Precision and reproducibility of quantitative coronary angiography with applications to controlled clinical trials. A sampling study.

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.

Abnormal activation of sterol synthesis in lymphocytes of atherosclerotic-susceptible pigeons and heterozygous familial hypercholesterolemic patients.

Delipidated human sera enhances the incorporation of [2-14C]acetate, but not mevalonate, into digitonin-precipitable sterols of pigeon lymphocytes. Show Racer and White Carneau pigeons exhibit inherited differences in induction of sterol synthesis dissociated from inheritance of hypercholesterolemia. Moreover, lymphocytes of three familial hypercholesterolemic individuals, having serum cholesterol level in the normal range by drug therapy, exhibited a higher activation of sterol synthesis by delipidated sera when compared to cells of normal individuals. It is suggested that genetic abnormality in lymphocytes of familial hypercholesterolemic can be dissociated from hypercholesterolemia.

In vivo hypertensive arterial wall uptake of radiolabeled liposomes.

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.

Arterial wall oxygenation, oxyradicals, and atherosclerosis.

The oxygen supply of inner media and thickened intima of atherosclerosis prone arteries depends largely on diffusion from the endothelium. Conditions which increase wall thickness and oxygen diffusion or reduce oxygen transmissibility produce hypoxia and steep PO2 gradients within the wall. Cerebral injury and myocardial reperfusion studies indicate that intermittent hypoxia and steep PO2 gradients lead to oxyradical formation and tissue damage. Products of lipid and sterol peroxidation are found in atherosclerotic plaques and can be generated by arterial wall cells in culture. It is likely that peroxidation occurs directly within the arterial wall. Sufficient oxyradical generation occurs during normal oxygen metabolism that local scavenger mechanisms are required to avoid tissue damage. Experimental hypertension, hyperlipemia and balloon injury produce medial hypoxia with steep PO2 gradients and redistribution of the pattern of arterial wall antioxidant enzymes. This suggests that minor deviations from normal arterial wall anatomy and function can lead to oxyradicals which can be directly injurious and can amplify the atherogenic potential of lipoprotein infiltration.

Very early aortic responses during atherosclerosis induction in rabbits: measurement by duplex ultrasound. I. Non-invasive study of aortic hyperresponsiveness to serotonin.

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 rabbit fed the cholesterol-rich diet displayed an enhanced vasoconstriction to serotonin (P less than 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.

Light- and electron-microscopic characteristics of artrial smooth muscle cell cultures subjected to hypoxia or carbon monoxide.

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 whereever 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.

Relationship of arterial wall uptake of radiolabeled liposomes to the presence of monocyte/macrophage cells in the hypertensive and atherosclerotic arterial wall.

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.

Computerized edge tracking and lesion measurement in coronary angiograms. A pilot study comparing smokers with non-smokers.

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.

Regression of atherosclerosis: what does it mean?

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.

Spatial reconstruction of human femoral atheromas showing regression.

Reports of atherosclerotic changes in human subjects previously described have been based on evaluation of arteriographic edge contours. They imply unchanged roentgenographic and physiologic conditions, including identical patient positioning and vascular tone which cannot always be obtained in sequential studies. We have previously described the development of quantitative angiographic densitometry which permits measurement of vascular cross-sectional chord length distributions and areas, independent of rotational changes in vascular position. In this paper we report on application of the method to sequential femoral angiograms in two patients in whom there were significant increases in vascular cross-sectional area after a program of exercise and risk reduction. The method excludes interpretive errors due to circumferential changes in vascular tone.

Can atherosclerotic lesions regress? Angiographic evidence in humans.

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.

Prevention or reversal of atherosclerosis: review of current evidence.

Treatment with lipid-reducing agents is associated with reduced morbidity and mortality from coronary heart disease. Such treatment appears to work at the level of the atherosclerotic lesion, causing stabilization, slowed progression and, in some cases, regression of lesions. Morbidity and mortality studies of cholestyramine and gemfibrozil treatment have shown that a reduction of lipid levels was associated with reduced mortality from coronary heart disease; niacin treatment has been shown to have long-term effects on reducing cardiovascular mortality. Angiographic studies have documented that beneficial effects of treatment with lipid-reducing agents and intensive computer-assisted diet counseling occur at the level of the coronary atherosclerotic lesion.

Fat and cholesterol intake of attendees at two national USA cardiovascular annual meetings.

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.

Clinical data versus noninvasive testing as an estimate of coronary status.

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.

Measurement of atherosclerotic luminal irregularity and obstruction by radiographic densitometry.

This report describes a procedure to quantify stenosis and to detect enface plaques in single plane angiograms. We derived an optical density function proportional to local arterial chord length from arteriographs over a wide range of conditions. Standard radiographs were made of silicone rubber bolus used as the radiopaque medium in cadaver arteries. Replicate arterial casts filled with iodine-bearing contrast medium were radiographed for comparison. Identical atherosclerotic areas in both film sets were scanned with a microdensitometer and vessel chord lengths used to construct arterial cross sections for comparison with vessel casts. Cross-sectional areas derived from cadaver and phantom films were highly correlated with those derived from cast slices (r = 0.997). Thus, luminal cross-sectional areas were accurately estimated independent of plaque location, and accuracy of chord length measurement was +/- 0.28 mm in vessels four to 10 mm in diameter.

Abnormal serum lipid patterns in primary renal allograft recipients.

The blood lipids profile was determined in 59 patients with successful primary renal allografts, who were followed for an average period of 31.8 months (range, 6 to 80 months). Elevated levels of cholesterol (greater than 250 mg/100 ml) were found in 51% of the patients, elevated levels of triglycerides were found in 56%, and elevated levels of phospholipids in all but one of the patients who were studied (45 of 46). Correlation analysis revealed significant relationships among the systolic blood pressure with total cholesterol (r equals 0.36, P less than 0.01), triglycerides (r equals 0.56, p is less than 0.001), and phospholipids (r equals 0.40, P is less than 0.001). No significant correlations were found between the lipid levels and daily prednisone dosage or with the duration of the period following transplantation. The most significant finding in our study was an elevation of serum phospholipid level--a pattern unreported previously in transplant recipients but which has been reported to be associated with hepatic derangement in nontransplant population. Of 32 patients who had elevated levels of serum phospholipids, the liver function tests were abnormal in 22 patients (69%).

The Program on the Surgical Control of the Hyperlipidemias: a status report.

The Program on Surgical Control of the Hyperlipidemias (POSCH) is a multicentered secondary coronary heart disease intervention trial utilizing maximal plasma lipid reduction as achieved by the partial ileal bypass operation. With over 500 patients recruited into this trial at present, the 4-year sequential lipid changes are statistically highly significant and include an approximate 30% plasma total cholesterol and 40% low density lipoprotein (LDL)-cholesterol reduction, with a slight increase in the high density lipoprotein (HDL)-cholesterol and a marked increase in the HDL-cholesterol:LDL-cholesterol ratio of about 75% or higher. A definitive answer to the lipid-atherosclerosis theory corollary--whether a decrease in the plasma cholesterol engenders a reduction in the incidence or severity of atherosclerotic cardiovascular disease--can be expected from these marked lipid changes in POSCH.

Noninvasive methods for evaluation of atherosclerosis in man.

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.

A computerized quantitative food frequency analysis for the clinical setting: use in documentation and 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.

Nutrient Analysis System--a computerized seven-day food record system.

A self-recording, directly computer-readable, seven-day food record system (the Nutrient Analysis System [NAS]) was developed using the National Heart, Lung, and Blood Institute Food Table as a data bank for the nutrient analysis. This article describes the system and reports the results of a study which evaluates the system in an experimental setting. It is concluded that the Nutrient Analysis System is no less accurate or biased than the traditional written food record method under the conditions of this test. Additionally, NAS is a system which allows for efficient use of professional time and immediate availability of nutrient analysis for use in counseling.