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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

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.)

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.

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. >

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.

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 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.

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.

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.

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).

Most computer methods that quantify coronary artery disease from angiograms are designed to analyze frames recorded during the end-diastolic portion of the cardiac cycle. The purpose of this study was to determine if end diastole is the best portion of the cardiac cycle to sample, or if other sampling schemes produce more precise and/or reproducible estimates of coronary disease. 20 cinecoronary angiograms were selected at random from a controlled clinical trial testing the effects of plasma lipid lowering on atherosclerosis. Sampling schemes included sequential and random sampling of two to five frames within the complete cardiac cycle, systole, and diastole. Three vessel measures and percent stenosis were evaluated for each sampling scheme. From the sampling experiment, it was determined that sampling sequentially end diastole yielded the most precise estimates (i.e., exhibiting minimum variability within a cycle) of the vessel measures. With regard to reproducibility (i.e., similar values across cycles), sampling randomly within the cycle was best. Overall, the average diameter of a vessel segment was the most precise and the most reproducible of the measures. Sample size calculations are given for each of these measures under the best sampling scheme.