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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 4 1106-1113
Copyright © 1998 by The Endocrine Society

From the Clinical Research Centers

Normal Postprandial Lipemia and Chylomicron Clearance in Offspring of Parents with Early Coronary Artery Disease1

Arnold H. Slyper, Svetlana Zvereva2, Gordon Schectman, Raymond G. Hoffmann, Joan Pleuss and John A. Walker

Medical College of Wisconsin, Milwaukee, Wisconsin 53209; and St. Luke’s Medical Center (J.A.W.), Milwaukee, Wisconsin 53215

Address all correspondence and requests for reprints to: Arnold H. Slyper, M.D., MACC Fund Research Center, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226.


   Abstract
Top
 Abstract
Introduction
 Experimental Subjects
 Materials and Methods
 Results
 Discussion
 References
 
To assess the importance of postprandial lipemia and delayed chylomicron clearance as early atherogenic risk factors, 60 male offspring of parents with early coronary artery disease (CAD) and 41 controls were administered a fat-rich meal containing vitamin A. There were no significant differences between CAD-positive (CAD+) offspring and CAD-negative controls for areas under the postprandial curves for triglyceride and plasma, chylomicron, and chylomicron remnant retinyl palmitate. Older CAD+ offspring, aged 31–45 yr, had significantly increased very low density lipoprotein (VLDL) cholesterol, VLDL triglyceride, VLDL apoprotein B, and areas under postprandial curves for triglyceride and plasma, chylomicron, and chylomicron remnant retinyl palmitate than younger CAD+ offspring, aged 15–30 yr. Correcting for waist/hip ratio eliminated significant differences between the two groups for VLDL and areas under the triglyceride and chylomicron remnant curves, but this was not the case for the insulin sensitivity index. We conclude that neither increased postprandial lipemia nor abnormalities of chylomicron clearance are important early atherogenic risk factors in this population. An increase in age is associated with increased VLDL and postprandial lipemia and decreased chylomicron remnant clearance. This is due mainly to an increase in the waist/hip ratio and not to a change in insulin sensitivity.


   Introduction
Top
 Abstract
 Introduction
Experimental Subjects
 Materials and Methods
 Results
 Discussion
 References
 
A RELATIONSHIP between postprandial lipemia and coronary artery disease was suggested by early studies (1, 2, 3, 4). Simpson et al. (5) also noted increased triglyceride concentrations in chylomicron and very low density lipoprotein (VLDL)-containing lipoprotein fractions at the peak of lipemia in 34 patients with coronary disease. Increased postprandial plasma triglyceride concentrations and area under the triglyceride curve were found in 61 normotriglyceridemic coronary patients (6). Katzel et al. (7) demonstrated increased postprandial triglyceride levels in plasma, chylomicrons, and VLDL in 12 athletic, normolipidemic older men with asymptomatic myocardial ischemia (exercise-induced ST segment depression on an electrocardiogram). Chylomicron clearance abnormalities have also been demonstrated in coronary survivors. When ingested together with fat, vitamin A remains predominantly with chylomicrons, and blood levels of retinyl palmitate can be used to track the postprandial clearance of chylomicrons and chylomicron remnants. Simons et al. (8) studied 82 patients with documented coronary artery disease (CAD) and found an increased ratio of apoprotein B-48 to apoprotein B-100 in an Sf greater than 60 lipoprotein fraction 4 h postprandially. Increased retinyl palmitate was also seen in a 24-h postprandial specimen, although not at earlier time points. Syvanne et al. (9) demonstrated increased postprandial remnant retinyl ester and delayed remnant clearance from a Sf 60–400 lipoprotein fraction in 15 coronary patients. Groot et al. (10) studied 20 normolipidemic coronary patients and found peak postprandial triglyceride and retinyl palmitate levels similar to those in controls in a lipoprotein fraction with a density less than 1.019 g/mL, but a significant delay in the clearance of triglyceride and retinyl palmitate. These studies support the hypothesis, first postulated by Zilversmit (11), that atherogenesis is related to delayed clearance of potentially atherogenic remnant lipoproteins (11, 12, 13). These postprandial abnormalities could be due to a variety of genetic conditions, such as familial combined hyperlipidemia, familial dyslipidemic hypertension, visceral obesity, and lipoprotein lipase deficiency.

The purpose of this study was to examine whether the offspring of parents with early CAD exhibit postprandial lipemia and delayed chylomicron clearance. This would provide an indication of their importance as early coronary risk factors. We studied male offspring of parents with CAD on or before age 60 yr (CAD+ offspring) and compared them to healthy offspring controls who had no history of parental coronary artery disease (CAD-) and who were matched to CAD+ offspring by age and body mass index. Because of our interest in age-related aspects of postprandial lipemia and chylomicron clearance, CAD+ and CAD- offspring were recruited into two groups according to age: younger offspring, aged 15–30 yr, and older offspring, aged 31–45 yr.


   Experimental Subjects
Top
 Abstract
 Introduction
 Experimental Subjects
Materials and Methods
 Results
 Discussion
 References
 
CAD+ subjects were male offspring of a parent with documented evidence of major CAD on or before age 60 yr. All parents had a history of coronary angioplasty, coronary bypass surgery, or myocardial infarction (including fatal myocardial infarction). Exclusion criteria for the parents were a low density lipoprotein (LDL) cholesterol level and family history suggestive of familial hypercholesterolemia, and treatment for diabetes mellitus with an oral hypoglycemic agent or insulin within 1 yr of the diagnosis of coronary disease. These facts were verified from their medical records. Subjects were recruited into 2 groups based on age: 20 younger CAD+ offspring, aged 15–30 yr inclusive, and 40 older CAD+ offspring, aged 31–45 yr inclusive. All but 3 CAD+ offspring had familial coronary artery disease, with a history of coronary disease in both a parent and a grandparent. Based on the Lipid Research Clinic’s Prevalence Study 90th percentile values for LDL cholesterol and fasting triglyceride, 2 of the younger CAD+ offspring were hypercholesterolemic, and 1 was hypertriglyceridemic; 1 subject in each of the other groups was hypertriglyceridemic (14). All adolescents were at Tanner stage V of pubertal development. Subjects were recruited into the study regardless of previously known lipid values. Obesity was not an exclusion criterion, although none of the subjects was morbidly obese. All subjects were healthy, without evidence of gastrointestinal, renal, cardiac, endocrine, or other significant chronic disease. All CAD- offspring were male and met the following criteria: 1) absence of a history of coronary angioplasty, coronary bypass surgery, or myocardial infarction in either parent; 2) absence of a history in the grandparents suggestive of CAD if either of the subjects’ parents was less than 60 yr of age at the time of the study; and 3) absence of parental diabetes. CAD- offspring were matched to CAD+ offspring by age and body mass index. Each of the younger CAD+ offspring was matched to a single CAD- offspring, and 2 older CAD+ offspring were matched to a single older CAD- offspring. However, 3 of the older CAD+ offspring were matched to a single older CAD- offspring. There were 20 CAD- offspring in the younger age group and 21 CAD- offspring in the older age group.


   Materials and Methods
Top
 Abstract
 Introduction
 Experimental Subjects
 Materials and Methods
Results
 Discussion
 References
 
The study was approved by the institutional review board of the Medical College of Wisconsin (Milwaukee, WI). At a preliminary examination and after obtaining informed consent, the subject’s height, weight, and blood pressure were measured. The blood pressure recorded was the average of three readings from the right arm after the subject had been resting for 10 min in the supine position. The waist/hip ratio was the ratio of a waist measurement at the level of the umbilicus and a hip measurement at the level of the greater trochanter. Smoking and alcohol intake were recorded from a lifestyle questionnaire. The composition of the subjects’ diets was analyzed by means of either a 1-day (at the beginning of the study) or a 3-day food diary, and food frequency records. Values recorded were the means of values from the food recall and food frequency records.

Each subject underwent a fat tolerance test. The subject was instructed on achieving an adequate carbohydrate intake for 3 days before the test. No alcohol was permitted for 3 days before the test or smoking from the prior evening. After a 12-h overnight fast, the subject was admitted to the Clinic Research Center, an iv catheter was inserted, and a baseline triglyceride sample was taken. At this time, a blood specimen was taken into an ethylenediamine tetraacetate-containing tube for determination of fasting lipoproteins. The fat load consisted of 70 g/m2 fat provided as heavy whipping cream without any additives. Aqueous vitamin A (60,000 U/m2 body surface area) was added to the test meal. The test meal was administered over 10 min together with a glass of water. Subjects remained fasting for the duration of the test, and blood samples for triglyceride and retinyl palmitate determinations were drawn at hourly intervals for 12 h.

A frequently sampled iv glucose tolerance test was performed on each subject within 6 weeks of the fat tolerance test, as previously described (15). Three days before the test, the subject was instructed on a weight-maintaining diet containing at least 150 g carbohydrate. No alcohol was permitted for 3 days before the test, and smoking was prohibited from the prior evening. After a 12-h overnight fast, the subject was admitted to the Clinical Research Center, and iv catheters were inserted into both arms. Three baseline samples were taken for serum insulin and plasma glucose measurements at -20, -15, and -10 min. At time zero, 0.3 g/kg 50% glucose was injected over 1 min. Blood was taken from the contralateral arm at 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 19, 22, 24, 25, 27, 30, 40, 50, 60, 70, 90, 100, 120, 140, 160, and 180 min. At 20 min, 300 mg tolbutamide, diluted in 10 cc sterile water, were injected over 20 s. For adolescents less than 17 yr of age, the dose of tolbutamide was 5 mg/kg, to a maximum dose of 300 mg, and the test was terminated after a 90-min specimen was obtained. Each sample was centrifuged and stored immediately at -20 C.

Lipoproteins were harvested from plasma by low speed ultracentrifugation. VLDL, LDL, and high density lipoprotein (HDL) were isolated by preparative ultracentrifugation at densities less than 1.019, 1.019 to 1.063, and greater than 1.063 g/mL, respectively, as described by Schumaker et al. (16), using a 50.3 Ti Beckman rotor (Beckman, Palo Alto, CA) at 18 C. Lipoprotein cholesterol was measured using a standard kit (Boehringer Mannheim Corp., Indianapolis, IN). Inter- and intraassay coefficients of variation for cholesterol measurement were 3.8% and 3.2%, respectively. Triglyceride was measured using a standard kit (Stanbio Laboratory, San Antonio, TX). Inter- and intraassay coefficients of variation were 3.2% and 2.0% respectively. The VLDL apoprotein B concentration was measured by a double antibody sandwich enzyme-linked immunosorbent assay. Affinity-purified goat antihuman apoprotein B Ig, goat antihuman apoprotein B Ig alkaline phosphatase conjugate, and apoprotein B standard were obtained from the laboratory of Dr. Anh Le (Division of Arteriosclerosis and Lipid Metabolism, Emory University School of Medicine, Atlanta, GA). The interassay coefficient of variation was 6.8%, and the intraassay coefficient of variation was 6.2%.

Chylomicrons and chylomicron remnants were separated using the method of Dullaart et al. (17). Plasma was spun at a density of 1.006 g/mL at 17,000 rpm for 30 min at 4 C in a 50.3 Ti rotor, and the chylomicron-containing supernatant was aspirated. This step was repeated to ensure complete chylomicron separation. The infranatant from this separation was subjected to ultracentrifugation at a density of 1.006 g/mL at 39,000 rpm for 20 h at 4 C in a 50.3 Ti rotor, and the supernatant Sf 20–400 fraction containing chylomicron remnants was aspirated. All procedures were performed under yellow light.

Aliquots of plasma, chylomicrons, and chylomicron remnants were kept in foil-wrapped tubes. Retinyl palmitate was extracted by a modification of the method of Frolik et al. (18). Before extraction, a known quantity of retinyl acetate was added to each sample as an internal standard. The extracted material was dried under a nitrogen stream and brought to a final volume with filtered ethanol. Retinyl palmitate was quantitated by high performance liquid chromatography at 300 nm using a Dionex HPLC with a variable wavelength detector and integrator (Dionex Corporation, Itasca, IL), a Whatman Partisil ODS-10 column (Whatman, Clifton, NJ), and an Alcott 738 autosampler (Alcott Chromatography, Norcross, GA). Inter- and intraassay coefficients of variation for retinyl palmitate were 7.0% and 2.0%, respectively. The areas under the postprandial curves for triglyceride and retinyl palmitate were estimated using the method of trapezoids.

Glucose was measured enzymatically using a Beckman Glucose Analyzer 2. The interassay coefficient of variation was 5.4%, and the intraassay coefficient of variation was 1.3%. Insulin was measured by RIA using a commercial kit (Incstar Corp., Stillwater, MN). The interassay coefficient of variation for insulin was 5.4%, and the intraassay coefficient of variation was 5.8%.

Analysis of glucose and insulin values was performed by the modified minimal modeling method of Bergman (15). The model assumes that injected glucose is distributed rapidly into a single compartment and that plasma glucose falls by two components: a component that is independent of the incremental insulin response, and a second component that is dependent on insulin. The glucose effectiveness index is a measure of the effect of glucose to enhance its own disappearance at basal insulin, and the insulin sensitivity index (SI) is a measure of the ability of insulin to diminish endogenous glucose production and to augment glucose utilization. In subjects less than 18 yr of age, the glucose tolerance test was terminated at 120 min (19). In all instances in which the tolerance test was terminated before the 180 min sample, either because of the age of the subject or because of hypoglycemia, values were extrapolated to 180 min.

Statistics

Offspring and controls were compared using a 2 x 2 factorial ANOVA; the factors were age group and CAD+ offspring vs. CAD- offspring. Results presented are the mean ± SEM. Because of skewing of the data for triglyceride, VLDL cholesterol, VLDL triglyceride, VLDL apoprotein B, and area under the triglyceride and retinyl palmitate curves, a logarithmic transformation was made to normalize the data. All statistical analyses were performed with the transformed data. The means reported are the back transforms of the means used in the test (the geometric mean) (20). An analysis of covariance was used to examine differences between younger and older CAD+ offspring adjusting for the covariates waist/hip ratio, body mass index (BMI), and SI. In this instance; the means of the logs were transformed back to obtain means on the actual scale. A repeated measures ANOVA with a test of interaction was used to compare the shapes of the retinyl palmitate curves over time. Comparisons of the time points were tested with Fisher’s protected LSD. All statistical analyses were performed using the Minitab statistical package (Minitab, State College, PA), except for comparisons of the shape of the postprandial curves, which were performed with SAS software (SAS Institute, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Experimental Subjects
 Materials and Methods
 Results
Discussion
 References
 
Characteristics and lipid concentrations of subjects and controls

Characteristics of the CAD+ and CAD- offspring, their fasting lipoprotein concentrations, and the compositions of their diets are shown in Tables 1Go and 2Go. Intergroup comparisons for the frequently sampled iv glucose tolerance test have been previously described (21) and are not presented here. There were no significant differences between CAD+ offspring and CAD- offspring, except for diastolic blood pressure (80.6 ± 1.6 vs. 74.0 ± 1.8 mm Hg; P < 0.01), total cholesterol (178.7 ± 4.8 vs. 156.4 ± 5.0 mg/dL; P < 0.05), and LDL cholesterol (98.9 ± 3.7 vs. 85.0 ± 3.7 mg/dL; P < 0.01). Results are the mean ± SEM. Comparisons between CAD+ and CAD- offspring within their own age group showed no significant differences between older CAD+ and CAD- offspring. However, there were significant differences between younger CAD+ and younger CAD- offspring for fasting triglyceride (68.6 ± 15.8 vs. 92.5 ± 8.0 mg/dL; P < 0.05), protein intake (15.3 ± 0.6 vs. 17.5 ± 0.6% of daily calories; P < 0.05), and cholesterol intake (287 ± 20 vs. 413 ± 33 mg/day; P < 0.01).


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  		Table 1. Characteristics and fasting lipoprotein concentrations of CAD+ and CAD- offspring

 

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  		Table 2. Diet composition, alcohol intake, and smoking for CAD+ and CAD- offspring

 
To examine age-related changes in potential coronary risk factors, we compared older CAD+ to younger CAD+ offspring. Older CAD+ offspring had an increased BMI (26.7 ± 0.5 vs. 23.4 ± 0.7 kg/m2; P < 0.01), waist/hip ratio (0.938 ± 0.008 vs. 0.845 ± 0.011; P < 0.001), diastolic blood pressure (84.1 ± 1.6 vs. 73.6 ± 3.0; P < 0.01), total cholesterol (183.4 ± 5.7 vs. 169.1 ± 8.4 mg/dL; P < 0.05), fasting triglyceride (113.9 ± 9.6 vs. 68.6 ± 15.8 mg/dL; P < 0.01), VLDL cholesterol (21.3 ± 2.4 vs. 14.1 ± 1.8 mg/dL; P < 0.01), VLDL triglyceride (60.8 ± 5.6 vs. 40.0 ± 13.1 mg/dL; P < 0.05), and VLDL apoprotein B (19.2 ± 1.1 vs. 14.5 ± 1.0 mg/dL; P < 0.01). However, after correcting for waist/hip ratio, there were no significant differences between the two groups, which was not the case for BMI or SI. Corrected values were as follows: diastolic blood pressure, 82.5 ± 1.6 vs. 76.8 ± 3.0 mm Hg (P = 0.179); total cholesterol, 183.3 ± 5.7 vs. 170.0 ± 8.4 mg/dL (P = 0.344); fasting triglyceride, 104.1 ± 9.6 vs. 82.1 ± 15.8 mg/dL (P = 0.186); VLDL cholesterol, 19.4 ± 2.4 vs. 17.8 ± 1.8 mg/dL (P = 0.689); VLDL triglyceride, 57.8 ± 5.6 vs. 48.2 ± 13.1 mg/dL (P = 0.374); and VLDL apoprotein B, 18.4 ± 1.1 vs. 15.8 ± 1.0 (P = 0.203). Values corrected for BMI were as follows: diastolic blood pressure, 82.9 ± 1.6 vs. 76.0 ± 3.0 mm Hg (P = 0.043); total cholesterol, 183.2 ± 5.7 vs. 170.1 ± 8.4 mg/dL (P = 0.258); fasting triglyceride, 108.6 ± 9.6 vs. 75.4 ± 15.8 mg/dL (P = 0.015); VLDL cholesterol, 21.2 ± 2.4 vs. 14.9 ± 1.8 mg/dL (P = 0.054); VLDL triglyceride, 61.3 ± 5.6 vs. 42.9 ± 13.1 mg/dL (P = 0.042); and VLDL apoprotein B, 19.1 ± 1.1 vs. 14.7 ± 1.0 mg/dL (P = 0.012). Values corrected for SI were as follows: diastolic blood pressure, 83.8 ± 1.6 vs. 74.2 ± 3.0 mm Hg (P = 0.004); fasting triglyceride, 112.1 ± 9.6 vs. 70.8 ± 15.8 mg/dL (P = 0.002); VLDL cholesterol, 22.0 ± 2.4 vs. 13.9 ± 1.8 mg/dL (P = 0.007); VLDL triglyceride, 62.5 ± 5.6 vs. 41.2 ± 13.1 mg/dL (P = 0.011); and VLDL apoprotein B, 19.3 ± 1.1 vs. 14.3 ± 1.0 (P = 0.002).

Comparison of the postprandial triglyceride and retinyl palmitate curves

The postprandial curves for triglyceride and plasma, chylomicron, and chylomicron remnant retinyl palmitate are shown in Figs. 1Go and 2Go. There were no significant differences between CAD+ and CAD- offspring for areas under the postprandial curves for triglyceride and plasma, chylomicron, and chylomicron remnant retinyl palmitate (Table 3Go). This was also the case for areas under the curves when CAD+ and CAD- offspring were compared within their own age group. However, there were significant differences between younger CAD+ and younger CAD- offspring in the shape of the postprandial plasma, chylomicron, and chylomicron remnant retinyl palmitate curves over time. For the plasma retinyl palmitate curves, this was at a significance level of P < 0.01; for the chylomicron retinyl palmitate curves, P < 0.01; and for the chylomicron remnant curves, there was a marginal significance level of P = 0.075. Significant differences were also apparent for several time points (Figs. 1Go and 2Go).



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  		Figure 1. Postprandial curves for CAD+ and CAD- offspring. A, Postprandial triglyceride curves. B, Postprandial plasma retinyl palmitate curves. C, Postprandial chylomicron retinyl palmitate curves. D, Postprandial chylomicron remnant retinyl palmitate curves. Values are the mean ± SEM. Each subject received 70 g/m2 fat in the form of whipping cream together with aqueous vitamin A (60,000 U/m2). Plasma triglyceride and retinyl palmitate in plasma, chylomicrons (Sf = >400), and chylomicron remnants (Sf = 20–400) were measured hourly.

 


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  		Figure 2. Postprandial curves for younger and older CAD+ and CAD- offspring. A, Postprandial triglyceride curves. B, Postprandial plasma retinyl palmitate curves. C, Postprandial chylomicron retinyl palmitate curves. D, Postprandial chylomicron remnant retinyl palmitate curves. Values are the mean ± SEM. Plasma triglyceride and retinyl palmitate in plasma, chylomicrons (Sf = >400), and chylomicron remnants (Sf = 20–400) were measured hourly. *, P < 0.05 for level of significance comparing retinyl palmitate concentrations at various time points in younger CAD+ and younger CAD- offspring.

 

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  		Table 3. Areas under the postprandial triglyceride and retinyl palmitate curves for CAD+ and CAD- offspring

 
Comparing older CAD+ offspring to younger CAD+ offspring, older CAD+ offspring had significantly increased areas under the postprandial curves for triglyceride and plasma, chylomicron, and chylomicron remnant retinyl palmitate. Comparisons were also made after correcting for BMI, waist/hip ratio, and SI (Table 4Go). For the area under the postprandial triglyceride curve, the only correction to eliminate a difference between the two groups was for waist/hip ratio. For the areas under the plasma and chylomicron retinyl palmitate curves, a significant difference remained between the two groups after correcting for BMI, waist/hip ratio, and SI, although the difference was marginal after correcting for the waist/hip ratio (P = 0.06). For the area under the chylomicron remnant retinyl palmitate curve, correcting for the waist/hip ratio had a major influence, and there was no longer a significant difference between the two groups. Pearson correlation coefficients for the 60 CAD+ subjects are shown in Table 5Go.


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  		Table 4. Comparisons between younger and older CAD+ offspring after correcting for BMI, waist/hip ratio, and SI

 

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  		Table 5. Pearson correlation coefficients for areas under the postprandial triglyceride and retinyl palmitate curves for CAD+ offspring

 

   Discussion
Top
 Abstract
 Introduction
 Experimental Subjects
 Materials and Methods
 Results
 Discussion
References
 
We have demonstrated that young males at risk for CAD because of their family history have neither elevated postprandial triglyceride concentrations nor delayed chylomicron and chylomicron remnant clearance compared to normal male controls without a history of parental coronary disease. CAD+ offspring were matched to CAD- offspring by age and BMI. Blood levels of vitamin A were used as a chylomicron marker, and the area under the postprandial retinyl palmitate curve was used as an indicator of chylomicron (Sf = >400) and chylomicron remnant (Sf = 20–400) clearance. This study, therefore, provides no support for the hypothesis that postprandial lipemia and abnormalities of chylomicron clearance are important atherogenic risk factors in young male adults at risk for coronary disease because of their family history.

A study of a similar nature was performed by Uiterwaal et al. (22), who studied the offspring of a parent with CAD and compared postprandial triglyceride and postprandial plasma retinyl palmitate concentrations (but not chylomicron and chylomicron remnant retinyl palmitate concentrations) in 80 patients and 55 controls. Offspring were 15–30 yr of age, and risk status was categorized on the basis of a positive or negative angiogram in a single parent. Patients had significantly increased postprandial triglyceride concentrations, and an age-adjusted repeated measures analysis showed the postprandial triglyceride curves to be significantly different from those in controls over time. However, there was no significant difference between the postprandial plasma retinyl palmitate curves. Our results are at variance with those of Uiterwaal et al. with respect to the postprandial triglyceride curves, but in agreement with respect to the postprandial plasma retinyl palmitate curves.

Of interest is the observation that diastolic blood pressure and LDL cholesterol concentrations were higher in CAD than CAD- offspring. There were no significant differences in diet composition, alcohol intake, or smoking between the two groups, suggesting a genetic influence. Increased levels of cholesterol and LDL cholesterol have been noted in prior offspring studies (23, 24).

Because of our interest in age-related aspects of lipid metabolism, offspring were recruited into two age groups: younger offspring, aged 15–30 yr, and older offspring, aged 31–45 yr. Unexpectedly, when comparisons were made within each age group, we found the shape of the retinyl palmitate curves over time for the younger CAD+ offspring to be significantly different from those for the younger CAD- offspring, as were concentrations of retinyl palmitate at several time points during the tolerance test, indicating more efficient chylomicron and chylomicron remnant clearance in the younger CAD+ offspring. We have no satisfactory explanation for this observation. One possibility to consider is that the lower fat and protein diets of the younger CAD+ offspring were responsible for the decreased postprandial retinyl palmitate levels. Interestingly, Uiterwaal et al. (22) also found their sons of coronary patients to be consuming diets that were lower in fat than those of the controls. However, when comparisons were made after controlling for the fat content of the diet (data not shown), we found this to have little effect on the level of significance.

Important findings from this study were that older CAD+ offspring had significantly increased BMI, waist-hip ratio, fasting triglyceride, and VLDL cholesterol, triglyceride, and apoprotein B concentrations than younger CAD+ offspring. Areas under the postprandial curves for triglyceride and retinyl palmitate in plasma, chylomicron, and chylomicron remnants were also significantly increased. Noteworthy, however, there were no differences between the two groups with respect to LDL and HDL cholesterol. These results are consistent with data from previous studies examining the influence of age on postprandial triglyceride and chylomicron clearance. Cohn et al. (25) studied 22 men and women, aged 22–79 yr, and showed that older subjects had greater postprandial lipemia than younger subjects. Krasinski et al. (26) infused lipoproteins labeled with retinyl ester into subjects over age 50 yr and subjects aged 18–30 yr and demonstrated a shortened retinyl ester residence time in the younger subjects. Tollin et al. (27), on the other hand, infused intralipid (AB Vitrum, Stockholm, Sweden) into male and female subjects, and showed a decrease in the clearance of triglyceride from the blood with age for women, but not for men. The data from our study extend these observations by showing significant age differences in postprandial triglyceride concentrations and chylomicron clearance in young male subjects.

There is a strong age dependence to coronary artery disease. While this could be the consequence of a long evolutionary process in the development of atherogenic plaque, it seems more likely that clinical disease is due to a metabolic environment more favorable to accelerated atherogenesis. Our data suggest that such an environment is unlikely to arise from changes in the cholesterol content of LDL and HDL. However, an increase in VLDL and postprandial lipemia, or a decrease in chylomicron clearance could possibly promote such an environment, for example by decreasing the clearance of potentially atherogenic intermediate density lipoproteins or impairing reverse cholesterol transport via HDL.

We were also interested in the factors responsible for these age-related changes and, therefore, compared lipoproteins and postprandial curves for the older and younger CAD+ offspring after correcting for BMI, waist/hip ratio, and SI. Correcting for SI had little impact on the significance of difference between the two groups for either the triglyceride or retinyl palmitate curves. However, correcting for the waist/hip ratio had a major impact for fasting triglyceride, VLDL cholesterol, VLDL triglyceride, VLDL apoprotein B, area under the postprandial triglyceride curve, and area under the chylomicron remnant retinyl palmitate curve. We conclude from this that a maturational change in body fat distribution accounts for a major part of the age-related increase in VLDL and postprandial lipemia and the decrease in chylomicron remnant clearance.

In conclusion, we have shown that male offspring of parents with early CAD have neither increased postprandial lipemia nor abnormalities of chylomicron and chylomicron remnant clearance, as demonstrated by areas under the postprandial retinyl palmitate curves, suggesting that these are not important early atherogenic risk factors in young males at risk for CAD because of their family histories. We have also demonstrated in these subjects that an increase in age is associated with an increase in VLDL and area under the postprandial curves for triglyceride and plasma, chylomicron, and chylomicron remnant retinyl palmitate. An increase in the waist/hip ratio accounts for a major portion of these changes. We hypothesize that these changes, although not necessarily atherogenic, may promote an environment in susceptible individuals that is more conducive to atherogenesis.


   Footnotes
 
1 This work was supported in part by a Grant-in-Aid from the American Heart Association, Wisconsin Affiliate; the Children’s Hospital Foundation of the Children’s Hospital of Wisconsin (Milwaukee, WI); the R. D. and Linda Peters Research Endowment, Medical College of Wisconsin; and General Clinical Research Center Grant 5-M01-RR-00058. Back

2 Supported in part by a grant from the Helen Bader Foundation (Milwaukee, WI). Back

Received April 2, 1997.

Revised September 17, 1997.

Accepted December 12, 1997.


   References
Top
 Abstract
 Introduction
 Experimental Subjects
 Materials and Methods
 Results
 Discussion
 References
 

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