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Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:1829-1838

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:1829-1838.)
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Articles

Association of Postprandial Triglyceride and Retinyl Palmitate Responses With Newly Diagnosed Exercise-Induced Myocardial Ischemia in Middle-Aged Men and Women

Henry N. Ginsberg; Jeff Jones; William S. Blaner; Alicia Thomas; Wahida Karmally; Leslie Fields; David Blood; Melissa D. Begg

From the Department of Medicine (H.N.G., J.J., W.S.B., A.T., D.B.), College of Physicians and Surgeons, Columbia University; the Irving Center for Clinical Research (W.K.), Columbia Presbyterian Medical Center; Harlem Hospital Center (L.F.); and the Division of Biostatistics (M.D.B.), School of Public Health, Columbia University, New York, NY.

Correspondence to Henry N. Ginsberg, Department of Medicine, College of Physicians and Surgeons, Columbia University, 630 W 168th St, New York, NY 10032.


*    Abstract
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 *Abstract
down arrowIntroduction
 down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Abstract Although strong evidence exists linking fasting plasma levels of LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C) to risk for development of coronary artery disease (CAD), the data in support of an independent role for fasting triglyceride (TG) concentrations are weak. Humans are in the postprandial state most of the day, however, and results from both basic and clinical studies suggest that postprandial TG levels may be atherogenic. Previous studies have not, however, attempted to determine if postprandial TG levels are associated with CAD independent of other traditional risk factors or plasma lipid levels, particularly fasting plasma concentrations of TG and HDL-C. Ninety-two men and 113 women (mean age, 51.6 and 53.6 years, respectively) were recruited from populations undergoing diagnostic exercise electrocardiographic or thallium stress tests at our medical centers. Twenty-six men and 24 women had positive tests. We chose exercise-induced myocardial ischemia (EIMI) as the criterion for defining case and control subjects because we wanted participants who did not have a prior diagnosis of CAD. Blood samples were obtained for measurement of plasma TG, TG-rich lipoprotein TG, and retinyl palmitate (RP) levels 2, 3.5, 5, and 8 hours after the subjects had consumed a fatty test meal. Logistic regression models were developed to test for associations between each variable and case-control status. Among men but not women postprandial TG and RP responses were associated with EIMI independent of age, race, and smoking status. In the male group, the odds ratio (OR) for an increase in postprandial TG response of approximately 1 SD was 1.69 (P=.007); the OR for an increase in RP response of 1 SD was 2.47 (P=.011). However, when fasting TG was added to the model, the OR for postprandial TG area in the men was reduced to 1.44 (P=.17); the OR for postprandial RP area in the men was reduced to 1.88 (P=.12). There was no effect of adding other risk factors, including LDL-C and HDL-C, to the model. Significant effect modification by body mass index (BMI) on the relationship between postprandial responses and case-control status was observed. In men with BMI <30, the OR was 1.83 for postprandial TG (P=.041) and 2.77 for postprandial RP (P=.032) in models that included fasting TG, LDL-C, and hypertension. In men with BMI >30, the ORs for TG (0.67) and RP (0.59) were not significant. Postprandial TG and RP levels were not associated with EIMI in either BMI group among the women. Our results suggest that the accumulation of intestinal lipoproteins in the postprandial period may be directly atherogenic in this group. We did not find any association between postprandial lipemia and EIMI in the women we studied. Overall, however, our results indicate the need for a prospective study of the role of postprandial lipoproteins in the development of atherosclerotic cardiovascular disease.


Key Words: postprandial lipemia • triglycerides • chylomicron remnants • coronary artery disease • risk factors • obesity


*    Introduction
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 up arrowAbstract
 *Introduction
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 down arrowResults
 down arrowDiscussion
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Prospective epidemiological, case-control, and angiographic studies1 2 3 have all demonstrated a relation between plasma cholesterol, particularly LDL-C and HDL-C, and the risk for CAD. Several intervention trials4 5 in which reductions in LDL-C levels are associated with reduced rates of CAD events, reversal and stabilization of coronary lesions, and reduced mortality support these studies. Increases in HDL-C concentrations may have played a significant role in the positive outcomes in some of these studies.

The evidence in favor of a role for elevated fasting levels of plasma TGs in the development of CAD is much weaker.6 The absence of a consistent, independent link between fasting TGs and CAD may result in part from the large day-to-day variability of plasma TG concentrations and in part from the strong inverse relationship between fasting TG and HDL-C concentrations. Another possibility is that postprandial TG levels, rather than fasting levels, are a better indicator of risk.7 Sporadic studies during the past 40 years have suggested a relationship between CAD and abnormal postprandial fat metabolism.8 9 10 11 Several recent case-control studies12 13 14 15 and increasing numbers of animal16 17 and tissue-culture18 19 studies have rekindled interest in the potential atherogenicity of postprandial TGRLs. As a result, we designed a case-control study to test the following hypotheses: that abnormalities in postprandial lipoprotein metabolism are associated with EIMI and that this association is independent of the major risk factors for CAD, including fasting plasma lipid and lipoprotein levels. On the basis of previous studies, we measured several parameters of postprandial lipemia, including plasma TGs, d<1.006 TG, and plasma RP. More detailed measurements of chylomicrons, remnants, and isolated apoB-48 or apoB-100 fractions were deemed unfeasible because of the large number of subjects we studied. A companion study examined the same hypotheses by using asymptomatic carotid atherosclerosis as the outcome.20


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
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 down arrowDiscussion
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Recruitment
Subjects were recruited from patient populations referred for either ECG exercise stress testing or thallium stress testing at the Columbia-Presbyterian Medical Center or the Harlem Hospital Center of the City of New York. All subjects were referred by their private or clinic physicians because of the presence of symptoms suggestive or typical of CAD. Most patients also had known risk factors for CAD. Overall, the patient group studied was representative of a population sent for diagnostic evaluation of CAD. We chose to recruit from this population because we wanted individuals who had not changed their lifestyle (eg, diet and exercise) in ways that would affect their response to a fat load.

At the time of a subject's test, a member of the recruitment team reviewed the historical and physical examination data collected by the stress-test laboratory staff. If the subject met inclusion and exclusion criteria (see below), he or she was interviewed, and the study protocol was described. If the individual agreed to participate, he or she was given an appointment for the test. Follow-up telephone calls were made prior to the test date to ensure continued availability and willingness to participate. Every attempt was made to schedule the study within 2 weeks of the stress test to avoid potential confounding of the test by lifestyle changes or medical intervention. Approximately 90% of our population participated in the study before returning to their own physicians. All medical center physicians were informed about the study prior to its start, and most agreed to allow their patients to participate without further notification. Physicians who requested notification were notified before the study. The protocol was approved by the Institutional Review Boards at the Columbia-Presbyterian Medical Center and the Harlem Hospital Center.

Inclusion and Exclusion Criteria
Inclusion and exclusion criteria are listed in Table 1Down. All subjects referred for stress testing were potentially eligible for entry into the study. Men and women of all ethnic groups were recruited. The age range was 20 to 75 years. Exclusion criteria included a history of documented CAD; unstable angina; a history of or treatment with medications for diabetes mellitus; use of lipid-altering drugs more recently than 4 weeks before the stress test (6 months in the case of probucol); use of oral contraceptives or postmenopausal replacement hormone therapy; or significant lactose intolerance or fat malabsorption. Patients with any serious medical illnesses, including liver, kidney, or thyroid disease, were also excluded. Patients taking thiazide diuretics or ß-blocking agents were not excluded from the study, but their exposure to these drugs was recorded.


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  		Table 1. Inclusion and Exclusion Criteria

Categorization of Patients
All subjects underwent symptom-limited treadmill exercise according to the Bruce protocol; one or two preliminary stages were added at the discretion of the supervising physician. Cardiac rhythm and the computer-averaged 12-lead ECG were monitored continuously. Blood pressure was measured during each stage of exercise and more often when clinically indicated. The ECG was monitored during 8 minutes of recovery with the patient supine or until the ECG had returned to baseline. Exercise was terminated prior to limiting symptoms only for ventricular tachycardia or a fall in blood pressure of 15 mm Hg or more that was confirmed by repeat measurement. For thallium studies, the thallium was injected 60 to 90 seconds before termination of exercise, and recovery was shortened to 4 minutes. Scintigraphic imaging was started as soon as possible after recovery (usually within 10 minutes of injection). Imaging was performed by using a large field-of-view rotating gamma camera (Picker SX-70) equipped with a parallel-hole collimator. A 5-minute planar image in the anterior view was acquired first followed by single-photon emission computed tomography acquisition over a 180° arc from the 45° left posterior oblique to the 45° right anterior oblique position (6° intervals; 40 seconds per image). Repeat imaging was performed 4 hours later by using the same technique. Transaxial reconstruction with filtered back projection was performed by using standard clinical techniques (Picker Odyssey computer), and paired-exercise and redistribution tomographic slices were displayed in the standard short, vertical long, and horizontal short axes for interpretation.

An ischemic ECG response was defined either as a horizontal or downsloping ST depression of 0.1 mV from the isoelectric line (defined by the end of the PR segment) in the presence of normal resting repolarization; as an upsloping ST depression of 0.15 mV below the isoelectric line measure 60 msec beyond the J-point in the presence of normal resting repolarization; or as an ST depression of 0.15 mV below baseline ST level regardless of contour in the presence of abnormal resting repolarization. ST segment changes were considered uninterpretable in the presence of a paced rhythm, a left bundle-branch block, or (for changes in the right precordial leads) a right bundle-branch block. Perfusion scans were interpreted visually by experienced observers. Breast attenuation artifacts were identified and excluded from interpretation. Subjects were classified as case or control subjects on the basis of these interpretations of their stress tests. Stress-test results were later reviewed in a blinded fashion by one of the investigators (H.N.G.) after completion of the entire study, and any tests that were deemed inconclusive were excluded. The major reasons for exclusion were inadequate exercise and failure to reach 85% of predicted heart rate. Four subjects were eliminated from analysis because of inadequate exercise. Thallium stress-test results were used as the basis for classification if they were available, irrespective of accompanying ECG changes. Of the 50 case subjects, 22 (44.0%) were classified by thallium stress testing. Of the 155 control subjects, 66 (42.6%) had taken thallium stress tests. Fifteen male case (57.7%) and 31 male control subjects (47.0%) were classified by thallium stress testing; in the female group the numbers were 7 (29.2%) and 35 (39.3%), respectively.

Classification of case and control subjects by using coronary angiography would have reduced the potential for misclassification. However, our goal was to study individuals without previous diagnosis of CAD. This strategy enabled us to recruit participants before diet and drug regimens or exercise programs had been instituted. We found that very few individuals were sent for angiography without either prior diagnostic studies or prior myocardial infarction. It is clear that our decision to use EIMI to define case-control status increased the chance for misclassification of case and control subjects, particularly among the women. However, we believed that this approach avoided the problem of diet, exercise, and other lifestyle changes that would have been present in many individuals with a prior diagnosis of CAD; such changes would have certainly confounded our ability to analyze the response to a dietary fat load.

Postprandial Lipemia Protocol
The patients were admitted to the Irving Center for Clinical Research at the Columbia-Presbyterian Medical Center on the morning of their study. All subjects had fasted for 12 hours prior to admission. Vital signs and waist and hip measurements were obtained, and a history and physical examination were completed by a staff physician. During the 8-hour sampling period, food frequency was assessed by using the Block questionnaire, and an estimate of physical activity was determined by using a shortened version of the questionnaire developed by Paffenbarger. These questionnaires assessed dietary and physical activity patterns for the previous 12 months. Smoking and alcohol histories were also recorded.

Fasting blood samples were obtained for measurements of baseline lipid and lipoprotein levels, a complete blood count, and a standard chemistry panel. The patient was then given the fat formula to drink within a 15-minute period, and blood samples were obtained at 2, 3.5, 5, and 8 hours. Patients were free to walk around between blood samplings, but they were placed in bed for at least 30 minutes before each venipuncture. Only calorie-free and caffeine-free beverages were allowed during the 8-hour period of blood sampling.

Fat Formula
The formula used as the fat test was prepared 24 hours in advance and contained heavy whipping cream, ice cream, safflower oil, and a powdered protein source (Promod, Ross Laboratories). The nutrient composition of the formula, based on a body surface area of 2 m2, included 105 g fat with 52 g saturated fat, 48 g carbohydrate, 32 g protein, and 300 mg cholesterol, and it provided 1265 calories. Vitamin A (100 000 U per 2 m2 body surface) was added in the form of Aquasol A (Astra Pharmaceuticals). Lactaid was also added to each formula preparation as a precaution against lactose intolerance in any of the participants. On the day of the test the appropriate volume of formula, based on the patient's surface area, was measured and served.

Laboratory
Blood for plasma was drawn into sterile tubes containing EDTA (1.0 mg/mL), and samples for serum were placed in empty sterile tubes. Samples were immediately placed on ice and kept at 4°C until centrifugation. Plasma or serum was separated from cells by centrifugation at 2500 rpm for 30 minutes at 4°C. Plasma to be used for determination of retinyl ester levels was protected from light and stored under nitrogen at -80°C until assayed. All plasma and serum samples were stored at 4°C or at -80°C, depending on the assay for which they were to be used. Plasma was stored at -80°C after addition of aprotinin.

All measurements were performed without the laboratory workers' knowledge of case-control status. Determinations of cholesterol and TGs in whole plasma, of cholesterol in HDL, and of TGs in d<1.006 lipoproteins were performed in the Core Lipid Laboratory of the Special Center of Research in Arteriosclerosis at the Columbia-Presbyterian Medical Center. This laboratory participates in the standardization program of the Centers for Disease Control and Prevention, Atlanta, Ga. Cholesterol and TG levels were determined by using enzymatic methods using a Hitachi 714 automated spectrophotometer. The interassay coefficients of variation for these measurements are less than 3% at present. In every fourth study, one of the timed samples was drawn in duplicate and labeled as a sixth sample. TG levels were measured in these extra samples, and the duplicates were compared. The mean±SD values for the blinded samples were 229.8±140.0 and 230.4±141.1 mg/dL. The reliability coefficient between duplicate samples exceeded 99%.

HDL-C was measured after precipitation of plasma apoB-containing lipoproteins with 10 g/L dextran sulfate and 0.5 mol/L MgCl2 (final concentrations, 0.91 mg/mL and 0.045 mol/L, respectively).21

TGRLs (d<1.006) were isolated from plasma by ultracentrifugation by using a TLA-100.3 fixed-angle rotor in a Beckman TL-100 ultracentrifuge. Plasma (2.0 mL) was mixed with 1.0 mL buffer, and the d<1.006 lipoproteins were isolated in the top 2.0 mL after a 3.5-hour centrifugation at 100 000 rpm.

Plasma RP levels were measured by reversed-phase high-performance liquid chromatography by using a procedure similar to that described by Bieri et al.22 This procedure employs an internal standard technique for the calculation of retinyl ester levels. The within-assay and between-assay coefficients of variation for retinol and retinyl ester determinations are less than 7%. For retinoid determinations, 100 µL serum or plasma was denatured by adding 100 µL ethanol containing internal standard retinyl acetate, and the retinoids were extracted first into hexane and then into benzene for injection onto the high-performance liquid chromatography column. Chromatography was performed on a 4.6x25-mm Beckman 5-µm Ultrasphere ODS column with 70% acetonitrile/15% methanol as solvent. The flow rate was 2.0 mL/min. Retinyl esters were detected by absorbance at 325 nm, and levels were determined from a standard curve by relating integrated peak area ratios of the retinoid of interest and the internal standard retinyl acetate to mass ratios of the two compounds. Standard curves were constructed by using authentic retinyl esters. Although this method provides accurate measures of RP, retinyl oleate, and retinyl stearate, a pilot study of the first 60 study participants indicated that there were no qualitative differences in the postprandial patterns of these esters. We chose, therefore, to use only RP for data analysis.

The pattern of each subject's apoE isoforms was determined by polymerase chain reaction by using the Hha I restriction enzyme.23 Briefly, leukocyte DNA was amplified by polymerase chain reaction by using specifically synthesized oligonucleotide primers and Taq polymerase. The amplified apoE products were then digested with 5 U Hha I enzyme at 37°C for 4 hours, and the digest was subjected to electrophoresis on a 12% nondenaturing polyacrylamide gel for 3 hours at a constant current of 10 mA. The gels were treated with ethidium bromide for 10 to 15 minutes, and the DNA fragments were visualized by UV illumination. DNA fragments of known size were used as markers.

Statistical Methods
The objective of this study was to compare abnormalities in postprandial lipoprotein metabolism between case and control subjects. We decided at the outset to measure postprandial lipid metabolism as the AUC of lipid measurements made over time, as this would reflect both the magnitude (height) and duration (width) of lipoprotein concentration over the period from baseline to 8 hours after the test meal. The formula used to compute the AUC is based on the trapezoid rule and measures AUC above the baseline measurement: AUC= 1.75y2+1.5y3.5+2.25y5+1.5y8-7y0, where yt equals the measurement taken t hours after baseline for t=0, 2, 3.5, 5, and 8.

Case-control comparisons for demographic and fasting and postprandial lipid data were made by Pearson's {chi}2 test for discrete variables and by Student's t test for continuous variables. To accommodate unequal variances, the approximate t statistic was used. Logistic regression models were used to relate case-control status (the binary outcome) to several covariates simultaneously.24 In particular, logistic regression allowed us to study the association between the AUC and case-control status while adjusting for other factors (see below). Comparable analyses were conducted separately for postprandial plasma TGs, TGRL-TGs, and RP.

The relationship between case-control status and AUC (plasma TGs, TGRL-TGs, or RP) was assessed via a logistic model, adjusting for age, race (black versus other), and smoking history (ever versus never). Subsequently, the most important confounder under consideration, baseline TGs, was added to the model. A series of other covariates followed. These included hypertension, LDL-C, and HDL-C. The decision to include or exclude each of these potential confounders was based on both the significance level of the variable in the model and the degree to which its addition to the model affected the estimated coefficient of the AUC variable. Finally, a selected group of interaction terms was tested, one by one, in the logistic model. These included apoE genotype, WHR, and BMI. Evaluation criteria again included significance level as well as effect size. We chose ORs for a 500-unit difference in plasma TG AUC and a 300-unit difference in RP AUC to enhance comparability between our results and those presented in the companion article by the ARIC investigators.20 Those values represent approximately 1 SD in each AUC for the entire ARIC study group.

Early in the analyses, it became evident that there was a substantial and statistically significant interaction between AUC and gender as they related to case-control status. For this reason, logistic models were fitted separately for men and women to facilitate interpretation and to avoid problems related to multicolinearity between covariates in the same model.


*    Results
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 up arrowIntroduction
 up arrowMethods
 *Results
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Demographic data and fasting lipid measurements describing the case and control subject populations are presented in Table 2Down. There were 92 men (26 case and 66 control subjects) and 113 women (24 case and 89 control subjects). There were somewhat more blacks among case compared with control subjects, particularly among the women; this seemed to result from a disproportionate recruitment of case versus control subjects at the Harlem Hospital site, which was the source of nearly all the black subjects. There were also very few white female cases. Indeed, the difference in ethnic distribution between female case and control subjects was statistically significant. This may have contributed to our inability to find an association between postprandial lipemia and case-control status in the women (see below).


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  		Table 2. Case-Control Subject Characteristics by Sex

The mean age of the male case subjects was significantly greater than that of the male control subjects (57.5±9.3 versus 49.3±10.4 years). We carried out subgroup analyses to determine if age affected the TG response to a fat load: it did not. Age was, however, the first variable entered into our logistic model. In contrast, there was no difference between the mean age of the female case and control subjects (55.5±11.1 versus 53.1±10.5 years). Smoking did not differ between the male case and control subjects, but female case subjects smoked more than female control subjects. There were no significant differences in BMI or WHR between case and control subjects of either sex. Prevalence of hypertension as determined by the measurement of blood pressure on the day of the study did not differ between case and control subjects.

Although the differences did not reach statistical significance (Table 2Up), there were higher levels of fasting TC and LDL-C in male case subjects compared with control subjects (TC, 5.25±1.17 versus 4.92±0.95 mmol/L; LDL-C, 3.38±0.90 versus 3.29±0.83 mmol/L). HDL-C tended to be lower in the male case subjects as well (0.92±0.27 versus 1.00±0.24 mmol/L). Fasting TG levels were, however, significantly increased in male case subjects (2.08±1.53 versus 1.39±0.69 mmol/L). These modest differences in fasting lipid levels are consistent with those observed in several other case-control studies of postprandial lipemia in which either TC, LDL, or HDL levels did not differ between groups.12 13 14 15 25 In contrast, female case and control subjects had essentially identical fasting lipid concentrations. Of note, the mean fasting TG levels in the female case and control subjects were the same as those in the male control subjects. The distribution of apoE genotypes was similar in the case and control subjects for both genders.

In both the men and the women there was a trend toward a difference in the use of ß-blockers between case and control subjects: use tended to be higher in male case and female control subjects. However, use of ß-blockers was not associated with differences in postprandial responses in either gender. Thiazide use was similar in both sexes for case and control subjects.

The plasma TG, TGRL-TG, and RP AUC responses were increased in male case versus control subjects (Table 3Down). In the women, postprandial responses actually tended to be lower in the case subjects. The sex differences in the case versus control subject postprandial TG, TGRL, and RP responses can be seen clearly in the FigureDown.


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  		Table 3. Postprandial Responses by Sex



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  		Figure 1. Line graphs showing postprandial plasma TG, TGRL-TG, and RP responses for male and female case ({circ}) and control ({bullet}) subjects during the 8-hour test.

On the basis of these fasting and postprandial data, we used multiple logistic regression to determine if the postprandial plasma TG, TGRL-TG, or RP AUC responses to a fat meal were associated with case-control status, controlling for demographic and baseline measurements. The models confirmed the presence of effect modification by gender on the association between postprandial responses and case-control status (TGs, P=.009; RP, P=.054). When men were analyzed separately, both the postprandial plasma TG and RP responses were significantly associated with case-control status in models that included age, race, and smoking. The OR for an increase in the postprandial TG response of 500 units ({approx}1 SD for the entire study population) was 1.69 (P=.007) (Table 4Down). An increase in the postprandial RP response of 300 units (1 SD) was associated with an OR of 2.47 (P=.011) (Table 5Down). However, after addition of fasting TG levels to the model, neither the postprandial TG nor RP areas were significantly associated with case-control status. Once fasting TG level had been added to the model, the ORs for postprandial AUC responses in the men were essentially unaffected by the single or combined additions of other covariates, including hypertension, LDL-C, and HDL-C. The findings were similar for the TGRL AUC results (data not shown).


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  		Table 4. Logistic Regression Results: Postprandial TG


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  		Table 5. Logistic Regression Results: Postprandial RP

Since obesity is known to affect several aspects of TG metabolism and to be associated with increased plasma TG concentrations, we studied whether WHR or BMI affected the association between postprandial lipemia and CAD. We did not see significant differences in either BMI or WHR between case and control subjects (Table 2Up). We did, however, observe effect modification by BMI on the relation between postprandial AUC response and case-control status in the men. After dividing the total male group into subgroups with BMI greater or less than 30 (28% of the men had BMI>=30), we found that both postprandial TG and postprandial RP responses were associated significantly with case-control status in the "thin" men (Tables 4Up and 5Up). Thin men (BMI<30) had a 1.83-fold increase in risk associated with an increase in postprandial TG response of 1 SD (P=.041); similarly, a 1-SD increase in RP response was associated with a 2.77-fold increase in risk in the thin men (P=.032). These ORs were significant in the model with fasting TGs, hypertension, and LDL-C. Addition of HDL-C to this model had no effect on the OR. In contrast, increased TG and RP AUC responses were not associated with EIMI in "obese" (BMI>=30) male cases. The effect of obesity on the association between either TG or RP response and case-control status paralleled its effect on the AUC responses themselves (Table 6Down): there were no differences in postprandial responses between male case and control subjects who had BMI>=30. These results are in close agreement with those presented by the ARIC investigators in the companion article.20


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  		Table 6. Postprandial Responses by Sex, Case-Control Status, and BMI

In the women, there was no association between postprandial TG, TGRL, or RP responses and case-control status. In fact, in these multiple logistic models, higher postprandial responses tended to be associated with lower risk in this group (Tables 4Up and 5Up). Of particular interest was the observation that "thin" (BMI<30) women had a positive association between the postprandial RP response and case-control status (OR 2.02) (Table 5Up). The effect of obesity on postprandial TG and RP responses in the women can be seen clearly in Table 6Up, which shows that female control subjects with BMI>=30 actually had significantly smaller TG and RP areas compared with female case subjects with BMI>=30. We did not find interaction effects between WHRs and postprandial responses in either men or women.

Because of the reported effect of apoE genotype on postprandial chylomicron and chylomicron remnant metabolism, we also planned to look for similar interactions in our subjects. We did not see any significant differences in the prevalence of apoE genotypes between case and control subjects. In addition, we could not demonstrate any association between apoE genotype and either TG or RP responses to the fat meal (data not shown). We did, however, observe a significant interaction between apoE and postprandial response in predicting case-control status in the men. Thus, men with the {varepsilon}3/3 genotype had ORs of 4.3 and 4.0 for increased postprandial TG and RP responses, respectively. In contrast, there was an apparent protective effect of an increased postprandial response in men with the {varepsilon}4 allele (ORs 0.8 and 0.1 for TG and RP responses, respectively). However, the small numbers of men with the {varepsilon}4 allele prevented our drawing any definitive conclusions about the apoE interaction in this study. No significant apoE-postprandial response interactions were seen in the women.


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
In this study we have demonstrated that the responses of both plasma TGs and RP to a meal containing fat and vitamin A are associated with the presence of EIMI in men with BMI<30. More than 70% of the men in this study had BMI<30. The relationship between these postprandial responses and EIMI remained significant in this nonobese group of men after adjustment for several major risk factors for CAD, including smoking, hypertension, and LDL-C. Additionally, the association between either postprandial TG or RP responses and EIMI remained significant in the nonobese men after adjustment for fasting plasma TG and HDL-C levels.

This investigation extends results from case-control studies in which abnormalities in postprandial lipid metabolism were observed in men with CAD. Simons et al12 used the ratio of apoB-48 (a marker of chylomicrons and chylomicron remnants) to apoB-100 (a marker of hepatic lipoproteins) in plasma obtained 4 hours after a fat load as a measure of the postprandial lipoprotein level. Those investigators found that a higher apoB-48/apoB-100 ratio was associated with the presence of CAD in men after adjustment for age, TC, and HDL-C. They did not adjust for fasting TGs in their final multiple logistic regression model, nor did they measure postprandial TG or RP levels. In the present study, we found that the method used to determine the apoB-48/apoB-100 ratio during the postprandial period was not adequate to allow reliable analysis of the data, and thus we did not present the results of that analysis.

Simpson et al13 have demonstrated that post–fat load plasma TG and RP responses are elevated in men with CAD compared with those without, but they did not adjust the results for any baseline variables. De Groot et al14 report that postprandial TG and RP responses are significantly greater in male CAD patients after coronary artery bypass surgery compared with men without CAD who were matched for age and LDL-C. No multivariate analyses were performed in that study, however, even though there were significant correlations between fasting TG concentrations and both postprandial responses. Patsch et al15 have determined that age and postprandial TG, fasting apoB, and fasting HDL2 cholesterol concentrations provide the greatest sensitivity and specificity for predicting the presence of CAD in a group of men. Although the data were adjusted for fasting plasma TGs in that study, the authors did not test the hypothesis that the postprandial TG response was independently associated with the presence of CAD. RP response was not determined.15

Why should increased postprandial levels of chylomicrons and/or chylomicron remnants predict the presence of CAD or EIMI? There is a large body of data indicating that cholesteryl ester–enriched remnant lipoproteins (whether intestinal or hepatic in origin) can enter the vessel wall in animal models of hyperlipidemia and atherosclerosis.7 16 Tissue-culture studies demonstrating the ability of these same lipoproteins to convert macrophages to foam cells support the results from the animal studies.18 Bersot et al26 found that feeding a fat load to normal subjects resulted in accumulation of TGRLs that caused lipid accumulation in cultured macrophages. Accumulation of intestinally derived TGRLs could, therefore, be directly atherogenic in humans. In addition, abnormalities in the catabolism of intestinal lipoproteins could retard the normal conversion of hepatic VLDL to LDL, resulting in the accumulation of atherogenic VLDL remnants. Recovery of VLDL- or ß-VLDL–like particles from normal human aorta27 and human atherosclerotic lesions28 has been demonstrated.

Delayed clearance of dietary TGs could, via the action of cholesteryl ester transfer protein, also alter both HDL and LDL metabolism.29 30 31 Cholesteryl ester transfer protein mediates the exchange of cholesteryl ester in HDL for TGs in chylomicrons and VLDL, and the level of circulating TGRLs in the circulation is a major driving force for this exchange.29 32 A consequence of increased core-lipid exchange would be lower HDL-C concentrations33 and increased plasma clearance of apoA-I.34 35 Thus, increased postprandial TG and RP responses could be indicative of abnormalities in HDL metabolism that could unfavorably affect reverse cholesterol transport.36 Cholesteryl ester transfer protein also mediates core-lipid exchange between LDL and TGRLs, and small dense LDL is commonly present in individuals with both fasting and postprandial hypertriglyceridemia.37 38 39 The observations suggesting that small dense LDL might be more susceptible to oxidative modification40 41 provide another mechanism whereby increased postprandial lipemia could be a marker of atherogenicity. Thus, although postprandial TG and RP responses were associated with CAD in the men we studied independent of fasting HDL-C and LDL-C concentrations, postprandial changes in those lipoprotein fractions could be a link between defective metabolism of chylomicrons and their remnants and CAD. Of particular relevance to this issue is the report by Lechleitner et al38 that indicates that postprandial LDL may be predisposed to oxidation and thereby more likely to load macrophages with cholesterol. On the other hand, Karpe et al42 43 report stronger relationships between postprandial accumulation of small chylomicron remnants and atherosclerosis than between the postprandial fall in HDL levels and disease.

Our results in men are concordant with those from a companion investigation of postprandial lipemia and carotid atherosclerosis.20 In the ARIC study, postprandial TGs were independently associated with carotid atherosclerosis in men with BMI<30 but not in obese men. In contrast to our finding in men, we did not observe any relationship between either postprandial TG or RP responses and EIMI in the women we studied. There are no previous studies of postprandial lipemia and CAD in women. However, the companion study by the ARIC investigators did find an association between postprandial lipemia and carotid atherosclerosis in women. Several epidemiological studies6 suggest that fasting plasma TGs are better markers for CAD risk in women than in men. Why did we observe a striking gender difference in our study? Although only fasting plasma TG concentrations differed significantly between male case and control subjects (Table 2Up), TC and LDL-C tended to be higher and HDL-C lower in the male case subjects. These results are similar to the baseline lipid results reported by Simons et al,12 Simpson et al,13 de Groot et al,14 Patsch et al15 and Karpe et al.25 In contrast, fasting lipids were essentially identical in the female case and control subjects.

Could this lack of an association between either fasting or postprandial lipid levels in the women be the result of greater misclassification of case-control status compared with the men? ECG stress tests are clearly less specific in women, with a greater frequency of false-positive tests.44 45 We reexamined our results, therefore, using only individuals in whom case-control status was determined by thallium stress testing, in which false-positive results are significantly reduced.46 In the men who had thallium stress tests, we found associations between postprandial responses and EIMI that were remarkably similar to those observed in the full analysis. Specifically, in the 46 men (50%) who had thallium stress tests, the OR for an increase in TG area of 1 SD (1.8) was identical to that of the entire group. In the 42 women (37%) who had thallium stress tests, the OR for TG area was 0.9 (compared with 0.7 for all the women; see Table 4Up). Thus, we found essentially the same differences between the male and female groups; postprandial responses were not associated with the presence of EIMI in the women who were categorized by thallium stress testing. We also analyzed the data by using positive thallium stress tests plus strongly positive exercise stress tests (ST depression >0.15 mm) to identify case subjects and only negative thallium tests to identify control subjects: the results were unchanged in both groups of patients. Finally, when we added the negative exercise stress test group to the negative thallium group to enlarge the control group, the results were also unchanged for both men and women. We believe, therefore, that the results observed in the total study group cannot be attributed wholly to bias in case-control determinations. We would note again that we designed our protocol to enable us to study men and women with no prior history or diagnosis of CAD. We chose this approach to avoid lifestyle (eg, diet and exercise) changes that would independently affect postprandial lipid metabolism. Using EIMI to determine case-control status was the only way to achieve that goal while also achieving adequate recruitment.

Rather than misclassification, we believe that it is more likely that our results were biased by the higher proportion of black female case subjects and/or the paucity of white female case subjects compared with female control subjects (Table 2Up). There is evidence that blacks have lower TG and higher HDL-C levels than whites47 ; data for Hispanics are less clear, particularly for the Hispanics in our population, who are mainly from the Caribbean region. It is possible that the lack of differences in fasting lipid levels (particularly TGs and HDL-C) between the female case and control subjects resulted from the marked disparity in the number of blacks and whites in the two groups. In subgroup analyses (data not presented) we found a trend toward lower postprandial TG responses among the blacks, particularly the black women. The effect of ethnic heterogeneity in our study, together with unbalanced recruitment of ethnic populations into the female case and control groups, can be inferred from the companion study by the ARIC investigators,20 who report no association between postprandial lipemia and carotid atherosclerosis in their black population.

The ARIC investigators noted that the presence of obesity modified the association between postprandial responses and carotid disease. We also observed an interaction between obesity and the association between postprandial responses and EIMI: the ORs for 1-SD increases in postprandial TG and RP responses rose to 1.83 and 2.77, respectively, in thin men, and became statistically significant in models that included several covariates, including fasting TG levels. In the obese men, the ORs fell to 0.67 and 0.59 for TG and RP levels, respectively (NS for both). The women classified as thin (BMI<30) had ORs of 1.00 and 2.02, respectively, for increases in TG and RP responses of 1 SD; this was in contrast to ORs of 0.43 and 0.32, respectively, for the obese women. A discussion of potential mechanisms whereby obesity might confound the relationship between postprandial lipemia and atherosclerosis is presented in the companion article from the ARIC investigators.20

We did not see a significant relationship between apoE genotype and postprandial response. This was somewhat surprising in view of previous studies demonstrating prolonged chylomicron remnant clearance in subjects with the {varepsilon}2/2 genotype.48 49 We saw no consistent effect, however, of the presence of a single {varepsilon}2 allele on postprandial RP response (we studied only one {varepsilon}2/2 subject). This finding contrasts with results from the ARIC group, in which that response was increased by 50% in a large group of whites with one {varepsilon}2 allele compared with all others.50 On the other hand, several smaller studies have also failed to see an effect of a single {varepsilon}2 allele on postprandial clearance of chylomicrons or their remnants.25 51 52 We did see an interaction between apoE genotype, postprandial response, and case-control status in the men, in whom {varepsilon}3/3 was associated with increased ORs for elevated postprandial responses, and {varepsilon}4 was associated with lower ORs. We have no hypothesis to explain this result at present and believe that further investigations of this question with much larger numbers of subjects are needed. In any event, apoE genotype must be considered in any study of postprandial lipoprotein metabolism.

In summary, despite some differences, our study and the parallel ARIC study20 demonstrate that increased postprandial responses to a standardized fat meal were significantly and independently associated with the presence of EIMI and carotid disease, respectively. We found that in the men we studied with BMI<30, who made up more than 70% of the total group, both postprandial TG and RP responses were associated with EIMI independent of several traditional risk factors, including fasting levels of HDL and LDL. In addition, we found that in this nonobese male group the associations were also independent of fasting TG levels. These results have important implications for our understanding of atherosclerotic cardiovascular disease. First, the demonstration that measures of postprandial responses were associated with the presence of atherosclerotic cardiovascular disease independent of both LDL-C and HDL-C concentrations indicates that the accumulation of TGRLs in plasma might be directly atherogenic. This possibility is supported by the finding in both our study and the companion study20 that the association between postprandial responses and atherosclerosis was observed only in participants with BMI<30, despite the demonstration in the ARIC study that obesity did not modify the association between postprandial responses and levels of HDL-C or LDL size.20 Second, the results suggest that the inability of previous studies6 to identify fasting plasma TG levels as independent determinants of CAD might have resulted from the lack of more "potent" postprandial data and the confounding effects of obesity in those studies.

At present we do not recommend that fat-tolerance tests (with several blood samples measured over the course of the day) become part of the routine evaluation of all patients at risk for atherosclerosis. For most nonobese or modestly obese subjects, we believe that the fasting plasma TG concentration should be used, together with the LDL-C and HDL-C levels, to assess risk for atherosclerotic disease.53 54 A postprandial TG level might be useful for better determination of risk in nonobese men with normal fasting plasma TG levels, particularly in the presence of reduced plasma levels of HDL-C. For significantly obese patients, the predictive power of both fasting and postprandial TG remains unclear; further studies are necessary to identify an accurate surrogate for abnormal postprandial lipid metabolism that is independent of obesity. We also believe that the question of possible sex or ethnic differences in the association of postprandial lipemia and atherosclerotic cardiovascular disease requires further investigation. In particular, studies with numbers of white and black women that are adequate to allow for separate analyses should be performed. Finally, on the basis of the results of our study, the accompanying study by the ARIC investigators,20 and previous reports12 13 14 15 (including a recent study of normolipidemic offspring of men with CAD55 ), it seems that a prospective study focusing on postprandial lipoprotein metabolism and risk for atherosclerotic cardiovascular disease is in order.


*    Selected Abbreviations and Acronyms
 
AUC = area under the curve
BMI = body mass index
CAD = coronary artery disease
ECG = electrocardiogram
EIMI = exercise-induced myocardial ischemia
HDL-C = HDL cholesterol
LDL-C = LDL cholesterol
OR = odds ratio
RP = retinyl palmitate
TC = total cholesterol
TG = triglyceride
TGRL = triglyceride-rich lipoprotein
WHR = waist-hip ratio


*    Acknowledgments
 
This work was supported by grants HL 45460, HL 36000, HL 21006, and RR 645 from the National Institutes of Health. The authors wish to thank Mary Tresgallo, Catherine Galvin, and Robert Lee for their tireless efforts in recruitment; Susan Wilt and Lynn Johnson for assistance in study design; Colleen Ngai and Xiao-Jie Wang for technical support; and the staff of the Irving Center for Clinical Research.


*    Footnotes
 
The study is dedicated to the memory of Jay Brown, MD, who devoted himself to the health and care of the Harlem community.

Received February 25, 1995; accepted August 17, 1995.


*    References
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  1. Castelli WP, Garrison RJ, Wilson PW, Abbott RD, Kalousdian S, Kannel WB. Incidence of coronary heart disease and lipoprotein cholesterol levels: the Framingham Study. JAMA. 1986;256:2835-2838. [Abstract]
  2. Kannel WB, Neaton JD, Wentworth D, Thomas HE, Stamler J, Hulley SB, Kjelsberg MO. Overall and CHD mortality rates in relation to major risk factors in 325 348 men screened for the MRFIT. Am Heart J. 1986;112:825-836. [Medline] [Order article via Infotrieve]
  3. Wallace RB, Anderson RA. Blood lipids, lipid-related measures, and the risk of atherosclerotic cardiovascular disease. Epidemiol Rev. 1987;9:95-119. [Free Full Text]
  4. Blankenhorn DH, Hodis HN. Arterial imaging and atherosclerosis reversal. Arterioscler Thromb. 1994;14:177-192. [Abstract/Free Full Text]
  5. Pedersen TR, Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-1389. [Medline] [Order article via Infotrieve]
  6. Austin MA. Plasma triglyceride and coronary heart disease. Arterioscler Thromb. 1991;11:2-14. [Abstract/Free Full Text]
  7. Zilversmit DB. Atherogenesis: a postprandial phenomenon. Circulation. 1979;60:473-483. [Abstract/Free Full Text]
  8. Moreton JR. Chylomicronemia, fat tolerance, and atherosclerosis. J Lab Clin Med. 1950;35:373-383.
  9. Pomeranze J, Beinfield WH, Chessin M. Serum lipid and fat tolerance studies in normal, obese and atherosclerotic subjects. Circulation. 1954;10:742-746. [Medline] [Order article via Infotrieve]
  10. Seller RH, Brachfeld J, Sandberg H, Bellet S. Use of I131-labelled fat in the study of lipid handling in patients with coronary artery disease. Am J Med. 1959;237:231-240.
  11. Brown DF, Heslin AS, Doyle JT. Postprandial lipemia in health and in ischemic heart disease. N Engl J Med. 1961;264:733-737.
  12. Simons LA, Dwyer T, Simons J, Bernstein L, Mock P, Poonia NS, Balasubramaniam S, Baron D, Branson J, Morgan J, Roy P. Chylomicrons and chylomicron remnants in coronary artery disease: a case-control study. Atherosclerosis. 1987;65:181-189. [Medline] [Order article via Infotrieve]
  13. Simpson HS, Williamson CM, Olivecrona T, Pringle S, Maclean J, Lorimer AR, Bonnefous F, Bogaievsky Y, Packard CJ, Sheperd J. Postprandial lipemia, fenofibrate and coronary artery disease. Atherosclerosis. 1990;85:193-202. [Medline] [Order article via Infotrieve]
  14. Groot PHE, van Stiphout WAHJ, Krauss XH, Jansen H, van Tol A, van Ramshorst E, Chin-On S, Hofman A, Cresswell SR, Havekes L. Postprandial lipoprotein metabolism in normolipidemic men with and without coronary artery disease. Arterioscler Thromb. 1991;11:653-662. [Abstract/Free Full Text]
  15. Patsch JR, Miesenbock G, Hopferwieser T, Muhlberger V, Knapp E, Dunn JK, Gotto AM Jr, Patsch W. Relation of triglyceride metabolism and coronary artery disease: studies in the postprandial state. Arterioscler Thromb. 1992;12:1336-1345. [Abstract/Free Full Text]
  16. Daugherty A, Lange LG, Sobel BE, Schonfeld G. Aortic accumulation and plasma clearance of B-VLDL and HDL: effects of diet-induced hypercholesterolemia in rabbits. J Lipid Res. 1985;26:955-963. [Abstract]
  17. Fielding CJ. Metabolism of cholesterol-rich chylomicrons: mechanism of binding and uptake of cholesteryl esters by the vascular bed of the perfused rat heart. J Clin Invest. 1978;62:141-151.
  18. Van Lenten BJ, Fogelman AM, Jackson RL, Shapiro S, Haberland ME, Edwards PE. Receptor-mediated uptake of remnant lipoproteins by cholesterol-loaded human monocyte-macrophages. J Biol Chem. 1985;260:8783-8788. [Abstract/Free Full Text]
  19. Lindqvist P, Ostlund-Lindqvist A-M, Witztum JL, Steinberg D, Little JA. The role of lipoprotein lipase in the metabolism of triglyceride-rich lipoproteins by macrophages. J Biol Chem. 1983;258:9086-9092. [Abstract/Free Full Text]
  20. Sharret AR, Chambless LE, Heiss G, Paton CC, Patsch W. Postprandial lipoproteins and atherogenesis: the ARIC study of asymptomatic carotid artery disease. Arterioscler Thromb Vasc Biol. In press.
  21. Warnick GR, Nguyen T, Albers AA. Comparison of improved precipitation methods for quantification of high-density lipoprotein cholesterol. Clin Chem. 1985;31:217-222. [Abstract/Free Full Text]
  22. Bieri JG, Tolliver TJ, Catignani GL. Simultaneous determination of alpha-tocopherol and retinol in plasma or red cells by high pressure liquid chromatography. Am J Clin Nutr. 1979;32:2143-2149. [Abstract/Free Full Text]
  23. Hixson J, Vernier D. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhAI. J Lipid Res. 1991;31:545-548. [Abstract]
  24. Breslow NE, Day NE. Statistical Methods in Cancer Research, I: The Analysis of Case-Control Studies. Lyon: International Agency for Research on Cancer; 1980.
  25. Karpe F, Steiner G, Olivecrona T, Carlson LA, Hamsten A. Metabolism of triglyceride-rich lipoproteins during alimentary lipemia. J Clin Invest. 1993;91:748-758.
  26. Bersot TP, Innerarity TL, Pitas RE, Rall SC Jr, Weisgraber KH, Mahley RW. Fat feeding in humans induces lipoproteins of density less than 1.006 that are enriched in apolipoprotein (a) and that cause lipid accumulation in macrophages. J Clin Invest. 1986;77:622-630.
  27. Yla-Herttuala S, Jaakola O, Ehnholm C, Tikkanen MJ, Solakiva T, Sarkioja T, Nikkari T. Characterization of two lipoproteins containing apolipoproteins B and E from lesion-free human aortic intima. J Lipid Res. 1988;29:563-570. [Abstract]
  28. Rapp JH, Lespine A, Hamilton RL, Colyvas N, Chaumeton AH, Tweedie-Hardman J, Kotite L, Kunitake ST, Havel RJ, Kane JP. Triglyceride-rich lipoproteins isolated by selected-affinity anti–apolipoprotein B immunosorption from human atherosclerotic plaque. Arterioscler Thromb. 1994;14:1767-1774. [Abstract/Free Full Text]
  29. Tall AR. Plasma lipid transfer proteins. J Lipid Res. 1986;27:361-367. [Medline] [Order article via Infotrieve]
  30. Tall AR. Plasma high density lipoproteins: metabolism and relationship to atherogenesis. J Clin Invest. 1990;86:379-384.
  31. Deckelbaum RJ, Granot E, Oschry Y, Rose L, Eisenberg S. Plasma triglyceride determines structure-composition in low- and high-density lipoproteins. Arteriosclerosis. 1984;4:225-231. [Abstract/Free Full Text]
  32. Mann CJ, Yen FT, Grant AM, Bihan BE. Mechanisms of plasma cholesteryl ester transport in hypertriglyceridemia. J Clin Invest. 1991;88:2059-2066.
  33. De Bruin TWA, Brouwer CB, Gimpel JA, Erkelens DW. Postprandial decrease in HDL cholesterol and HDL apo A-I in normal subjects in relation to triglyceride metabolism. Am J Physiol. 1991;260:E492-E498. [Abstract/Free Full Text]
  34. Horowitz BS, Goldberg IJ, Merab J, Vanni T, Ramakrishnan R, Ginsberg HN. Increased plasma and renal clearance of an exchangeable pool of apolipoprotein A-I in subjects with low levels of high density lipoprotein cholesterol. J Clin Invest. 1993;91:1743-1752.
  35. Goldberg IJ, Blaner WS, Vanni TM, Moukides M, Ramakrishnan R. Role of lipoprotein lipase in the regulation of high density lipoprotein apolipoprotein metabolism: studies in normal and lipoprotein lipase-inhibited monkeys. J Clin Invest. 1990;86:463-473.
  36. Reichl D, Miller NE. Pathophysiology of reverse cholesterol transport: insights from inherited disorders of lipoprotein metabolism. Arteriosclerosis. 1989;9:785-797. [Free Full Text]
  37. Austin MA, King MD, Vranizan KM, Krauss RM. Atherogenic lipoprotein phenotype: a proposed genetic marker for coronary heart disease risk. Circulation. 1990;82:495-506. [Abstract/Free Full Text]
  38. Lechleitner M, Hoppichler F, Foger B, Patsch JR. Low-density lipoproteins of the postprandial state induce cellular cholesteryl ester accumulation in macrophages. Arterioscler Thromb. 1994;14:1799-1807. [Abstract/Free Full Text]
  39. Karpe F, Tornvall P, Olivecrona T, Steiner G, Carlson LA, Hamsten A. Composition of human low density lipoprotein: effects of postprandial triglyceride-rich lipoproteins, lipoprotein lipase, hepatic lipase and cholesteryl ester transfer protein. Atherosclerosis. 1993;98:33-49. [Medline] [Order article via Infotrieve]
  40. Chait A, Brazg RL, Tribble DL, Krauss RM. Susceptibility of small, dense, low-density lipoproteins to oxidative modification in subjects with the atherogenic lipoprotein phenotype, pattern B. Am J Med. 1993;94:350-356. [Medline] [Order article via Infotrieve]
  41. de Graaf J, Hendriks JCM, Demacker PNM, Stalenhoef AFH. Identification of multiple dense LDL subfractions with enhanced susceptibility to in vitro oxidation among hypertriglyceridemic subjects: normalization after clofibrate treatment. Arterioscler Thromb. 1993;13:712-719. [Abstract/Free Full Text]
  42. Karpe F, Steiner G, Uffelman K, Olivecrona T, Hamsten A. Postprandial lipoproteins and progression of coronary atherosclerosis. Atherosclerosis. 1994;106:83-97.[Medline] [Order article via Infotrieve]
  43. Karpe F, Bard J-M, Steiner G, Carlson LA, Fruchart J-C, Hamsten A. HDLs and alimentary lipemia: studies in men with previous myocardial infarction at a young age. Arterioscler Thromb. 1993;13:11-22. [Abstract/Free Full Text]
  44. Weiner DA, Ryan TJ, McCabe CH, Kennedy JW, Schloss M, Tristani F, Chaitman BR, Fisher LD. Exercise stress testing: correlations among history of angina, ST-segment response and prevalence of coronary-artery disease in the coronary artery surgery study (CASS). N Engl J Med. 1979;301:230-235. [Abstract]
  45. Dunn RL, Matzen RN, VanderBrug-Medendorp S. Screening for the detection of coronary artery disease by using the exercise tolerance test in a preventive medicine population. Am J Prev Med. 1991;7:255-262. [Medline] [Order article via Infotrieve]
  46. Mahmarian JJ, Boyce TM, Goldberg RK, Cocanougher MK, Roberts R, Verani MS. Quantitative exercise thallium-201 single emission computed tomography for the enhanced diagnosis of ischemic heart disease. J Am Coll Cardiol. 1990;15:318-329. [Abstract]
  47. Brown SA, Hutchinson R, Morrisett J, Boerwinkle E, Davis CE, Gotto AM Jr, Patsch W. Plasma lipid, lipoprotein cholesterol, and apoprotein distributions in selected US communities. Arterioscler Thromb. 1993;13:1139-1158. [Abstract/Free Full Text]
  48. Hazzard WR, Bierman EL. Delayed clearance of chylomicron remnants following vitamin-A-containing oral fat loads in broad-B disease (type III hyperlipoproteinemia). Metabolism. 1976;25:777-801. [Medline] [Order article via Infotrieve]
  49. Weintraub MS, Eisenberg S, Breslow JL. Dietary fat clearance in normal subjects is regulated by genetic variation in apolipoprotein E. J Clin Invest. 1987;80:1571-1577.
  50. Boerwinkle E, Brown S, Sharrett AR, Heiss G, Patsch W. Apolipoprotein E polymorphism influences postprandial retinyl palmitate but not triglyceride concentrations. Am J Hum Genet. 1994;54:341-360. [Medline] [Order article via Infotrieve]
  51. Brenninkmeijer BJ, Stuyt PMJ, Demacker PNM, Stalenhoef AFH, van't Laar A. Apo E polymorphism and the removal of remnants of triglyceride-rich lipoproteins in normolipidemic subjects during a carbohydrate-rich diet. Clin Nutr. 1989;8:127-133.
  52. Brown AJ, Roberts DCK. The effect of fasting triacylglyceride concentration and apolipoprotein E polymorphism on postprandial lipemia. Arterioscler Thromb. 1991;11:1737-1744. [Abstract/Free Full Text]
  53. Manninen V, Tenkanen L, Koskinen P, Huttunen J, Manttari M, Heinonen O, Frick MH. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study. Circulation. 1992;85:37-45. [Abstract/Free Full Text]
  54. Assmann G, Schulte H. Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (the PROCAM experience). Am J Cardiol. 1992;70:733-737. [Medline] [Order article via Infotrieve]
  55. Uiterwaal CSPM, Grobbee DE, Witteman JCM, van Stiphout WA, Krauss XH, Havekes LM, de Bruijn AM, van Tol A, Hofman A. Postprandial triglyceride response in young adult men and familial risk for coronary atherosclerosis. Ann Intern Med. 1994;121:576-583.[Abstract/Free Full Text]



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