© 1995 American Heart Association, Inc.
Articles |
Association of Postprandial Triglyceride and Retinyl Palmitate Responses With Asymptomatic Carotid Artery Atherosclerosis in Middle-aged Men and Women
The Atherosclerosis Risk in Communities (ARIC) Study
From the Epidemiology and Biometry Program, National Heart, Lung, and Blood Institute, Bethesda, Md (A.R.S.); the Departments of Biostatistics (L.E.C.) and Epidemiology (G.H., C.C.P.), University of North Carolina School of Public Health, Chapel Hill; and the Department of Medicine, Baylor College of Medicine, and The Methodist Hospital (W.P.), Houston, Tex.
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Abstract |
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Abstract Blood lipid alterations after a fatty meal may be atherogenic, but there is little information regarding their associations with disease independent of fasting lipids. Asymptomatic atherosclerosis cases (n=229) and 373 control subjects free of atherosclerosis, as defined by carotid intima-media thickness on ultrasound images, were given a fatty meal with vitamin A, followed by 3.5- and 8-hour measurements of triglycerides (TGs), TG-rich lipoprotein TGs, apoproteinB48, and retinyl palmitate. Among white men and women but not among blacks, case status was associated with greater postprandial responses of TGs and TG-rich lipoprotein TGs, but only in nonobese persons (body mass index <30 kg/m2). The associations were strong and significant after controlling for coronary risk factors (odds ratio,
2.0) and fasting TGs
(odds ratio, 1.5). Associations with other postprandial lipid
measurements did not persist after controlling for fasting lipids.
Elevated postprandial TGs appear to be an independent risk factor for
carotid intimal thickening in nonobese whites. The lack of such a
relation in obese subjects and the lipid profile they manifest suggest
that postprandial TGs must be accompanied by accumulation of TG-rich
lipoprotein remnants to be atherogenic.
Key Words: atherosclerosis • carotid artery diseases • lipoproteins
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Introduction |
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Associations between atherosclerotic diseases and elevated fasting plasma LDL-C and reduced fasting plasma HDL-C are well established.1 However, many individuals without fasting lipid abnormalities develop atherosclerotic diseases, and several lines of evidence suggest that nonfasting lipid measurements may be more relevant to atherogenesis. Typical American diets are associated with measurable postprandial lipemia 18 hours per day.2 A number of studies have consistently shown that in the hours following a fatty test meal, plasma TGs are higher in men with CHD than in control subjects without CHD.3 4 5 6 7 8 9 10 CHD cases also usually have higher fasting TG levels than do control subjects, and given the high correlation between fasting and postprandial TG values, these studies have often been too small to evaluate the independent effects of postprandial TGs. Furthermore, many of these studies were not designed to select representative cases or comparable control subjects, and clinically recognized CHD, along with the medications and changes in diet and activity that accompany it, may affect TG responses. It is preferable, therefore, to evaluate associations between postprandial lipemia and asymptomatic atherosclerosis cases and comparable control subjects from the same population, as has been done in one small study of hypercholesterolemic subjects.11
The ARIC Group performed one of two collaborating case-control studies to evaluate the role of postprandial lipemia in atherosclerosis. From a population of individuals who were free of clinical atherosclerotic disease, ARIC investigators selected case and control subjects on the basis of ultrasound imaging evidence of extracranial carotid atherosclerosis. The other study, which was performed at Columbia University and reported in a companion article,12 selected clinical CHD cases prior to treatment and control subjects. Both studies used common protocols and measured the same lipids: plasma TGs, TGs in the d<1.006–g/mL fraction (containing TGRLs), and, as markers of intestinal lipoproteins, plasma RP and the ratio of apoB48 to apoB100 in the d<1.006–g/mL plasma fraction. The objectives of this two-study collaboration were to evaluate the associations between postprandial lipemia and atherosclerotic diseases after adjustment for the major coronary risk factors (including fasting plasma lipid and lipoprotein levels) and to compare two sets of these postprandial lipemia associations in those with carotid atherosclerosis and those with CHD.
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Methods |
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The population for this study was drawn from the ARIC Study cohort, which was selected as a probability sample of 15 800 men and women between the ages of 45 and 64 years from four US communities. In three of these communities (Forsyth County, North Carolina; the suburbs of Minneapolis, Minn; and Washington County, Maryland), all age-eligible residents were included in the sampling frame. In the fourth community (Jackson, Miss), only black residents were sampled. Details of sampling and procedures are provided in manual 2 for visit 1 of the ARIC Study protocol.13
Participants in the postprandial study were selected from the ARIC cohort as cases of carotid atherosclerosis or as control subjects on the basis of measurements of carotid artery intima-media wall thickness on ultrasound images. These measurements provide an index of carotid atherosclerosis, which is strongly associated with fasting lipids, smoking, blood pressure, and other established CHD risk factors.14 15 Cases had either two measurements of maximum carotid artery wall thickness that were >2.5 mm or bilateral thickening, corresponding to a maximum thickness >1.7 mm at the internal carotid artery, 1.8 mm at the carotid bifurcation, or 1.6 mm at the common carotid segments. To supplement the number of case subjects who were black, criteria for this group were relaxed to 1.2, 1.675, and 1.0 mm, respectively, in the three carotid regions. These criteria resulted in case selection at approximately the 95th percentile wall thickness value for whites and at the 90th percentile for blacks. Control subjects in both ethnic groups had maximum wall thickness values <75th percentile in all carotid segments and in the popliteal artery. All cases and control subjects were required to meet criteria for minimum ultrasound visualization of artery wall boundaries.
After selection of these candidate cases and control subjects, individuals with the following self-reported manifestations of cardiovascular disease were excluded: a history of angina on effort; physician-diagnosed heart attack, transient ischemic attack, or stroke; or intermittent claudication. Cases were then matched pairwise with control subjects within strata defined by community, race, sex, and 10-year age group. For each case, a control subject with an ultrasound exam date close to that of the case subject was randomly chosen from among those with the highest level of wall boundary visualization.
The postprandial study was integrated into the second exam of the ARIC cohort at the four centers during 1990 through 1993. The study was approved by each institutional review board, and separate informed consent was obtained from each. Details of the study procedures have been described.16 Cases and control subjects were identified by the ARIC Coordinating Center, and lists of eligible participants were distributed as pairs of identification numbers. The identification of each participant as a case or control subject was not known to the field staff, laboratory staff, or participants themselves. Whenever feasible, both members of a case-control pair were scheduled for examination during the same week to allow simultaneous shipment of their blood samples to the lipid laboratory. A screening interview was conducted during recruitment to exclude pregnant women and individuals with specific medical conditions: hypertriglyceridemia (reported by either the participant or as a fasting TG level >4.52 mmol/L [400 mg/dL]); gall bladder disease; pancreatitis; intestinal malabsorption; chronic liver or kidney disease; use of insulin, hypoglycemic or lipid-lowering medications, thyroid preparations, ß-blocking agents, or contraceptive hormones; and reported intolerance for dairy products or other constituents of the test meal.
Nonlipid variables such as anthropometric measures, fasting insulin level, medication use, blood pressure at rest, and smoking habits were collected by trained personnel according to the standardized ARIC Study protocol.13 Hypertension was defined as the mean of two blood pressures at rest that exceeded 140/90 or self-reported use of antihypertensive medication. A follow-up interview was conducted by telephone 3 days after the fat-tolerance test to document digestive problems suggestive of malabsorption.
Fat-Tolerance Test
On the day of the fat-tolerance test, participants arrived
at the examination center between 7 and 8:30 AM after
fasting and abstaining from heavy physical work or exercise for 12
hours. A fasting blood specimen was drawn before the test meal was
administered. The liquid test meal consisted of heavy whipping cream,
ice cream, safflower oil, chocolate syrup, and powdered protein
(Promod, Ross Laboratories) and contained 1265 kcal, 32 g protein, 48 g
carbohydrate, 105 g fat (52 g saturated), 300 mg
cholesterol, and 100 000 IU vitamin A (Aquasol, Armour
Pharmaceutical Co) for each 2 m2 of body surface area,
which was calculated as W0.425 x
H0.725, where W is body weight in kilograms and H is
body height in centimeters.17 Lactaid was added to the
test meal as a precaution against lactose intolerance. Test meals were
consumed within 15 minutes, after which time the participants were
instructed to take nothing by mouth except water, unsweetened black
coffee or tea, or sugarless soft drinks for 8 hours and to abstain from
exercise and heavy physical work; they were, however, permitted to take
prescribed medications. Blood specimens were drawn 3.5 and 8 hours
after the participant began drinking the test meal. The limitation to
only two postprandial blood collections has little affect on the
classification of postprandial response. Correlations between responses
that were calculated from two postprandial samples and from four
postprandial samples (measured in our companion study12 )
exceeded .97 for all postprandial measures used. Participants remained
at the examination center until the 3.5-hour-postprandial sample
was drawn, then left, and returned for the 8-hour-postprandial
collection. Medication use, consumption of any food or alcohol, or
participation in heavy work or exercise during the test period were
documented by interview before the 8-hour sample was
taken.16
Postprandial blood specimens were collected into tubes containing EDTA (1.5 mg/mL blood). Plasma was separated by centrifugation (1500g, 20 minutes at 4°C), stored under N2 at 4°C for 1 to 3 days, and shipped on crushed ice to the central laboratory at the Baylor College of Medicine, Houston, Tex. Lipid measurements were performed within 7 days after arrival of the samples at the laboratory, with the exception of RP in plasma, which was stored under N2 in light-protected ampoules at -70°C and analyzed in batches.
Laboratory Methods
Total plasma cholesterol and TGs were measured
enzymatically on a Cobas-Fara centrifugal analyzer (Roche
Diagnostics) with commercially available kits (catalog Nos.
236691 and 701912, respectively; Boehringer Mannheim
Diagnostics). The HDL-C level was determined by measuring
cholesterol content in the supernatant liquid after
precipitation of the plasma with MgCl2 and dextran
sulfate.18 LDL-C levels were calculated according to the
formula of Friedewald et al.19 ApoB levels were determined
by radioimmunoassay.20
TGRLs (d<1.006 g/mL) were isolated by ultracentrifugation from 5 mL of plasma of the fasting blood sample and of the 3.5- and 8-hour-postprandial specimens.21 Samples were spun for 18 hours at 10°C at 105 000g in a Beckman 50.3 rotor. TGs in the top fraction were obtained by tube slicing and were determined by the enzymatic procedure described above.
RP levels in plasma were determined by high-pressure liquid chromatography (high-pressure liquid chromatography pump model 501, tunable absorbance detector model 486, sample processor model 712, and data module model 743; all from Waters Instruments) as previously described.22
The apoB48-apoB100 ratio in TGRLs was determined exactly as described previously.22 In brief, aliquots of the d<1.006–g/mL fraction were subjected to SDS gel electrophoresis on a 3% stacking gel and 5% separating gel. The gels were stained with 0.25% (vol/vol) Coomassie Brilliant Blue G-250 for 1 hour and destained in 40% (vol/vol) methanol and 10% (vol/vol) acetic acid, and relative abundances of apoB48 and apoB100 were determined by scanning the gels with a laser densitometer for 20 hours. The apoB48-apoB100 ratio rather than the absolute level of apoB48 is reported, because the ratio is measured more reliably with this method.
ApoE genotypes were determined by restriction isotyping. Genomic DNA was extracted from buffy coats, amplified by the polymerase chain reaction23 using the primers reported by Emi et al,24 and restricted with Hha I, as suggested by Hixson and Vernier.25 Digested DNA was then subjected to electrophoresis on 12% polyacrylamide gels under nondenaturing conditions. ApoE polymorphisms were typed from the ethidium bromide–stained gels.
LDL particle size was determined by gradient gel electrophoresis using 2% to 16% nondenaturing polyacrylamide-agarose gels (PAA 2% to 16%, Pharmacia). Aliquots of plasma that had been stored for no longer than 1 week at 4°C were mixed with a solution of 40% (vol/vol) sucrose and 0.1% (vol/vol) bromophenol blue and subjected to electrophoresis in a Pharmacia GE 2/4 apparatus at 120 V for 18 hours at 10°C using 0.09 mol/L Tris, 0.08 mol/L boric acid, and 0.003 mol/L Na2EDTA, pH 8.3, as the running buffer. Gels were stained with Sudan black B for 20 hours, destained in a 50% (vol/vol) Cellosolve solution (Sigma) for 2 to 3 days, and stored in 25% (vol/vol) Cellosolve26 to restore gel size and shape before scanning on an Ultrascan XL laser densitometer equipped with the GSXL software package (LKB Instruments Inc). Two plasma standards, each derived from a single donor and containing either small, dense or large, buoyant LDL, as determined by zonal ultracentrifugation,27 were analyzed with all unknown plasma specimens. LDL particle size was assigned to subclass pattern A, B, or I according to the nomenclature of Krauss and Burke.28 Assignment was made by three independent observers. For quality-control purposes, approximately 5% of samples were reanalyzed. All samples subjected to repeated analyses showed complete agreement with their original assignment.
Quality Control
For internal quality control of lipid and apoprotein
measurements, control plasma pools were used. The CVs were 2.7% for
TGs, 3.7% for HDL-C, 5.2% for LDL-C, 13% for RP, and 9% for apoB.
External quality control consisted of our laboratory's participation
in the Centers for Disease Control and Prevention Lipid Standardization
Program. In addition, aliquots from a subset of samples were taken from
the blood collection tubes, stored at each field center for an
additional week, and sent to the central laboratory in the subsequent
weekly mailing in a blinded fashion, thereby providing a measure of
overall variability (ie, variability due to storage, shipping, sample
processing, transcription, and analyses). The CVs for these
blinded replicates for TGs, RP, LDL-C, and HDL-C were 15%, 18%, 8%,
and 11% respectively, with corresponding correlations of .95, .93,
.85, and .95.
The fat content of the test meal was measured after extraction according to a modification29 of the method of Folch et al30 and gravimetric determination after evaporation of the organic solvents. Fat content averaged 0.266 g/mL and varied little among 153 test meals analyzed (SD, 0.018 g/mL; CV, 6.8%).
Comparability between the Columbia and Baylor laboratories was assessed by blinded parallel analyses of aliquots from the same postprandial samples. The correlation between values obtained at the two laboratories was .90 for RP (54 pairs of measurements) and .99 for TGs (37 pairs). Compared with Baylor measurements, Columbia values were 10% higher for RP and 4% higher for TGs.
Statistical Methods
Means and proportions for cases can be interpreted as estimates
for the entire population of cases who met the selection criteria for
this study (as we included a random sample of such cases and with the
assumption that refusals were also random). Corresponding control
values can be interpreted as adjusted to the case distribution of
community, race, sex, and 10-year age group. Likewise, case-control
comparisons can be interpreted as adjusted for these variables.
The primary analysis of the association between postprandial lipids and case-control status used race-specific conditional logistic regression models, which were based on strata defined by community, sex, age group, and 6-month period of examination. Formally, these are models of probability of "caseness" (carotid atherosclerosis) as a function of the level of postprandial lipids, controlling by design for the variables defining the conditioning strata and other covariates in the model.31
The postprandial lipid values in these models are AUCs of lipid measurement above baseline plotted versus time, as approximated by the three time points available. AUCs for TGs can be interpreted as time (8 hours) multiplied by the difference between the fasting TG value and its mean over the 8-hour period, with negative values set to zero. The AUC was found to discriminate between cases and control subjects better than other indicators of response, such as 8-hour values. Modifications of associations according to sex, smoking status, hypertension, LDL-C, BMI, and other factors that are known to be related to postprandial lipemia or to carotid atherosclerosis were evaluated by inclusion of appropriate interaction terms in the models.
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Results |
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A total of 528 white and 124 black ARIC participants met carotid wall thickness criteria as cases (Table 1
), and 326
whites and 75 blacks were invited to participate in this study as cases
or control subjects. An additional 456 blacks met the relaxed case
criteria and 110 of them were invited to participate. The pool of
eligible control subjects was much larger. Of the potential cases, 18%
to 25% were excluded on the basis of evidence of
cardiovascular disease, as were 7% to 11% of
potential control subjects. Refusal rates were 
8%. Other conditions
that resulted in exclusion were found in 37% to 49% of potential
cases and 19% to 26% of potential control subjects. A few study
participants had test-meal intolerance or failed to consume the
full test meal. Remaining for study were 170 white and 59 black cases
and 274 white and 99 black control subjects.
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Table 2 shows the sex, age, and mean carotid
intima-media thickness of white and black cases and control
subjects and their risk factor levels after adjustment for age, sex,
community, and date of examination. As designed, within each racial
group cases and control subjects were similar with respect to sex and
age. In whites, mean carotid wall thickness was 1.19 mm in cases and
0.63 mm in control subjects, a difference of 0.56 mm. The maximum value
for mean carotid wall thickness for cases was 2.26 mm; only 9% had a
mean thickness exceeding 1.5 mm, and 13% had carotid stenosis,
defined as any lumen narrower than 2 mm.
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For blacks, the difference between cases and control subjects was only 0.35 mm because of the relaxed case criteria used. Only 25 black participants qualified as cases on the basis of case criteria used for whites, too few for separate analysis.
Compared with control subjects, white cases had higher mean fasting LDL-C and TG levels and lower HDL-C levels. More were current smokers, more had hypertension, and mean BMI was greater in cases. Among blacks there were no significant case-control risk factor differences; although differences were generally in the expected direction, but fasting TG levels were somewhat lower in black cases than control subjects.
Analyses of postprandial lipids were performed separately for
each race. Mean fasting and postprandial levels of TGs, TGRL TGs, RP,
and percent of apoB48, adjusted for age, sex, community, and date of
initial examination, are shown for white participants in Figs 1 through 4. In cases, TG levels rose from a fasting mean of 1.66 mmol/L to 3.45
mmol/L at 3.5 hours after the test meal and declined to 2.57 mmol/L at
8 hours (Fig 1). TGRL TGs rose from 1.06 mmol/L in
fasting plasma to 2.53 mmol/L at 3.5 hours and 1.74 mmol/L at 8 hours
(Fig 2). For both total TGs and TGRL TGs and for each of
the three time periods, the levels were substantially and significantly
(P<.0001) higher in white cases than control subjects. RP
levels, usually less than the detection limit of 0.5 µg/dL in fasting
plasma, rose in white cases to 84 µg/dL at 3.5 hours and 127 µg/dL
at 8 hours (Fig 3). Levels in control subjects were
similar to those in cases in fasting and 3.5-hour plasma samples but
were lower at 8 hours (P<.01). The apoB48 concentration in
fasting plasma was approximately 3% of the TGRL apoB100 concentration
in white cases and control subjects, increased to 6% in the 3.5-hour
plasma, and declined in the 8-hour plasma to 4.4% in cases and to
3.9% in control subjects (P<.05 for the difference at 8
hours; Fig 4). Mean fasting and postprandial levels of
TGs, TGRL TGs, RP, and apoB48 percent were also examined for blacks. No
significant case-control differences were found.
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Independent associations of postprandial AUCs with case-control
status were evaluated in analyses that controlled for fasting
TGs; risk factors; and the selection factors of age, sex, community,
and date of examination. Potential interactions involving sex, smoking
status, hypertension, diabetes, serum insulin level, LDL-C (>4.13
mmol/L [160 mg/dL]), waist-hip ratio (greater than the median),
and BMI (>30 kg/m2) were tested. Only the AUC interaction
with BMI was consistent in both races and significant or nearly
significant (P<.10) in these models. Average AUCs with
their SDs in the population were 8.04±5.31 (mmol/L)xhours for TGs,
6.10±4.85 (mmol/L)xhours for TGRL TGs, and 580±306 (µg/dL)xhours
for RP. The ORs in Table 3 correspond to approximate
1-SD–higher values of the AUCs, ie, 500 and 450 (mg/dL)xhours (5.64
and 5.08 [mmol/L]xhours, respectively) for TGs and TGRL TGs and 300
(µg/dL)xhours for RP. For white participants, these ORs were 1.22
for TGs, 1.28 for TGRL TGs, and 1.03 for RP (none significant).
However, ORs differed by BMI group for TGs and TGRL TGs (each
interaction significant at P<.05) and for RP
(P=.09 for interaction) and were consistently higher
in the BMI<30 kg/m2 group. In this BMI group, comprising
81% of white participants, ORs were substantial and statistically
significant for TGs (1.47) and for TGRL TGs (1.52) but not for RP
(1.12). Corresponding ORs were <1.0 (not significant) for the BMI
30
kg/m2 group.
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A similar pattern of AUC-BMI associations was observed in black
subjects (Table 3
), but none of the ORs were significant. ORs for the
BMI<30 kg/m2 group were 1.22 for TGs and 1.25 for TGRL
TGs, with corresponding ORs <1.0 for the BMI30 kg/m2
group. No substantial associations were seen for RP.
Control for fasting HDL, in addition to fasting TGs and the covariates
listed in Table 3, had little effect on the significant associations
reported. ORs for TGs in whites with a BMI <30 kg/m2 were
reduced from 1.47 to 1.44 after inclusion of HDL-C. For TGRL TGs the
ORs were reduced from 1.52 to 1.49.
There were no significant interactions between apoE genotype
and TG AUC effects, but ORs tended to be higher for those with the 4/3
genotype (OR, 2.37 in whites and 1.60 in blacks; Table 4). Only the OR for apoE genotype 4/3 in whites
was statistically significant.
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Fasting TGs were consistently higher in the BMI30
kg/m2 group than in the BMI<30 kg/m2 group, by
41% in white control subjects (P<.001), 16% in white
cases (P<.05), 10% in black control subjects (NS), and 3%
in black cases (NS). Also, TGRLs appeared to be larger in the BMI30
kg/m2 group. A linear model regressing fasting TGRL TGs
against BMI group, TGRL apoB, age, race, and sex showed a 0.28–mmol/L
higher TGRL TG for any fixed apoB level in the BMI30
kg/m2 group than in thinner subjects (P<.0001).
In contrast, a similar analysis of denser lipoproteins showed
only a 0.02–mmol/L higher TG value in the BMI30 kg/m2
group (NS). Thus, TGRLs in the BMI30 kg/m2 group were
more TG enriched than in the BMI<30 kg/m2 group.
Because BMI modified the association between postprandial TGs and case-control status, it was important to study whether BMI also modified the associations between postprandial TGs and either HDL-C level or LDL size. The results indicated that BMI did not significantly modify these associations. This was examined by using two linear regression models. The first related TG AUC to age, sex, BMI group, HDL, and the interaction term (BMI groupxHDL). This model, which was run separately in white cases and control subjects, showed that higher postprandial TGs were consistently related to lower fasting HDL-C values, but these associations were not significantly or consistently modified by BMI in the two groups. The second model related TG AUC to age, sex, case-control status, BMI group, LDL size, and the interaction term (BMI groupxLDL size) and was run in white cases and control subjects together. Postprandial TGs were associated with smaller LDL particle sizes, but BMI interactions with this association were not significant.
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Discussion |
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This study shows an association between postprandial TGs and carotid atherosclerosis, as defined by measures of intima-media thickness, that is independent of fasting lipids and other risk factors in nonobese, middle-aged white subjects. Unfortunately, there were too few cases with sufficient carotid thickening for an adequate test of this hypothesis in blacks. This is the first report from a study with several features that were designed to assure case-control comparability: selection of cases and control subjects from the same community-based population samples; matching on key variables; blinded simultaneous assays of case and control plasma; and lack of participant awareness of their case-control status, making them unlikely to differ in any dietary or other health behaviors related to plasma lipid levels. Care was taken to reduce bias by excluding persons who were using any medication or having any medical condition that might have selectively affected postprandial lipemia. Because cases were asymptomatic, with mean intima-media thicknesses
2 mm, the findings of this
study pertain to the early stages of carotid
atherosclerosis. Thus, this study confirms, but only in
nonobese whites, previous studies that have shown associations between
elevated postprandial TG levels and cardiovascular
disease and provides evidence that postprandial TG elevation is not a
consequence of the disease, its medications, or its lifestyle changes
but is more likely involved in atherogenesis.
A 1-SD–greater postprandial AUC for TGs or TGRL TGs conveyed ORs of
approximately 1.5 in nonobese whites, after adjustment for LDL-C and
fasting TGs (Table 3), clear evidence of independent associations with
carotid disease. Associations that were adjusted for fasting TGs,
however, may underestimate the pathogenic importance of postprandial
lipids: remnants of intestinal and hepatic TGRLs occupy very similar
metabolic pathways, for example, and postprandial lipid
metabolism is complex. Associations of postprandial TGs
with disease can also be studied by using the 8-hour post–test
meal TG level (rather than the post–test meal TG increase) as the
independent variable and not including fasting TG as a
covariable. When this is done, associations with disease are
strengthened, with ORs for 1-SD elevations in nonobese whites (in the
same model used in Table 3) of 2.01 for TGs (P<.0001) and
2.04 for TGRL TGs (P<.0001). Thus, post–test meal TGs
are independently associated with disease in this group, as shown in
Table 3, and the net association may be strong, as discussed in this
paragraph. More informative estimates of the strength of that
association must await more specific measures of atherogenic lipid
changes that occur postprandially.
Finding substantially lower ORs in the BMI30
kg/m2 group than in thinner participants, despite elevated
fasting TG levels in the former, was unexpected. These subjects were
given more of the test meal, as the quantity was scaled to body surface
area. If the quantity were inappropriately large relative to their
usual dietary intake, this could have led to an atypical postprandial
response unrelated to the extent of their carotid
atherosclerosis. We do not believe this to be the
explanation for the lower OR in the BMI30 kg/m2 group.
Body surface area is believed to be approximately proportional to a
person's caloric need,32 and scaling by body surface area
is often used in postprandial lipid research.8 10 11 33 34
As a result, an average test meal quantity was only 13% greater in the
BMI30 kg/m2 subjects. Furthermore, Patsch et
al10 also found postprandial lipemia to be strongly
associated with CHD, despite their use of a test meal that contained
30% more fat than in the present study.
Our companion study12 confirmed a lower OR in persons with a greater BMI. This replication of results justifies speculation regarding possible BMI effects. Elevated fasting TGs in persons with a greater BMI concur with studies showing that even normolipidemic obesity is associated with increased VLDL TG production rates.35 36 37 Increased VLDL TG production is expected to augment postprandial lipemia, because intestinal and hepatic TGRLs compete for a common clearance pathway. Lewis et al38 found the increment in postprandial TGs to be threefold greater in obese than control subjects, while the retinyl ester increment was only 1.6-fold greater, suggesting a greater role for hepatic TG secretion in postprandial triglyceridemia in obesity.
How then can the impact of BMI on the association of postprandial TGs with atherosclerosis be explained? Current concepts suggest that postprandial triglyceridemia per se is not harmful but serves as a marker of complex processes that may ultimately promote atherosclerosis. When the integrated level of TGRLs in the postprandial state is high, CETP-mediated transfer of CE from HDL and LDL to TGRLs in exchange for TGs is extensive. Hence, HDL-C levels decrease, LDL particle size is reduced, and CE-rich remnants of TGRLs are formed. Each of these consequences of postprandial TG metabolism is potentially atherogenic.
It is conceivable that the postprandial response in obese persons may
be atypical with respect to any of the consequences described above.
Our data show no influence of BMI on the relation between postprandial
TG and HDL-C levels, suggesting that CETP-mediated transfer of lipids
between HDL and TGRLs does not differ. Similarly, BMI appears to have
no significant effect on the relation between postprandial TGs and LDL
particle size. Ginsberg et al39 also report that BMI does
not modify the associations between postprandial TGs and either HDL-C
level or LDL particle size. However, fasting TGRLs had a higher TG
content for any fixed apoB level in the BMI30 kg/m2
group, indicating that for equal TG levels, this group had fewer TGRL
particles than the BMI<30 kg/m2 group.
Thus, in obese individuals, hepatic secretion of larger, less dense TGRLs may abolish the marker function of postprandial TG measurements. If this conclusion were confirmed in other studies, our findings would imply that an impaired TG metabolism is atherogenic because of its association with TGRL remnant accumulation rather than its effects on LDL particle size or HDL-C levels. Differences in TG metabolism with levels of obesity may also explain the general inconsistency in results of studies on TGs as a risk factor for cardiovascular diseases.40
Because our companion study showed clear differences in the postprandial TG association with CHD by sex, we examined the same associations in relation to carotid atherosclerosis. No sex interactions were significant. Among whites, we found a pattern similar to that in the Columbia study, ie, somewhat increased ORs in men. For TGRL TGs, ORs were 1.36 in men and 1.09 in women, and in the BMI<30 kg/m2 group, 1.56 and 1.34, respectively. The pattern was reversed in blacks, however: 0.84 in men and 1.31 in women.
Postprandial lipoprotein associations may be stronger for CHD than for
early atherosclerosis. Whites with a BMI<30
kg/m2 in our study had an OR of 1.47 for carotid
atherosclerosis for each 500 (mg/dL)xhours (5.64
[mmol/L]xhours) increase in TG AUC (Table 3), compared with an OR of
2.3 for CHD in men in the Columbia study that used a similar
analysis. We recently reported41 a higher fasting
LDL-C–apoB ratio in ARIC subjects with asymptomatic
carotid thickening than in comparable subjects with clinical CHD. We
suggested that the difference might be due to a greater role for
elevated TGs in the CHD cases, as TGs may be thrombogenic and elevated
TG levels are associated with lower LDL-C–apoB ratios. If the greater
role for postprandial lipemia in CHD than in early
atherosclerosis were confirmed, it might suggest, as we
earlier hypothesized, that disorders of TG metabolism may
have a greater influence on the later atherothrombotic processes
associated with clinically apparent ischemic coronary
disease than on early arterial thickening, as studied
here.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This research was carried out as a collaborative study supported by grant No. UO1 HL45467 and contracts N01-HC55015, N01-HC55016, N01-HC55018, N01-HC55019, N01-HC55020, N01-HC55021, and N01-HC55022 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md. We are indebted to the following for their assistance: Bowman Gray School of Medicine, Winston-Salem, NC: Regina deLacy, Delilah Cook, Carolyn Bell, Theresa Crotts, and Suzanne Pillsbury; The Johns Hopkins University, Baltimore, Md: Joel G. Hill, Patricia M. Crowley, Joyce B. Chabot, and Patricia Hawbaker; Methodist Hospital, Houston, Tex: Val Creswell, Julita Samoro, Wanda Wright, and Karima Ghazzaly; University of Minnesota, Minneapolis: Barbara Kuehl, Anne Murrill, Bryna Lester, and Jennifer Hill; University of Mississippi Medical Center, Jackson: Cora Walls, Dorothy Washington, Mattye Watson, and Nancy Wilson; University of North Carolina, Chapel Hill: Carol Summers, Catherine Burke, Deanna Horwitz, Carmen Woody, Peter DeSaix, Mal Foley, Tom Goodwin, and Richard Hayes.
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Footnotes |
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Reprint requests to Dr A. Richey Sharrett, Epidemiology and Biometry Program, National Heart, Lung, and Blood Institute, National Institutes of Health, Rockledge Bldg Room 8164, Bethesda, MD 20892-7934. E-mail sharrett@nih.gov.
Received March 3, 1995; accepted July 28, 1995.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
-
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] - Ahmed M, Gannon MC, Nuttall FQ. Postprandial plasma glucose, insulin, glucagon and triglyceride responses to a standard diet in normal subjects. Diabetologia. 1976;12:61-67. [Medline] [Order article via Infotrieve]
- Barritt DW. Alimentary lipaemia in men with coronary artery disease and in controls. Br Med J. 1956;2:640-644.
- Brown DF, Heslin AS, Doyle JT. Postprandial lipemia in health and in ischemic heart disease. N Engl J Med. 1961;264:733-737.
- Denborough MA, Paterson B. Alimentary lipaemia in ischaemic heart disease. Clin Sci. 1963;25:115-122. [Medline] [Order article via Infotrieve]
- Harlan WR, Beischer DE. Changes in serum lipoproteins after a large fat meal in normal individuals and in patients with ischemic heart disease. Am Heart J. 1963;66:61-67. [Medline] [Order article via Infotrieve]
- 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]
-
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] - Simpson HS, Williamson CM, Olivecrona T, Pringle S, Maclean J, Lorimer AR, Bonnefous F, Bogaievsky Y, Packard CJ, Shepherd J. Postprandial lipemia, fenofibrate and coronary artery disease. Atherosclerosis. 1990;85:193-202. [Medline] [Order article via Infotrieve]
-
Patsch JR, Miesenbock G, Hopferwieser T, Muhlberger V,
Knapp E, Dunn JK, Gotto AM, 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] -
Ryu JE, Howard G, Craven TE, Bond MG, Hagaman AP,
Crouse JR. Postprandial triglyceridemia and carotid
atherosclerosis in middle-aged subjects.
Stroke. 1992;23:823-828.
[Abstract/Free Full Text] -
Ginsberg HN, Jones J, Blaner WS, Thomas A, Karmally
W, Fields L, Blood D, Begg M. Postprandial
triglyceride and retinyl ester response to a fat-meal
are independent predictors of coronary artery disease in
middle-aged men, but not women. Arterioscler Thromb
Vasc Biol. 1995;15:1829-1838.
[Abstract/Free Full Text] - National Heart, Lung, and Blood Institute. ARIC Study Operations Manual No 2: Cohort Component Procedures, Version 2.0. Chapel Hill, NC: ARIC Coordinating Center, School of Public Health, University of North Carolina; 1988.
-
Heiss G, Sharrett AR, Barnes R, Chambless LE, Szklo M,
Alzola C and the ARIC Investigators. Carotid
atherosclerosis measured by B-mode ultrasound in
populations: associations with cardiovascular risk
factors in the ARIC study. Am J Epidemiol. 1991;134:250-256.
[Abstract/Free Full Text] - Folsom AR, Eckfeldt JH, Weitzman S, Ma J, Chambless LE, Barnes RW, Cram KB, Hutchinson RG. Relation of carotid artery wall thickness to diabetes mellitus, fasting glucose and insulin, body size, and physical activity. Stroke. 1994;25:66-73. [Abstract]
- National Heart, Lung, and Blood Institute. ARIC Study Postprandial Lipoproteins and Atherosclerosis: Operations Manual, Version 2.0. Chapel Hill, NC: ARIC Coordinating Center, School of Public Health, University of North Carolina; 1991.
- Lohman TG, Roche AF, Martorell R. Anthropometric Standardization Reference Manual. Champaign, Ill: Human Kinetic; 1988.
-
Warnick GR, Benderson JM, Albers JJ. Dextran
sulfate-Mg2+ precipitation procedure for
quantification of high-density-lipoprotein
cholesterol. Clin Chem. 1982;28:1379-1388.
[Free Full Text] - Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein in plasma without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499-502. [Abstract]
- Schonfeld G, Lees RS, George PK, Pfleger B. Assay of total plasma apolipoprotein B concentration in human subjects. J Clin Invest. 1974;53:1458-1467.
- Lipid Research Clinics Program. Manual of Operations: Lipid and Lipoprotein Analyses. Bethesda, Md: US Dept of Health and Human Services, Public Health Service, National Institutes of Health; 1982.
- 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]
-
Saiki RK, Gelfand DH, Stoffel S, Scharf S, Higuchi R,
Horn GT, Mullis KB, Erlich HA. Primer-directed amplification
of DNA with thermostable DNA polymerase. Science. 1988;239:487-491.
[Abstract/Free Full Text] - Emi M, Wu LL, Robertson MA, Myers RL, Hegele RA, Williams RR, White R, Lalouel JM. Genotyping and sequence analysis of apolipoprotein E isoforms. Genomics. 1988;3:373-379. [Medline] [Order article via Infotrieve]
- Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res. 1990;31:545-548. [Abstract]
-
McNamara JR, Campos H, Ordovas JM, Peterson J, Wilson
PWF, Schaefer EJ. Effect of gender, age, and lipid status on low
density lipoprotein subfraction distribution: results from the
Framingham Offspring Study.
Arteriosclerosis. 1987;7:483-490.
[Abstract/Free Full Text] - Patsch W, Ostlund R, Kuisk I, Levy R, Schonfeld G. Characterization of lipoprotein in a kindred with familial hypercholesterolemia. J Lipid Res. 1982;23:1196-1205. [Medline] [Order article via Infotrieve]
- Krauss RM, Burke DJ. Identification of multiple subclasses of plasma low density lipoproteins in normal humans. J Lipid Res. 1982;23:97-104. [Abstract]
- Carlson LA. Determination of serum triglycerides. J Atheroscler Res. 1963;3:334-336.
-
Folch J, Lees M, Sloane-Stanley GH. A simple
method for the isolation and purification of total lipids from animal
tissues. J Biol Chem. 1957;226:497-509.
[Free Full Text] -
Prentice RL, Pike R. Logistic disease incidence
models and case-control studies. Biometrika. 1979;66:403-411.
[Abstract/Free Full Text] - Kleiber M. The Fire of Life: An Introduction to Animal Energetics. Huntington, NY: Robert E Krieger Publishing Co; 1975.
-
Genest J, Sniderman A, Cianflone K, Teng B,
Wacholder S, Marcel Y, Kwiterovich P.
Hyperapobetalipoproteinemia: plasma lipoprotein responses to oral fat
load. Arteriosclerosis. 1986;6:297-304.
[Abstract/Free Full Text] -
Weintraub MS, Rosen Y, Otto R, Eisenberg S, Breslow
JL. Physical exercise conditioning in the absence of weight loss
reduces fasting and postprandial triglyceride-rich
lipoprotein levels. Circulation. 1989;79:1007-1014.
[Abstract/Free Full Text] - Grundy SM, Mok HYI, Zech L, Steinberg D, Berman M. Transport of very low density lipoprotein triglycerides in varying degrees of obesity and hypertriglyceridemia. J Clin Invest. 1979;63:1274-1283.
- Kissebah AH, Alfarsi S, Adams PW. Integrated regulation of very low density lipoprotein triglyceride and apolipoprotein-B kinetics in man: normolipemic subjects, familial hypertriglyceridemia and familial combined hyperlipidemia. Metabolism. 1981;30:856-868. [Medline] [Order article via Infotrieve]
- Howard BV, Abbott WGH, Egusa G, Taskinen M-R. Coordination of very low-density lipoprotein triglyceride and apolipoprotein B metabolism in humans: effects of obesity and non-insulin-dependent diabetes mellitus. Am Heart J. 1987;113:522-526. [Medline] [Order article via Infotrieve]
- Lewis GF, O'Meara NM, Soltys PA, Blackman JD, Iverius PH, Druetzler AF, Getz GS, Polansky KS. Postprandial lipoprotein metabolism in normal and obese subjects: comparison after the vitamin A fat-loading test. J Clin Endocrinol Metab. 1990;71:1041-1050. [Abstract]
- Ginsberg HN, Jones J, Begg M. Postprandial lipemia predicts the presence of coronary artery disease in normal weight but not obese men. Circulation. In press.
- National Institutes of Health Consensus Development Panel on Triglyceride, High-Density Lipoprotein and Coronary Heart Disease. Triglyceride, high-density lipoprotein, and coronary heart disease. JAMA. 1993;269:505-510. [Medline] [Order article via Infotrieve]
-
Sharrett AR, Patsch W, Sorlie PD, Heiss G, Bond MG,
Davis CE. Associations of lipoprotein cholesterols,
apolipoproteins A-I and B, and triglycerides with carotid
atherosclerosis and coronary heart disease: the
Atherosclerosis Risk in Communities (ARIC)
Study. Arterioscler Thromb. 1994;14:1098-1104.
[Abstract/Free Full Text]
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