of arterial dimensions due to vessel pulsation and to mixing artifacts of the radio-opaque contrast. The problems appear solvable but the solutions may create new problems by making the measurements more difficult and time consuming.

A computer system has been developed to quantify the degree of atherosclerosis in the human femoral artery. The analysis involves first scanning and digitizing angiographic film, then tracking the outline of the arterial image and finally computing the relative amount of roughness or irregularity in the vessel wall. The image processing system and method are described.

For purposes of this discussion, assume that a conventional radiographic image such as film already exists and an optional enhancement step is available as a potential diagnostic aid. To decide if the enhancement is worth the trouble, several factors have to be considered: 1. Diagnostic value of enhancement. 2. Ease and speed of processing. 3. Cost of enhancement.© (1974) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

The prevalence of femoral atherosclerotic lesions in Type II and Type IV hyperlipoproteinemia has been determined by performing Limited Femoral Angiography in 18 Type II and 10 Type IV patients attending a clinic for therapy of hyperlipoproteinemia. Patients studied were those willing to volunteer for femoral angiography as an experimental procedure for determination of lesion prevalence and possible guide to evaluation of their therapy. Written informed consent was obtained from all prior to angiography.

Existing methods to quantify atherosclerosis in living persons directly from arterial images have virtually all been developed for use with conventional angiograms for the obvious reason that practical alternative methods for arterial visualization have not been available. As will be described later in this session, a number of important new noninvasive imaging techniques have emerged recently, which will provide additional possibilities for lesion quantitation. Intravenous digital radiography, for example, can be used to visualize most of the major arteries except the coronaries, and ultrasound systems are available for routine carotid artery imaging. Experimental ultrasound systems are under development that may be capable of imaging deeper arteries including the coronaries. Imaging systems using nuclear magnetic resonance have successfully visualized arteries in small animals and phantoms that simulate arteries in the millimeter range (1). While these noninvasive methods appear very likely to be used for quantitative lesion assessment in the near future, relatively little quantitative experience has been gained to date. Conversely, computer methods to quantify atherosclerosis from conventional selective angiograms have reached a stage of relative maturity, in which their use in clinical studies is practical and on-going. The intent of this paper is to outline lesion quantitation methods using the angiographic techniques for illustration and to discuss some of the physical factors, performance measurements, and image analysis problems that have common applicability to both invasive and noninvasive imaging.

The Cholesterol Lowering Atherosclerosis Study (CLAS) is a prospective, placebo-controlled, angiographic trial designed to test the hypothesis that aggressive lowering of LDL cholesterol with concomitant increase in HDL cholesterol will reverse or retard the atherosclerotic process. Specifically, CLAS was designed to determine whether combined therapy with colestipol plus niacin will produce clinically significant change in coronary, carotid, and femoral artery atherosclerosis and coronary bypass graft lesions. To this purpose, 188 subjects were randomized to diet plus drug or diet plus placebo. We report on methodological aspects of planning and evaluating this study, including the choice of the study population, procedures for recruitment, the experimental design including sample size considerations, methods for evaluating outcome, and methods for evaluating compliance to treatment. Comparison of baseline data indicated no significant differences between groups at the time of randomization. Subjects were predominantly male, Caucasian, 54 years of age, 20% above ideal weight, with normal blood pressure. The average age at bypass was 50 years. The average lipids were cholesterol (243 mg/dL), HDL (45 mg/dL), and LDL (168 mg/dL). Finally, the distribution of baseline coronary stenosis was equivalent between the two groups (average number of lesions per subject = 10.6).