Anne M. Shircore

Oxygenated Carotenoid Lutein and Progression of Early Atherosclerosis The Los Angeles Atherosclerosis Study

Background—Carotenoids are hypothesized to explain some of the protective effects of fruit and vegetable intake on risk of cardiovascular disease. The present study assessed the protective effects of the oxygenated carotenoid lutein against early atherosclerosis. Methods and Results—Epidemiology: Progression of intima-media thickness (IMT) of the common carotid arteries over 18 months was determined ultrasonographically and was related to plasma lutein among a randomly sampled cohort of utility employees age 40 to 60 years (n=480). Coculture: The impact of lutein on monocyte response to artery wall cell modification of LDL was assessed in vitro by quantification of monocyte migration in a coculture model of human intima. Mouse models: The impact of lutein supplementation on atherosclerotic lesion formation was assessed in vivo by assigning apoE-null mice to chow or chow plus lutein (0.2% by weight) and LDL receptor-null mice to Western diet or Western diet plus lutein. IMT progression declined with increasing quintile of plasma lutein (P for trend=0.007, age-adjusted;P =0.0007, multivariate). Covariate-adjusted IMT progression (mean±SEM) was 0.021±0.005 mm in the lowest quintile of plasma lutein, whereas progression was blocked in the highest quintile (0.004±0.005 mm;P =0.01). In the coculture, pretreatment of cells with lutein inhibited LDL-induced migration in a dose-dependent manner (P <0.05). Finally, in the mouse models, lutein supplementation reduced lesion size 44% in apoE-null mice (P =0.009) and 43% in LDL receptor-null mice (P =0.02). Conclusions—These epidemiological, in vitro, and mouse model findings support the hypothesis that increased dietary intake of lutein is protective against the development of early 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.

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.

Progression of Carotid Intima-Media Thickness and Plasma Antioxidants: The Los Angeles Atherosclerosis Study

Objective—Recent epidemiologic and animal model data suggest that oxygenated carotenoids are protective against early atherosclerosis. We assessed the association between atherosclerotic progression, measured by carotid intima-media thickness (IMT), and plasma levels of oxygenated and hydrocarbon carotenoids, tocopherols, retinol, and ascorbic acid. Methods and Results—Participants were from an occupational cohort of 573 middle-aged women and men who were free of symptomatic cardiovascular disease at baseline. Ultrasound examination of the common carotid arteries, lipid level determination, and risk factor assessment were performed at baseline and 18-month follow-up. Plasma levels of antioxidants were determined at baseline only. Change in IMT was related to baseline plasma antioxidant levels in regression models controlling for covariates. In models adjusted for age, sex, and smoking status, 18-month change in IMT was significantly inversely related to the 3 measured oxygenated carotenoids (lutein, &bgr;-cryptoxanthin, zeaxanthin; P <0.02 for all) and one hydrocarbon carotenoid, &agr;-carotene (P =0.003). After adjusting for additional cardiac risk factors and potential confounders, including high-sensitivity C-reactive protein, these associations remained significant (P <0.05). Conclusions—These findings suggest that higher levels of plasma oxygenated carotenoids (lutein, zeaxanthin, &bgr;-cryptoxanthin) and &agr;-carotene may be protective against early atherosclerosis.

Leisure time physical activity and early atherosclerosis: the Los Angeles Atherosclerosis Study

PURPOSE Some studies of leisure time physical activity find a cardiovascular benefit for moderate activity, whereas others find benefit only for regular vigorous activity. We examined the relation between physical activity and 3-year progression of carotid atherosclerosis. METHODS Baseline examinations were conducted during 1995 to 1996 with two follow-up examinations at 1.5-year intervals. Intima-media thickness of the common carotid arteries was determined by B-mode ultrasound in a cohort of 500 randomly sampled women and men, aged 40 to 60 years, who were asymptomatic for cardiovascular disease. Sedentary leisure activity was defined as the lowest quartile of a general activity measure, whereas vigorous activity was defined as aerobic activity > or = 3.5 times per week. The remainder defined the moderate activity group. Analyses were adjusted for confounding variables. RESULTS The mean (+/- SE) age- and sex-adjusted rates of progression of intima-media thickness declined from 14.3 +/- 1.7 microns per year in sedentary subjects, to 10.2 +/- 1.0 microns per year in moderately active subjects, to 5.5 +/- 1.5 microns per year in vigorously active subjects (P for trend <0.0001), and remained statistically significant after adjustment for other confounding factors (P for trend = 0.0004). Compared with the moderate activity group, the vigorous activity group had lower body mass index and resting heart rate and increased high-density lipoprotein cholesterol level, whereas the sedentary group had an increased resting heart rate. Workplace activity was not protective. CONCLUSION Physical activity during leisure is inversely related to the progression of atherosclerosis in the carotid artery. This benefit appears to increase throughout the activity continuum.

Work-related stress and early atherosclerosis.

The purpose of this study was to examine the link between work-related stress and early atherosclerosis as measured by common carotid artery intima-media thickness and focal lesions in the common carotid artery and bifurcation. Four hundred sixty-seven members of an occupational cohort (total N = 573) were examined via questionnaires and B-mode ultrasound. We used multiple linear and logistic models to regress lesion risk and intima-media thickness on work-related stress scores from a questionnaire administered at an 18-month follow-up examination. In an age-adjusted model, the prevalence of carotid lesions among men scoring in the highest stress quintile was 36% compared with 21% among men in the lowest quintile. We also observed an increase in intima-media thickness in the highest quintile relative to the lowest (difference = 0.048 ± 0.025 mm) among men. Among women, stress was not related to the prevalence of lesions or intima-media thickness. These findings suggest that men with greater work-related stress are at increased risk for atherosclerotic disease. Women in this age group may be protected from such effects, or current work-place questionnaires may not accurately assess stress in women.

Evaluation of colestipol/niacin therapy with computer-derived coronary end point measures. A comparison of different measures of treatment effect.

BackgroundThe 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 ResultsTreatment 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. ConclusionsThese 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.

Compensatory Vascular Changes of Remote Coronary Segments in Response to Lesion Progression as Observed by Sequential Angiography From a Controlled Clinical Trial

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.

Comparison of computer- and human-derived coronary angiographic end-point measures for controlled therapy trials.

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.

A second look at quantitative coronary angiography: some unexpected problems

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.