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Reproductive Endocrinology |
Departments of Pathological Biochemistry (N.S., J.L., G.L., M.M., J.S., C.J.P.) and Obstetrics and Gynaecology (I.A.G.), Glasgow Royal Infirmary, Glasgow, United Kingdom, G4 OSF
Address correspondence and requests for reprints to: Dr Naveed Sattar, Department of Pathological Biochemistry, Macewen Building, Royal Infirmary NHS Trust, Glasgow G4 0SF, United Kingdom.
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Abstract |
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2,
P < 0.001). LDL profile change was evident at the
lowest triglyceride concentrations in the 2 individuals with the
highest increments in triglyceride corrected for estrogen. On the basis
of these longitudinal observations, we conclude the following: 1) as
plasma triglyceride increases in pregnancy, there are parallel rises in
median concentrations of VLDL1, VLDL2 and IDL,
around 5-fold; 2) as a result of this progressive increase in plasma
triglyceride, in particular in VLDL1, the LDL profile is
altered in some individuals towards smaller, dense particles; 3) in
general, the higher the initial (booking) fasting plasma triglyceride
concentration or the larger the rate of change in triglyceride for a
given increment in estradiol, the greater the probability of change in
LDL profile towards smaller denser species; 4) significantly, LDL
subclass perturbation towards smaller denser species occurs not in a
gradual and progressive manner but exhibits "threshold" behavior;
and finally, 5) this threshold is achieved at differing gestational
ages and triglyceride concentrations for different women. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The role of small, dense LDL as a risk factor for coronary heart disease (CHD) is becoming well established (11, 12, 13, 14), and the above atherogenic mechanisms have been proposed. Furthermore, recently reported prospective studies have demonstrated that the presence of small, dense LDL particles precedes CHD (15, 16) and predicts the development of noninsulin dependent diabetes mellitus (17).
In men and in nonpregnant women, plasma triglyceride is the major determinant of small dense LDL, accounting for 40–60% of the variability of this fraction in the plasma (12, 14, 18, 19). In addition, recent cross-sectional studies (12, 19) have prompted the suggestion that, within the relationship between plasma triglyceride and the LDL subfraction profile, there is a threshold effect. At low-normal plasma triglyceride concentrations, there is a positive association between LDL-II (the major LDL species) concentration and plasma triglyceride. Above a certain plasma triglyceride value, however, (reportedly about 1.5 mmol/L in men) (12, 19), LDL-II concentration correlates negatively with plasma triglyceride, and LDL-III concentration, which had been relatively constant below this triglyceride concentration, correlates positively with plasma triglyceride. However, to the best of our knowledge no longitudinal studies have been designed to examine this phenomenon in individual subjects. The physiological changes in plasma triglyceride that accompany pregnancy provide such an opportunity.
In an earlier study of pregnant women, Silliman et al. (5) showed that the raised concentrations of plasma triglyceride that are prevalent 1 month before term are accompanied by a reduction in mean LDL size. Those women who experienced the greatest increase in plasma triglyceride exhibited the most significant shrinkage in their LDL particle diameter. By 6 weeks postpartum, reversal of this process was apparent, but the study design did not permit identification of the dynamics of the phenomenon or the timing of this particle size transition.
To address these issues, we have measured LDL subclasses throughout gestation using density gradient ultracentrifugation. This technique allowed us to examine quantitatively the relationship between plasma triglyceride and perturbations in the LDL subfractions during pregnancy. Our primary hypothesis was that, as pregnancy proceeded and plasma triglyceride increased, the LDL subfraction profile would be perturbed with the appearance of smaller, dense particles. A secondary hypothesis was that there would exist a threshold above which LDL-III formation accelerated. We also wished to define whatever simultaneous changes in the spectral distribution of very low and intermediate density lipoprotein particles would accompany this process. To gain insight into potential mechanisms responsible for these changes we undertook serial measurements of serum estradiol throughout pregnancy. We chose not to measure progesterone levels, however, as available evidence suggests that natural progesterones, in contrast to androgenic progestogens, have minimal, if any, effect on lipid metabolism (20).
Our results not only provide new information on the relationship between plasma triglyceride and LDL subfractions, but also extend our knowledge of the hyperlipidemia of pregnancy and form a basis for more extensive studies of preeclampsia, whose origins we have already speculated might be linked to the lipid derangements found in that condition (21).
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Subjects and Methods |
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Twelve pregnant women who registered for obstetric care at
Glasgow Royal Maternity Hospital were recruited. Eight were
multigravida with normal previous deliveries, and 4 were primigravida.
All women had no identifiable risk factors for the current pregnancy as
determined by detailed obstetric history. During the course of
pregnancy 1 woman emigrated and another woman had a positive test for
Down’s syndrome in the fetus and was excluded by mutual consent. The
remaining 10 women all had normal course and outcome of pregnancy, term
delivery, ate a customary diet, and did not receive any medication
known to interfere with lipid metabolism or lipid determination.
Additionally, none were phenotype apo E2/E2, an inherited trait that
may generate disturbances in the plasma lipid profile even in
normolipemic subjects. The subject characteristics are given in Table 1
. The study was approved by the Research Ethics
Committee of Glasgow Royal Infirmary University NHS Trust, and each
subject gave written informed consent.
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Experimental design
The pregnant women were first seen at 10 weeks gestation (± 1 week) and thereafter at 5-week intervals until delivery. Each woman was seen six times. The gestational age was confirmed by ultrasound. All subjects were sampled after an overnight fast of 12 h. Twenty-five mL of blood was collected by venepuncture into K2 EDTA (final concentration 1 mg/mL), lithium-heparin (5 mL), and plain tubes (5 mL). Plasma and serum were harvested at 4C by low speed centrifugation (3000 rpm). Aliquots of plasma for lipid and lipoprotein measurements and assessment of circulating hepatic lipase activity, and serum for estradiol determination were used immediately.
Plasma lipids, lipoproteins, and lipoprotein fractionation
Plasma total cholesterol, triglyceride, and high density lipoprotein (HDL) cholesterol were determined by a modification of the standard Lipid Research Clinics Protocol (22). Very low density lipoprotein1 (VLDL1) (Sf 60–400), Very low density lipoprotein2 (VLDL)2 (Sf 20–60), intermediate density lipoprotein (IDL) (Sf 12–20), and LDL (Sf 0–12) were prepared from plasma by a modification of the cumulative gradient ultracentrifugation technique described by Lindgren (23). The cholesteryl ester, triglyceride, free cholesterol, phospholipid, and proteins of the lipoprotein were assayed as described (24), and concentrations were calculated as the sum of the components (expressed as mg/dL plasma). Isolation of LDL subfractions from fasting plasma was achieved by density gradient ultracentrifugation using a discontinuous salt gradient (25). The LDL subfractions were displaced from the tube by upward displacement and identified by continuous monitoring of elute at 280 nm. In all subjects, as in the normal population, three peaks of LDL were present, LDL-I, LDL-II, and LDL-III. The individual subfraction areas beneath the LDL profiles were quantified using Beckman Data Graphics software (Data Graphics; Beckman Industries, Fullerton, CA). Integrated areas were subsequently adjusted by specific extinction coefficients calculated previously for LDL-I, -II, and -III to give percentage abundance (% LDL). The total LDL mass (all protein and lipid components) of sequentially prepared LDL (d = 1.019–1.063 g/mL) was subdivided in proportion to the percentage abundance values to give plasma concentration of the LDL subfractions.
Circulating lipoprotein lipase activity
Circulating hepatic lipase (HL) activity was determined in fasting plasma using a method that has been developed in our laboratory to measure the low amounts of the enzyme normally present in the circulation, i.e. without heparinization, which is normally used to release all hepatic lipase bound to endothelial sites (26). Circulating HL has been shown to be in equilibrium with that bound to the liver and as a result demonstrates good correlation with postheparin HL activity (26).
Statistical analysis
The lipid and lipoprotein data were parametrically distributed as judged by the examination of normal probability plots. Nevertheless, as numbers were small, data are presented as medians and ranges. Comparisons of lipoprotein composition and of changes in circulating hepatic lipase activity between 10 and 35 weeks were performed by Students paired t-test. The level of significance required in comparisons of lipoprotein composition analysis were subject to Bonferroni correction.
Associations between initial triglyceride concentration, triglyceride/estrogen ratio, and final percentage abundance LDL-III were tested by calculating the Pearson correlation coefficient (R) and the coefficient of determination (R2), which was expressed as a percentage, (i.e. R2 gives the percentage of variation in the dependent variable, which is explained by variation in the independent variable). The significance of association between pairs of variables was determined by linear regression.
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Results |
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As pregnancy progressed from 10 to 35 weeks, median plasma
triglyceride and cholesterol concentration in our subjects rose from
0.78–2.55 mmol/L, and from 4.40–7.20 mmol/L, respectively (Table 2).
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Mean ([se]) circulating hepatic lipase activity fell by 40%
(P = 0.0007) from 24.9 (1.9) to 15.8 (2.3) µmol free
fatty acids/mL/min, between 10 and 35 weeks gestation. HDL-cholesterol
concentration increased from a median of 1.68 mmol/L at 10 weeks to a
maximum at 20 weeks gestation of 2.00 mmol/L, and thereafter fell to a
concentration at 35 weeks of 1.70 mmol/L (Table 2
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VLDL subfractions and IDL composition and concentration during pregnancy
The rise in plasma triglyceride between 10 and 35 weeks
encompassed the range of concentrations seen in a normal population of
premenopausal women (Table 2) (19). The concentration of the large
triglyceride-rich VLDL (VLDL1), increased from a median of
19 mg/dL to 109 mg/dL at 35 weeks (Table 3). There was a
parallel increase in the smaller cholesterol-rich VLDL subfraction,
VLDL2 (17–103 mg/dL), so that the ratio of
VLDL1 to VLDL2 remained constant. Examination
of VLDL1 and VLDL2 compositions (Table 4), indicated that the make-up of the particles was not
significantly different between 10 and 35 weeks despite the increase in
plasma triglyceride. Further, the composition of these fractions was
similar to that seen in a recent cross-sectional survey of healthy
adults (19).
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), and the particle became more triglyceride-rich as pregnancy
progressed (Table 4). LDL subfraction mass, composition, and profile
Total LDL mass increased during gestation in all subjects so that
the median concentration increased by around 70% (200–353 mg/dL)
between 10 and 35 weeks. Compositional analysis revealed that the
lipoprotein became enriched in triglyceride and depleted in cholesteryl
ester over the period (Table 4).
On examining LDL subfractions it was seen that, in four of the ten
subjects (ED, LC, KA, CH), no significant change in the LDL subfraction
pattern occurred throughout gestation, so that the relative proportions
of LDL-I, LDL-II, and LDL-III were relatively unaltered (see Fig. 1, CH as a representative example, and Figs. 2 and 3). In contrast, in the other six
women (AM, AP, EG, IL, RM, AS), the LDL subfraction pattern was
modified towards a smaller denser pattern in a manner suggestive of a
threshold transition (see Fig. 1, AM as a representative example, and
Figs. 2 and 3), with the proportion of LDL-III increasing at the
expense of LDL-II. Once again, the proportion of LDL-I remained
unchanged (Table 3). Overall, therefore, median percent LDL-I remained
relatively unaltered at between 17–20%, whereas LDL-II declined from
69–49% as the relative proportion of LDL-III doubled (14–32%)
(Table 3).
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). Relationship between serum estradiol and lipoprotein perturbations
From 10 weeks to 35 weeks of pregnancy mean serum estradiol
concentration increased steadily from a mean of 10 nmol/L to greater
than 78 nmol/L. For each individual there was a strong relationship
between the rise in estradiol and the increment in plasma triglyceride
(R2 0.71–0.98, mean R2 = 0.92; Fig. 4) and plasma cholesterol (R2 0.79–0.97,
mean R2 = 0.87, data not shown). It was noted, however,
that the slope of the association between increments in serum estradiol
and plasma triglyceride differed between subjects (see Table 5 and Fig. 4). Additionally, the magnitude of rise in serum estradiol during
gestation correlated significantly (R2 = 41.7%,
P = 0.044) with the change in HDL cholesterol between
10 and 35 weeks (Fig. 5).
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When the rate of change in plasma triglyceride for a given
increment in estrogen was calculated (see Table 5 and Fig. 4) it
appeared that the present cohort could be divided into two, those with
a gradient of less than 2 and those with a gradient of more than 2
(mmol/nmol [mult] 10-2). Five of the six subjects who
developed high LDL-III levels were in the latter category, whereas
three of the four women in whom LDL-III percentage remained relatively
unchanged were in the former category. Similarly, the subjects could be
divided on the basis of starting triglyceride levels (Table 5). In five
of the six in whom the profile was altered towards a smaller denser LDL
pattern, starting plasma triglyceride was 0.8 mmol/L or above, whereas
it was below this level in the four subjects in whom no change in LDL
subclass proportions was apparent. As a result, both the 10-week
triglyceride and the the ratio of increment in triglyceride corrected
for estrogen correlated with 35 weeks concentration of small, dense
LDL-III and together these two parameters accounted for 67%
(P = 0.021) of its variability.
In addition, it was notable that the 35-week concentration of
VLDL1 was greater than 100 mg/dL only in those individuals
in whom alteration in the LDL profile was apparent (2,
P < 0.001), whereas hepatic lipase activity was not
significantly different (P > 0.05) between those group
of individuals demonstrating no change in LDL subclass pattern compared
with those exhibiting a significant increase in percentage LDL-III
(Table 5).
Characteristics of threshold triglyceride levels
The alteration in the LDL subclass profile, if it occurred, was
observed at differing gestational times and plasma triglyceride
concentrations in each subject (Table 5 and Figs. 2 and 3); that is,
the "threshold" triglyceride level at which LDL-III concentration
began to increase substantially exhibited wide variation. In subject
AS, for example, the LDL pattern altered early, sometime between 10 and
15 weeks, corresponding to a plasma triglyceride of 1.1–1.6 mmol/L. In
contrast, in subject RM, alteration in the profile was not evident
until 30 weeks and therefore must have commenced sometime between
25–30 weeks and at a plasma triglyceride concentration of between
2.3–2.5 mmol/L.
With respect to gestational age, the alteration in profile was
evident earliest in those women (AS, EG, IL) with the highest 10-week
plasma triglyceride levels. In contrast, alteration in the profile was
evident at the lowest triglyceride concentrations in those women (AS
and AP) exhibiting the highest triglyceride to estrogen gradients.
Additionally, AS had by far the lowest HDL-cholesterol concentration
throughout pregnancy (1.35–1.15 mmol/L), whereas AP had the highest,
around a 10-fold increment (12–123 mg/dL) in VLDL1
concentration (Table 5).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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As pregnancy progressed and plasma triglyceride increased across the normal range, VLDL1 and VLDL2 increased in parallel. The significant rise in VLDL2 concentration during gestation corroborates the results of one previous study (5). The results of that study allied to our data further highlight the uniqueness of the hyperlipidemia of pregnancy. To elaborate, in the normal nonpregnant population, higher concentrations of plasma triglyceride are associated with preferential higher VLDL1 concentrations (19). This particle is secreted by the liver to supply tissues with triglyceride fatty acids in the postabsorptive state. The concentration of VLDL2, the principal precursor in the circulation to IDL and LDL, does not change as dramatically. In the normal adult population, a high concentration of VLDL1 is associated with a failure of insulin action and increased risk of coronary heart disease. In contrast, as pregnancy progressed and high triglyceride levels developed, VLDL1 and VLDL2 rose together so that their ratio, instead of increasing 2-fold, as would be predicted from population studies in the nonpregnant subjects (VLDL1 to VLDL2 ratio at a plasma triglyceride of 0.5 mmol/L is 1.0 compared with 2.0 at plasma triglyceride of 2.5 mmol/L) (19), remained constant.
In the absence of kinetic data, it remains unclear to what extent the increase in VLDL subclass concentrations represent increased synthesis or reduced catabolism. Estrogen mediated increased synthesis is likely to be the predominant mechanism in early pregnancy. Micronized ethinyl estradiol has been reported to increase large VLDL (VLDL1) production rates of healthy post-menopausal women 1.8-fold (27), whereas more potent estrogens in oral contraceptives have been shown to promote increased plasma levels of both large (3-fold) and small VLDL (2.2-fold) subclasses by increasing production rates of both particles, fractional catabolic rates remaining unchanged (28). It follows, therefore, that the significant elevations in estradiol seen in gestation may favour balanced elaboration of both VLDL subclasses. However, relative insulin resistance is a feature of late gestation (29) and may also contribute to increased VLDL1 levels.
Reduced catabolism of VLDL (specifically VLDL1), however, may be an additional factor for increased VLDL concentrations in late pregnancy as a significant reduction (around 50%) in postheparin lipoprotein lipase (LpL) activity, and a significant negative correlation between LpL activity and VLDL levels during pregnancy has been reported previously (9). From studies in rats (29) it is known that adipose tissue is the main site of the decreased LpL activity seen in late gestation and that this change is caused by insulin resistance.
The rise in IDL concentration during pregnancy has also been previously demonstrated (5, 6). It is notable, however, that the degree in elevation in IDL concentration was significantly greater (almost double) than previously reported (19) in nonpregnant individuals for a similar increment in plasma cholesterol. This is in keeping with the markedly elevated VLDL2 levels in pregnancy and subsequent delipidation to IDL in the circulation. In line with previous studies (6, 7), as pregnancy progressed IDL and LDL particles became triglyceride-enriched, reflecting in part estrogen mediated inhibition of hepatic lipase activity with resultant reduced triglyceride hydrolysis of IDL and LDL particles, and second, an increase in the interchange of neutral lipids between lipoproteins (7, 30).
Recent work from our laboratory (12, 19) has suggested the presence of a critical triglyceride threshold at which significant changes in LDL subclasses may occur. The current longitudinal data from individual subjects, studied repeatedly during the appearance of the physiological hyperlipidemia, provides additional strong support for this important concept. In all subjects with the exception of AS, percent LDL-III (and LDL-III mass) changed little in early gestation despite increasing triglyceride concentrations. However, as gestation progressed and plasma triglyceride levels increased further, in six of the ten subjects the LDL profile changed dramatically with the proportion of LDL-III (and therefore LDL-III mass) increasing simultaneous to a decrease in LDL-II. Because we sampled at 4-week intervals, we were able to determine only an approximate gestational age or plasma triglyceride concentration at which LDL profile change first occurred. Nevertheless, there appeared to be considerable variation between individuals in the gestational age and plasma triglyceride intervals at which change in the LDL profile first manifested. In general, the alteration in profile towards small dense LDL-III was earliest in those individuals with the highest initial 10-week triglyceride concentrations. However, it may be significant that LDL profile alteration occurred at the lowest triglyceride concentrations in the two individuals with the highest triglyceride to estrogen increments, and that one of these two individuals had the lowest HDL-cholesterol level, whereas the other had the greatest proportional increase in VLDL1. Both low HDL-cholesterol and raised VLDL1 concentrations are associated with insulin insensitivity, and although none of our subjects developed frank glucose intolerance, relative insulin insensitivity may be linked to earlier LDL profile shift during pregnancy.
In each of the six patients in whom LDL profile change took place, as plasma triglyceride increased further the decrease in the proportion of LDL-II accompanying the dramatic LDL-III rise caused LDL-II mass to plateau and then decline (data not shown). In the other four patients, LDL subclass pattern did not alter by 35 weeks of gestation. Significantly, these four subjects also had the lowest triglyceride increments in gestation and presumably did not reach their critical threshold triglyceride concentration. These observations therefore provide a basis for understanding the previous relationships between LDL subclasses and plasma triglyceride described in population studies.
The most widely accepted mechanism of LDL subclass formation and modulation is that of neutral lipid exchange (12, 19). This process involves the transfer of triglyceride from triglyceride-rich lipoprotein (VLDL1 and chylomicron remnants) into the core of LDL in exchange for cholesteryl esters, a reaction mediated by cholesterol ester transfer protein (CETP). Although CETP activity has been shown to increase significantly by the second trimester of pregnancy before declining towards gestation (30), in most normal situations the activity of this enzyme is not rate limiting (31). In contrast, it is likely that VLDL1 concentration determines the rate of of triglyceride transfer into LDL since large triglyceride-rich VLDL is a preferred substrate for cholesteryl ester transfer protein action (32). It follows that during pregnancy, progressively increasing circulating concentrations of VLDL1 promote triglyceride enrichment of LDL particles. The subsequent hydrolysis of this newly acquired triglyceride in LDL via the action of hepatic lipase, even when the activity of this enzyme is low as in pregnancy, results in the remodelling of LDL subclasses into smaller, denser species. Nevertheless, as we have now shown, remodelling of LDL particles towards smaller, denser particles does not proceed immediately but requires in each individual patient that a specific triglyceride threshold is attained.
Why should there be a threshold for the formation of small, dense LDL? The recent model proposed by Tan et al. (19) is that a step-wise change in size from LDL-II to LDL-III occurs when HL acts upon a triglyceride-enriched LDL particle. It may be speculated that LDL-II has to have a certain minimum triglyceride enrichment so that in a single exposure to the lipase, sufficient surface and core lipids are removed to generate a conformational change in apolipoprotein B to a new, thermodynamically stable state, characteristic of LDL-III. Indeed, there is recent evidence (33, 34) to support the idea that apolipoprotein B configuration differs between small and large LDL.
Finally, it is noteworthy that triglyceride increments were minimal in those subjects who entered pregnancy with low basal triglyceride concentrations, whereas those subjects who entered pregnancy with higher basal triglycerides showed greatest increases and were frankly hyperlipidemic by 35 weeks. This was not because of differences in the increments in serum estradiol but may reflect different responses to estrogen stimulated hyperlipidemia. That is, pregnancy may reveal a latent hyperlipidemia caused possibly by an inherited lipolytic problem. We are not the first to suggest this possibility. Montes et al. (35) have described case examples of subjects who have triglyceride levels that are above the ninety-fifth percentile values at 36 weeks gestation and return to normal postpartum, but hyperlipidemia is present among family members. Interestingly, these subjects also appeared to have lower HDL cholesterol concentrations when not pregnant. It would be of interest to confirm these findings in larger studies.
In conclusion, the present study makes several new and important observations: 1) as plasma triglyceride increases in pregnancy, there are parallel rises in median concentrations of VLDL1, VLDL2, and IDL, around 5-fold; 2) as a result of this progressive increase in plasma triglyceride, in particular in VLDL1, the LDL profile is altered in some individuals towards smaller, dense particles; 3) in general, the higher the initial (booking) fasting plasma triglyceride concentration or the larger the rate of change in triglyceride for a given increment in estradiol, the greater the probability of change in LDL profile towards smaller denser species; 4) significantly, LDL subclass change towards smaller denser species occurs not in a gradual and progressive manner, but exhibits threshold behavior; and finally, 5) this threshold is achieved at differing gestational ages and triglyceride concentrations for different women.
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Acknowledgments |
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Footnotes |
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Received November 21, 1996.
Revised April 7, 1997.
Accepted April 27, 1997.
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