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The Cholesterol-Lowering Atherosclerosis Study (CLAS) was a randomized, placebo-controlled angiographic trial that tested the efficacy of colestipol plus niacin therapy for the reduction of blood low-density lipoprotein cholesterol level and the increase of blood high-density lipoprotein cholesterol

In vivo radiolabeled liposome uptake in 5 sham-operated, 7 coarctation-induced hypertensive, and 8 atherosclerotic arterial walls from New Zealand White rabbits was compared to determine the mechanism of arterial wall uptake of liposomes. Uptake between the three groups was significantly different (P less than 0.001) with a 3-fold difference in uptake between the sham-operated and hypertensive groups and the hypertensive and atherosclerotic groups. Liposome uptake was significantly higher in the atherosclerotic group of animals (P less than 0.05). Avidin-biotin immunoperoxidase staining for monocyte/macrophage cells revealed that liposome uptake increased concomitantly with arterial wall monocyte/macrophage cellular invasion and that liposome localization, determined by autoradiography, paralleled the monocyte/macrophage cellular distribution in both hypertensive and atherosclerotic arterial walls. This study provides the first direct evidence that liposomes can escape from the circulation and enter the diseased arterial wall. Furthermore, it suggests that one possible mechanism of arterial wall uptake of liposomes is via the monocyte/macrophage cell which avidly and preferentially engulfs liposomes and then passively carries them into the arterial wall during hypertensive and atherosclerotic lesion development. Liposomes could potentially be used to carry agents into the arterial wall in the study of arterial wall lesion development.

We report the use of a non-invasive ultrasound method to visualize and measure changes in serotonin reactivity of the abdominal aorta during the early stages of atherosclerosis development. Studies were performed at 0, 4, 8, and 14 weeks in New Zealand white rabbits fed a diet enriched with 0.5% cholesterol. Change in systolic vessel diameter at each examination was compared with changes in rabbits fed a control diet or rabbits on a diet enriched with cholesterol plus a concentrated marine lipid. After 4 weeks on the diets, the abdominal aortae of rabbits fed the cholesterol-rich diet displayed an enhanced vasoconstriction to serotonin (P < 0.01). The enhanced vasoconstriction was observed prior to visible morphologic changes, and progressed when restudied at succeeding examinations. Morphologic abnormalities became evident at 8 weeks in cholesterol-fed animals. Dietary supplementation with marine lipid, rich in polyunsaturated fatty acids, diminished the effect of the atherogenic diet on aortic vasoconstriction.

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 The Monitored Atherosclerosis Regression Study, a randomized, double-blind, placebo-controlled, 2-year trial of lovastatin monotherapy, found that coronary lesions < 50% diameter stenosis (%S) and coronary lesions > or = 50% S at baseline had different responses to therapy. We now report on clinical, lipid, and nonlipid risk factors of treatment response in these lesion subsets. METHODS AND RESULTS Two hundred seventy subjects, 37 to 67 years old, with plasma total cholesterol (TC) 190 to 295 mg/dL (4.91 to 7.63 mmol/L) and total triglyceride < 500 mg/dL (5.65 mmol/L) were randomized to low-fat, low-cholesterol diet and either lovastatin 80 mg/d or placebo. Logistic regression was used to model the association between risk factors and coronary lesion progression in mild/moderate (< 50% S) and severe (> or = 50% S) lesions in 220 angiogram pairs analyzed by computer quantitative coronary angiography. In the placebo group, risk factors (P < .05) for the progression of mild/moderate lesions were triglycerides and TC/high-density lipoprotein cholesterol (HDL-C). Risk factors for the progression of severe lesions were HDL-C (negative), low-density lipoprotein cholesterol (LDL-C)/HDL-C, and TC/HDL-C. TC/HDL-C was the predominant risk factor for both mild/moderate and severe lesions in the multivariate analysis. In the lovastatin group, with aggressive lowering of LDL-C and TC below 85 mg/dL and 156 mg/dL, respectively, risk factors for mild/moderate lesions included triglycerides and very-low-density lipoprotein-LDL-associated apolipoprotein C-III (apo C-III-heparin precipitate), a marker of triglyceride-rich lipoprotein particles. Apo C-III-heparin precipitate was the predominant risk factor in the multivariate analysis. Risk factors for severe lesions were LDL-C, LDL-C/HDL-C, TC/HDL-C, and apo B; LDL-C/HDL-C was the predominant risk factor. CONCLUSIONS These results indicate that triglyceride-rich lipoproteins and cholesterol-rich lipoproteins have a differential effect on mild/moderate and severe lesion progression, respectively. These results add to the growing evidence of the importance of triglyceride-rich lipoproteins as a risk factor for coronary artery disease and the need for treatment in the progression of atherosclerosis.

Major advances have been made in the understanding of the molecular mechanisms of atherosclerosis, the disease that still affects more than 50 percent of the population in highly industrialized countries. This volume covers the most recent advances in the treatment of hyperlipidaemia. It represents a necessary update because molecular mechanisms of atherogenesis have been discovered in the past few years and their molecular mechanisms of action identified. Extensively treated are the molecular mechanisms of the disease etiology of arteriosclerosis in relation to the major risk factor "hyperlipidaemia", rationale for more effective treatment of this disease by dietary means, the treatment of associated diseases, and the treatment using hypolipidaemic drugs.

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.

To assess the effects of lipid-lowering therapy with lovastatin on coronary angiographic findings in patients with coronary artery disease and to compare the findings with those of two lipid-lowering angiographic trials using similar end points.Randomized, double-blind, placebo-controlled, multicenter coronary angiographic trial.Community- and university-based cardiac catheterization laboratories.A total of 270 patients, 37 to 67 years old, with total cholesterol ranging from 4.92 to 7.64 mmol/L (190 to 295 mg/dL) and angiographically defined coronary artery disease.A cholesterol-lowering diet and either lovastatin, 80 mg/day, or placebo.Per-patient change in percent diameter stenosis as determined by quantitative coronary angiography (primary end point). Global change score, based on the consensus of blinded expert readers regarding angiographic change (secondary endpoint).Lovastatin lowered total cholesterol level by 32%, low-density lipoprotein cholesterol by 38%, and the apolipoprotein B by 26% and raised the high-density lipoprotein cholesterol by 8.5% (P0.001). Average percent diameter stenosis increased 2.2% in placebo recipients and 1.6% in lovastatin recipients (P0.20). For lesions 50% or greater, average percent diameter stenosis increased 0.9% in placebo recipients and decreased 4.1% in lovastatin recipients (P = 0.005). The mean global change score was +0.9 (indicating progression) in the placebo group and +0.4 in the lovastatin group (P = 0.002); 13 placebo recipients and 28 lovastatin recipients had global change scores indicating regression (P0.02).Treatment with lovastatin plus diet slows the rate of progression and increases the frequency of regression in coronary artery lesions (by global change score), especially in more severe lesions (by quantitative angiography). This is the third lipid-lowering trial to show a benefit using the global change score, an end point predictive of clinical coronary events. Differences between two of these trials, using quantitative coronary angiographic end points, may have theoretical bearing on the mechanisms by which lipid-lowering therapy operates at the level of the arterial wall.

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.

Two clinical trials with identical coronary and carotid end points indicate that aggressive reduction of blood lipoprotein level can induce beneficial change throughout the range of the atherosclerotic process. The drug treatments tested were combined colestipol/niacin and lovastatin. The data are most convincing for intrusive coronary lesions. There are also clear indications of benefit to very early pre-intrusive carotid lesions in men from CLAS and encouraging results from a small number of women in MARS.

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.

BACKGROUND. The Cholesterol Lowering Atherosclerosis Study, a controlled angiographic trial, has reported that new native coronary artery lesions are significantly reduced by aggressive blood lipid lowering therapy with colestipol plus niacin. To study factors relevant to primary atherosclerosis prevention, we have conducted an epidemiologic analysis of new native coronary lesion formation in placebo-treated patients. METHODS. Univariate and multivariate logistic regression procedures were used to examine age at entry into the study, number of years since bypass, body weight, diastolic and systolic blood pressure, plasma total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, non-HDL-cholesterol, and apolipoproteins A-I,B, and C-III. RESULTS. Significant univariate protective factors were older age (P less than .006), reduction of total plasma cholesterol (P less than .040), and systolic (P less than .024) and diastolic (P less than .022) blood pressure. Significant multivariate protective factors were older age (P less than .005) and reduction in systotic blood pressure (P less than .021). Blood pressure effects were not associated with use of specific antihypertensive agents. CONCLUSIONS. These data provide additional support for the control of hypertension and reduction of blood cholesterol level for primary and secondary ischemic heart disease prevention. They also indicate the existence of a population at high risk for early coronary lesion formation and the need for improved means to identify such individuals prior to the onset of clinical manifestations of ischemic heart disease.

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 Cholesterol Lowering Atherosclerosis Study, a randomized, angiographic clinical trial, has demonstrated the beneficial effect of niacin/colestipol therapy on coronary and femoral atherosclerosis. The primary outcome was a panel-determined consensus score evaluating global coronary changes determined angiographically at 2 years. This article presents an evaluation of interreader agreement in independently assessing the status of native coronary arteries and overall coronary condition. Parameters include 1) identification of the presence of lesions and lesion changes; 2) estimation of lesion severity (percent stenosis) and amount of change in lesion severity; and 3) global assessment of change in coronary status. Readers independently agreed on 1) presence of lesions (82%) and change in lesions (51%); 2) percent stenosis +/- 10% (76%) and change in stenosis +/- 10% (81%); and 3) global assessment of change in coronary status within one step (96%). Results of these analyses may be useful in effectively designing angiographic trials that use a panel of human evaluators as well as computerized methods for angiographic interpretation.

Angiographic evidence of coronary artery atherosclerosis regression has been demonstrated in controlled clinical trials. The significance of this regression appears to depend in a complex way on the degree of atherosclerosis present when a regression regimen is initiated. Angiographic trials indicate that lesion change is a continuum, with a gradual transition from progression to stability and regression. Divergent lesion change can be seen in the same patient with a progression of some lesions and a regression of others. This makes it necessary to perform a comprehensive survey of all visible coronary segments when evaluating angiograms to determine the outcome of a clinical trial. An important finding in clinical trials is that new lesion formation can be reduced. This indicates that effective control of atherosclerosis may be possible with procedures now available, but noninvasive coronary artery imaging methods need to be refined.

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.

Normalization of serum lipid levels should be initiated as soon as possible in patients with myocardial, cerebrovascular, or peripheral vascular disease. Clinical trials indicate that coronary artery disease and overall mortality rates can be reduced and atherosclerosis stabilized or reversed by lipid-lowering therapy. Treatment should lower low-density lipoprotein cholesterol levels to 130 mg/dL or less and total triglyceride levels to 150 mg/dL or less and increase high-density lipoprotein cholesterol levels to at least 52 mg/dL in men and 66 mg/dL in women. Nonlipid coronary risk factors should be eliminated when possible. Lipid-lowering therapy may consist of dietary modification and drug treatment with colestipol hydrochloride (Colestid), cholestyramine (Cholybar, Questran), lovastatin (Mevacor), gemfibrozil (Lopid), and nicotinic acid (Nicolar).

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.

Using five sham-operated and seven aortic coarctation-induced hypertensive New Zealand White rabbits intravenously injected with neutral small unilamellar vesicles loaded with [111In]nitrilotriacetic acid, we demonstrated in vivo that the normal aortic arterial wall participates in liposome uptake and that this uptake is increased in the hypertensive aortic wall by approximately threefold (p less than or equal to 0.0001). Among the three regions examined, aortic arch, thoracic aorta, and lower abdominal aorta, the difference in uptake between the normotensive and hypertensive arterial walls was significantly different, p less than or equal to 0.05, p less than or equal to 0.0001, and p less than 0.05, respectively. The uptake by the different regions of the hypertensive arterial wall is consistent with the pathological changes present in these areas. Furthermore, the extent of liposome uptake by the aortic wall is strongly correlated with the height of the blood pressure (r = 0.85, p = 0.001, n = 11). We conclude that neutral small unilamellar liposomes can be used to carry agents into the arterial wall in vivo in the study of hypertensive vascular disease and could be especially useful for the delivery of pharmacologically or biologically active agents that would otherwise be inactivated within the circulation or are impermeable to the arterial wall.

Evidence that atherosclerotic lesions can regress is derived from autopsy findings in starved human populations, animal-model studies of induced atherosclerosis, and clinical trials using angiography. Three angiographic trials, with a total of 317 subjects, have demonstrated stabilization of lesions. One of these trials has revealed clear evidence of lesion regression.

There are two general strategies to test the efficacy of drugs or dietary regimens which retard or reverse the progression of atherosclerosis in man. The first is to study effects on atherosclerosis-related morbidity or mortality. This strategy assumes that therapy effects will be powerful enough to emerge despite the presence of advanced complicated lesions, the known anatomic substrate for atherosclerosis morbidity and mortality. The second strategy is to measure the rate of atherosclerotic lesion change. In this case, it is assumed that therapy effects will be more pronounced on early stage lesions, but that long-range benefits will accrue if growth of these can be reversed or retarded.

In Reply.— The Cholesterol Lowering Atherosclerosis Study (CLAS) was designed to test lipid-lowering therapy by studying changes in the angiographic anatomy of the coronary arteries and was not designed to test effects on clinical events. It enrolled 188 subjects, an adequate number for a coronary angiographic end point but an insufficient number to evaluate treatment effects on clinical coronary events. The CLAS showed statistically strong and consistent treatment benefit to coronary anatomy after 2 years of treatment 1 and again after 4 years of treatment, as reported in our study. Other studies designed to test lipid-lowering effects on clinical coronary event rates have shown clear evidence for benefit. The Lipid Research Clinics Primary Prevention Trial (3806 randomized subjects) 2 and the Helsinki Heart Study (4801 randomized subjects) 3 both demonstrated a statistically significant reduction in clinical coronary events with lipid-lowering therapy. The Coronary Drug Project (2789 placebo, 1119 niacin-treated subjects)

In Reply.— Dr Simopoulos indicates the importance of analyzing the results of the Cholesterol Lowering Atherosclerosis Study (CLAS) for the effect of ω-3 and ω-6 fatty acids on new lesion formation. The CLAS data reported in JAMA were based on 24-hour recalls obtained from 1980, when the first subject was randomized, until 1986, when the last subject had a second angiogram. Conversion of recorded foods to nutrient composition was by the University of Minnesota Nutrition Coding Center with Data Tape 10, which did not have complete information on food content of ω-3 and ω-6 fatty acids, and so we did not analyze CLAS data for these fatty acids. During the CLAS we conducted computer-assisted diet counseling based on diet diaries recorded the week before each clinic visit. We stored food intake data from this new method but elected to report results from standardized 24-hour recalls first. We are now analyzing

The Cholesterol Lowering Atherosclerosis Study, a randomized, placebo-controlled trial of blood lipid lowering, demonstrated significant benefit in 2-year coronary angiograms. Using angiograms of subjects in the Cholesterol Lowering Atherosclerosis Study who received a placebo and 24-hour dietary recall data, we performed an epidemiologic study of risk factors for formation of new atherosclerotic lesions. Age and baseline plus on-trial lipid levels, blood pressure levels, and diet variables were included. Significant dietary energy sources were protein, carbohydrate, alcohol, total fat, and polyunsaturated fat. Each quartile of increased consumption of total fat and polyunsaturated fat was associated with a significant increase in risk of new lesions. Increased intake of lauric, oleic, and linoleic acids significantly increased risk. Subjects in the Cholesterol Lowering Atherosclerosis Study in whom new lesions did not develop increased dietary protein to compensate for reduced intake of fat by substituting low-fat meats and dairy products for high-fat meats and dairy products. These results indicate that when total and saturated fat intakes are reduced to levels recommended by the National Cholesterol Education Program, protein and carbohydrate are preferred substitutes for fat calories, rather than monounsaturated or polyunsaturated fat.

Smooth muscle cells from the tunica media of piglet aortae grown under hypoxic conditions undergo the following changes: First, they become modified by partial loss of myofilaments and proliferation of organelles, which are characteristics of young primitive cells. Second, an increase in number of pinocytotic vesicles at and below the cell surface, indicating increased extracellular uptake of material, can be detected. This is followed by accumulation of Oil Red O positive intracytoplasmic granules and vacuoles as well as the subsequent formation of mount-like protrusions. The latter consist of a core of extracellular material and necrotic debris covered with a cap of viable cells. A third feature of the cells subjected to hypoxia is a conspicuous rise in the number of lysosomes. This is considered to be a manifestation of a defense mechanism of the cells to remove undesirable material from cytoplasm. Cells exposed to an atmosphere rich in carbon monoxide exhibit basically the same alterations as those grown under hypoxic conditions; however, formation of mound-like aggregates is less prominent, while the rise in the number of lysosomes is more evident than in the hypoxic cells. The above alterations are similar to changes observed in smooth muscle cells of rabbit with experimental atherosclerosis. It is suggested that wherever the arterial smooth muscle cell is subjected to adverse conditions basically the same mechanism, consisting of dedifferentiation, increased permeability and lysosomal defense reaction, takes place.

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.

Accelerated atherosclerosis is known to occur in diabetes mellitus, but the exact mechanisms for this adverse consequence are unknown. Prospective determination of each patient's state of atherosclerosis coupled with serial comparisons between patients could be used to clarify relationships between insulin levels and growth rates of atherosclerotic lesions. Noninvasive measurements of atherosclerosis that are now feasible are phonoangiography, continuous-wave and pulsed Doppler ultrasound imaging, reflected beta-mode ultrasound imaging, computed axial tomography, and nuclear magnetic resonance imaging. An interesting new application of ultrasound beta-mode imaging for the estimation of localized arterial wall stiffness is described.

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 step from coronary angiography to surgery is taken primarily on the basis of the ejection fraction (EF) and number of diseased vessels (NV), taken jointly as coronary status (CS). This study reviewed (1) how well EF, NV and CS are estimated from clinical data, (2) how much improvement is gained by adding noninvasive data, (3) how good this model is when applied to a larger cohort and (4) whether the decision to angiography can be made on the basis of CS estimated from clinical data alone. A quantitative definition of CS was established as a principal component of EF and NV. Estimates of EF, NV and CS were made from clinical data of 60 patients. Correlations with the actual values were EF 87%, NV 93% and CS 93%. When noninvasive data were added to this model, the correlations increased to EF 95%, NV 99% and CS 98%. When the clinical data model was applied to 169 patients, the correlations decreased to EF 77%, NV 71 % and CS 74%. CS estimated from clinical data alone was set up as a test for angiography for 169 patients. This test had a sensitivity of 98% and a specificity of 63%, demonstrating the feasibility of using clinical data alone in deciding angiography.

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.

A computer method for detection and quantification of atherosclerosis from angiograms has been developed and used to measure lesion change in human clinical trials. The technique involves tracking the vessel edges and measuring individual lesions as well as the overall irregularity of the arterial image. Application of the technique to conventional arterial-injection femoral and coronary angiograms is outlined and an experimental study to extend the technique to analysis of intravenous angiograms of the carotid and cornary arteries is described.

In 1904, Marchand recognized the consistent association of fatty degeneration and vessel stiffening and introduced the term "atherosclerosis" to indicate this combination. Current research is focused principally on the lipid component, but there is evidence that both aspects are reversible. Atheromatous lipids add significantly to the volume of lesions and thus contribute to vascular obstruction and end-organ damage. Reversal of atherosis has been observed in all the major species used in atherosclerosis research; rabbits, swine, dogs, chicks, pigeons, and subhuman primates. Direct evidence for reversal in humans is based on angiographic trials and is less extensive. One femoral artery and one coronary artery trial indicate that the lesions can be stabilized. CLAS, the largest angiographic trial to date, indicates that coronary lesion reversal is possible. Clinical effects of sclerosis are more subtle, and there is little evidence that sclerosis alone leads to end-organ damage. However, it should be noted that atherosclerotic lesions producing end-organ damage invariably have a major fibrous component. Sclerotic vessels have reduced systolic expansion and abnormally rapid pulse wave propagation, which can be measured noninvasively. Primate studies indicate that sclerosis is induced by hypercholesterolemic diets and is reversible when these diets are withdrawn. Changes in sclerosis may be another useful indicator of the formation and reversal of lesions and may involve changes in EDRF. Future studies of atherosclerosis reversal should use a combination of measures to evaluate both atherosis and sclerosis.

Accelerated progression of atherosclerosis is known to occur in surgically bypassed coronary arteries in which the preoperative stenosis was greater than 50 per cent. To assess the effect of coronary bypass on vessels with lesser degrees of stenosis, we studied 85 men who had undergone coronary bypass surgery. In this group we identified bypass grafts placed in 37 arteries with minimal atherosclerosis, which was defined as less than 50 per cent stenosis of the vessel diameter. In the same 85 men there were 93 coronary vessels with minimal atherosclerosis for which a bypass graft had not been placed. Progression of atherosclerosis, defined as further loss of at least 25 per cent of the lumen, during an average follow-up period of 37 months was more than 10 times as frequent (38 per cent vs. 3 per cent) in bypassed arteries with minimal atherosclerosis as in comparable arteries that were not bypassed. These findings support the view that minimally diseased coronary arteries should not be bypassed.

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.

Several forms of familial hypercholesterolemia are now recognized. The most common is characterized by elevated serum cholesterol levels with normal or only modestly elevated serum triglyceride levels, currently classified as type II hyperlipoproteinemia. It is the current consensus that this form of familial hypercholesterolemia is transmitted by a single dominant gene, although polygenic inheritance has been proposed by McKusick as an alternate hypothesis. Decision as to the most probable mode of inheritance of familial hypercholesterolemia must be based upon family studies which enumerate a recognizable characteristic of hypercholesterolemia and compare the observed incidence with models for Mendelian inheritance. Several characteristics have been used over the years. Serum total cholesterol level is now most widely accepted, although attempts at use of the beta lipoprotein level are now in progress, and in the future use of other attributes can be anticipated. When the serum total cholesterol level is used the available evidence indicates that polygenic inheritance is more probable than transmission by a single dominant gene. The practical implications of this conclusion are (1) In family studies of hypercholesterolemia, the serum cholesterol level of both parents must be tested. (2) Genetic counseling should take into account the probability that children will have serum cholesterol levels more nearly resembling a midparent than either normal parent or hypercholesterolemic parent. (3) It is not possible to select any single cholesterol level as a valid characteristic for familial hypercholesterolemia. (4) Children who have borderline cholesterol values cannot be classified as having or not having the hypercholesterolemic trait. (5) The effect of any single medication or therapeutic procedure predictably will vary in different families.

SummaryA procedure is described for the isolation and characterization of the fatty acids of lecithin (plus lysolecithin) and sphingomyelin from blood serum. This procedure was employed for analysis of these fatty acids in 10 normal adult humans. The results indicate that serum lecithin is comprised of an approximately equal proportion of saturated and unsaturated fatty acids while sphingomyelin contains a series of saturated and monounsaturated fatty acids ranging from 14 to 25 carbon atoms. The major fatty acids of lecithin were 16:0, 18:0, 18:1 and 18:2 while the major sphingomyelin acids were 16:0, 18:0, 22:0, 24:1 and 24:0. There were no apparent age-dependent changes in the fatty acid composition of these lipids (16–56 years). The fatty acids of sphingomyelin appeared to vary in composition from subject to subject more than those of lecithin.

SummaryA technic is described for sampling the contents of the intestinal tract in human subjects repeatedly and at various intestinal levels over a 1-2 week intubation period. Prolonged transintes...

SummaryHigh speed color motion pictures of the heart in 10 dogs have shown rapid phasic color changes in the right atrium which alternate between red and cyan with each cardiac cycle. Frame by frame measurement of color at 10 msec intervals throughout one cardiac cycle in one dog has shown a major red peak beginning approximately 195 msec after the onset of the P wave. Although the cause of these color changes is not yet known, they may result from phasic changes in coronary arterial flow through the atrial wall.