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Annals of Clinical & Laboratory Science 37:335-342 (2007)
© 2007 Association of Clinical Scientists

Gender Influence on Postprandial Lipemia in Heterozygotes for Familial Hypercholesterolemia

Genovefa D. Kolovou1, Katherine K. Anagnostopoulou1, Dimitris S. Damaskos1, Constantinos Mihas2, Sofia Mavrogeni1, George Hatzigeorgiou1, Theodor Theodoridis3, Dimitri P. Mikhailidis4 and Dennis V. Cokkinos1
1 First Cardiology Department, Onassis Cardiac Surgery Center, Athens, Greece; 2 Internal Medicine Department, General Hospital, Kimi, Greece; 3 Hematology Department, Evagelismos Hospital, Athens, Greece; and 4 Department of Clinical Biochemistry, Royal Free Hospital, Royal Free and University College Medical School, London, UK

Address correspondence to Genovefa D. Kolovou, M.D., Onassis Cardiac Surgery Center, 356 Sygrou Ave, 176 74 Athens, Greece; tel 30 210 949 3520; fax 30 210 949 3336; e-mail: genovefa{at}kolovou.com.


   Abstract
Top
 Abstract
Introduction.
 Materials and Methods
 Results
 Discussion
 References
 
The aim of this study was to evaluate the influence of gender differences on triglyceride (TG) response after a fatty meal in clinically defined heterozygous (h) patients with familial hypercholesterolemia (FH). Nineteen hFH men were age-matched with an equal number of premenopausal women. Plasma TG was measured before and 2, 4, 6, and 8 hr after a standardized fat load. The men with hFH had a greater body mass index (BMI) than hFH women. An abnormal postprandial response was observed in 63% and 16% of hFH men and women, respectively. The mean TG-area under the curve value was higher in hFH men compared to hFH women. Both gender (p = 0.032) and BMI (p = 0.006) equally affected postprandial TG response, but fasting TG levels (p <0.001) were the main determinant. In summary, hFH men have higher BMI, fasting TG level, and postprandial TG level, compared to age-matched premenopausal hFH women, which may partially explain the earlier onset of coronary heart disease in hFH men.

Keywords: familial hypercholesterolemia, coronary heart disease, postprandial lipemia, men vs women


   Introduction.
Top
 Abstract
 Introduction.
Materials and Methods
 Results
 Discussion
 References
 
Familial hypercholesterolemia (FH) is an autosomal dominant disease, defined at the molecular level by mutations in the low-density lipoprotein (LDL) receptor gene. There are over 900 such mutations and the clinical manifestations vary among patients, as they are additionally influenced by factors such as age, gender, and life style. The onset of FH complications appears to be gender-dependent, since heterozygous (h) FH women develop coronary heart disease (CHD) about 10–15 yr later than hFH men [1]. Further, in the Cholesterol and Recurrent Events Study, pravastatin was more effective in preventing recurrent events in women than in men with CHD but not FH (risk reduction was 46% vs 29%, respectively) [2]. During this 5-yr study, the observed benefit occurred in women about 2 yr earlier than in men [2].

It took a long time for plasma triglyceride (TG) to be established as an independent CHD risk factor. Although TG often appears as a risk factor in univariate analyses, the relation is weakened or disappears in multivariate analyses that control for high-density lipoprotein (HDL) cholesterol [3]. A meta-analysis of 17 prospective population-based studies found hypertriglyceridemia to be an independent risk factor for CHD [4]. In fact, hypertriglyceridemia was the most common lipid abnormality seen in two-thirds of the women with CHD; the next most frequent abnormality was elevated TG with reduced HDL cholesterol [5]. Hokanson and Austin’s meta-analysis of multiple studies demonstrated that an 80 mg/dl increase in TG elevates CHD risk by 75% in women and 30% in men [6]. Elevated TG also serves as a marker for increases in TG-rich remnant lipoproteins produced during postprandial lipemia. Fasting TG level is the main predictor of postprandial hyperlipidemia magnitude. However, an abnormal postprandial outcome is also observed in subjects with normal TG levels. Karpe [7] suggested that elevated plasma TG measured at late postprandial time points after fat intake may reveal a state of fat intolerance linked to an elevated risk of CHD that is under genetic control and cannot always be detected by simple measurement of fasting plasma TGs. Since a large part of our lives is spent in a fed state, postprandial lipemia may be a more accurate CHD predictor than a fasting lipid profile by itself.

Therefore, another entity strongly associated with CHD is postprandial hypertriglyceridemia [8,9] which is characterized by the accumulation in the postprandial state of potentially atherogenic remnants of TG-rich lipoproteins, namely chylo-microns, very low-density lipoproteins (VLDL), and their remnants [10–12]. We hypothesized that abnormal postprandial TG clearance in hFH patients could be one of the reasons for gender heterogeneity in the risk of CHD. Therefore, we investigated whether gender-related factors are associated with increased protection from post-prandial lipemia in hFH women compared to age-matched hFH men.


   Materials and Methods
Top
 Abstract
 Introduction.
 Materials and Methods
Results
 Discussion
 References
 
Subjects.  We recruited hFH men (n = 19) and women (n = 19) aged ≥45 yr from the Lipid Clinic of the Onassis Cardiac Surgery Center in Athens, Greece. The subjects were age-matched. Heavy drinking, liver and renal disease, obesity, diabetes mellitus, hypertension, metabolic syndrome, hypothyroidism, and professional sport activity were exclusion criteria. All subjects were attending the clinic for the first time and none was receiving hypolipidemic treatment. The diagnosis of hFH was based on the following clinical criteria: (a) total cholesterol >290 mg/dl and LDL cholesterol >190 mg/dl, (b) presence of tendon xanthomas in the patient or in a 1st or 2nd degree relative, and (c) history of premature vascular disease in a first degree relative (>60 yr old) or in a second degree relative (>50 yr old) [13]. Smokers were defined as those who are or used to be smokers; non-smokers were defined as those who have never smoked.

This study is part of a series evaluating postprandial lipemia and FH and data from a number of our subjects have previously been used in 2 of our studies [14,15]. To our original pool of 46 patients, 13 hFH men and 9 hFH women were added; from that overall group of patients, a selection was performed to satisfy the criterion of matching age. This is our first study that directly compares age-matched men and premenopausal women. The center’s Institutional Review Board approved the study and all participants gave their informed consent. The study population was divided into 2 groups: (a) hFH premenopausal women, comprising 19 women age ≤45 yr (the women were considered premenopausal, since they had an unchanged and regular menstrual pattern for the previous 2 yr), and (b) hFH men, comprising 19 men, age-matched with the hFH women.

Fat-rich meal protocol and blood samples.  All patients were studied in the outpatient clinic between 8 am and 9 am after a 12 hr overnight fast. The fatty meal was consumed within a 20 min time span and plasma TG concentrations were measured before and at 2, 4, 6, and 8 hr after the fat load. During this 8 hr period, the participants had nothing to eat, drank only water, and did not smoke. In all 5 blood samples, plasma TG concentration was measured. Total cholesterol, HDL cholesterol, apolipoprotein A and B, lipoprotein(a), insulin, and glucose levels were measured only in the fasting state, since it has been shown that their levels do not present significant alterations postprandially [16]. Body mass index (BMI) was calculated as weight divided by height squared (expressed in kg/m2).

Fatty meal.  The fatty meal has been previously described [16]; briefly, this is a slight modification of the meal described by Patsch et al [17], consisting of 83.5% fat, 14.0 % carbohydrate, and 2.5 % protein. The total amount of the meal that patients consumed was based on their body surface areas (350 g per 2 m2). Since there are no official guidelines for postprandial TG level values, >220 mg/dl was considered an abnormal response to the fat load, in accordance with previous studies [16,18,19]. Thus, a TG response to the fatty meal was considered abnormal when any of the postprandial TG concentrations (at 2, 4, 6, or 8 hr) was higher than the highest TG concentration (220 mg/dl) observed in healthy subjects, during any time in our previous studies [16,18].

Determination of blood lipids and glucose.  Plasma total cholesterol, TG, and HDL cholesterol were measured using enzymatic colorimetric methods on a Roche Integra biochemical analyzer, with commercially available kits (Roche). The serum LDL cholesterol level was calculated using the Friedewald formula [20] in patients with TG levels <400 mg/dl. Apolipoprotein A, B, and lipoprotein(a) were measured by nephelometry (Nephelometer BN-100, Behring, Germany). Blood glucose was assayed by the hexokinase reaction with Dade Behring reagents and a Dimension (Dade Behring) analyzer. All samples were analyzed within 24 hr.

Statistical methods.  Values with numerical characteristics were tested for normality using the Shapiro-Wilk statistic. According to the results of the analysis, all but 2 variables deviated from normality; therefore their descriptive statistics are presented as median and inter-quartile range, except for BMI and apolipoprotein A, which had normal distributions and are shown as means and standard deviations. The Mann Whitney U statistic and Student’s t-test for independent samples were used to compare numerical values in the 2 groups of subjects. The comparison of clinical categorical variables was performed using Chi-square or Fisher’s exact tests, when at least one cell of the 2x2 table had an expected count less than 5. Area under the curve (AUC) for serial measurements of TG levels at baseline and after the fatty meal was calculated using the trapezoid rule. The incremental AUC was calculated after subtracting the baseline TG levels from the TG levels after the fatty meal for each patient. In order to assess the role of gender, BMI, HDL cholesterol, fasting TG, and fasting glucose levels on the abnormal TG response to fat load, we performed univariate and multivariate median (least absolute value) regression analysis, where the TG-AUC was the dependent variable and the aforementioned parameters the independent (explanatory) variables, since the candidate variables did not distribute normally. Calculation of the t statistic was performed in order to assess the significance of each dependent variable, and of the pseudo R2, which is a measure of how the model explains the variability of the dependent variable similar to the R2 statistic of linear regression. Cut-off point analysis using the receiver operating characteristic (ROC) curve was applied to evaluate the BMI level by which to achieve the best predictive ability regarding abnormal TG response. All tests were two-sided and the significance level was p <0.05. Data were analyzed using STATA (Version 9.0, Stata Corp., College Station, TX).


   Results
Top
 Abstract
 Introduction.
 Materials and Methods
 Results
Discussion
 References
 
All participants ingested the individually calculated fatty meal and tolerated it well. The clinical characteristics of all participants are shown in Table 1Go. The hFH men had higher BMI than the hFH women (p <0.001). Fasting plasma TG levels were higher in hFH men, but still within the reference range (TG <150 mg/dl) as defined by the NCEP Adult Treatment Panel (ATP) III, compared with the hFH women [140 (90) vs 77 (32) mg/dl, p = 0.004].


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  		Table 1. Clinical characteristics of the study groups.
 
Postprandial TG levels at 2, 4, 6, and 8 hr after the fatty meal as well as the TG-AUC values were higher in the hFH men compared to the hFH women (Table 1Go). Three of 19 (16%) in the hFH female group and 12 of 19 (63%) in the hFH male group had an abnormal TG response to the fatty meal.

Using univariate models (Table 2Go and Fig. 1Go), both BMI (p = 0.006) and fasting TG level (p <0.001) have positive correlation with the postprandial TG level, whereas female gender has negative correlation (p = 0.032). Additionally, fasting plasma TG levels seem to best explain the variability of postprandial TG value, having a greater R2 compared to BMI and gender (0.554 vs 0.163 and 0.159, respectively). Fasting glucose level, HDL, and waist circumference did not significantly affect postprandial TG levels.


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  		Table 2. Median regression analyses of postprandial TG data (expressed as TG-AUC) using univariate models.
 

Figure 1
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  		Fig. 1. Scatter plots of BMI and AUC-TG in men and women. BMI = body mass index. AUC-TG = area under the curve of plasma triglyceride concentrations.

 
A multivariate model that tested the combined effect of gender and BMI on TG-AUC showed that both explanatory variables did not significantly predict the dependent variable (coefficients: –415.17, 38.77; p values: 0.176, 0.432, respectively). However, when the same multivariate model was calculated having as dependent variable the TG level at each time period after the fatty meal (ie, 2, 4, 6, and 8 hr), a significant effect of gender on TG levels at 4 and 8 hr was found, after adjusting for BMI (gender coefficients: –81.22, –68.61; p values: 0.047, 0.013, respectively). BMI did not have a significant effect in any of the aforementioned models.

While comparing the men with the lowest fasting plasma TG levels (n = 8) to the group of hFH premenopausal women (n = 19), we note that although baseline TG levels are comparable [87.3 (29.4) vs 87.8 (52.1) mg/dl, p = 0.978], there is a significant difference in regard to postprandial lipemia at 2 and 4 hr after the fatty meal [179.6 (80.4) vs 110.9 (41.7) mg/dl, p = 0.010 and 220.1 (108.7) vs 141.8 (67.5) mg/dl, p 0.039, respectively].

The cut-off point analysis showed that BMI >25.25 kg/m2 was the optimal point that discriminated those who had an abnormal TG response after the fatty meal (sensitivity = 75% and specificity = 84%; area under the ROC curve = 0.776).


   Discussion
Top
 Abstract
 Introduction.
 Materials and Methods
 Results
 Discussion
References
 
We compared the postprandial TG response between men and premenopausal women who were clinically diagnosed as FH heterozygotes, a frequent (1:500) genetic metabolic disorder that leads to premature CHD in both sexes. The cohorts were age-matched (women 33 (11) yr vs men 32 (12) yr), had fasting blood lipid profiles with baseline TG levels within normal limits as defined by ATP III, though there was a significant difference between the two groups (p = 0.004), and comparable general characteristics. Therefore, it is likely that any differences observed between our subjects could be interpreted in the context of gender and differences in sex hormones, in addition to the known effects of BMI and baseline TG level.

In hFH subjects the production rate of VLDL apoB-100 is increased and this is even more pronounced in FH homozygotes with a null mutation that results in a negative receptor phenotype [21]. When compared to healthy controls, the VLDL apoB-100 production rate has been reported 50% higher in heterozygotes and 109% higher in homozygotes [21]. Based on animal studies, Twisk et al [22] showed that the LDL receptor binds apoB intracellularly and targets it for degradation, as well as capturing newly secreted VLDL for internalization and turnover. Therefore, in our carrier subjects who have LDL receptor insufficiency, neither pre-secreted apoB degradation nor re-uptake of nascent VLDL is carried out to the same degree as in subjects with physiological LDL receptors, thus resulting in an increased VLDL production rate. This process creates VLDL particles enriched in cholesterol and depleted in TG and could explain the low TG levels observed in most of our patients (82% in total had fasting TG levels <150 mg/dl; 18 women and 13 men, respectively). Only 16% of hFH women had fasting plasma TG levels >100 mg/dl compared to 74 % of hFH men, a difference that can in part be attributed to the higher BMI of the latter group. However, our results indicate a significant association of gender and postprandial TG response, even after adjusting for BMI.

Although the combined effects of gender and BMI on TG-AUC were not significant, we have reason to believe that they neutralized one another since a significant correlation of gender and TG response was found at 4 and 8 hr after the fatty meal, adjusting for BMI. In addition, 68% of the hFH men still had a normal fasting TG level as defined by ATP III (TG <150 mg/dl). This could be of importance especially in women, for whom the LDL cholesterol level is not as strong a predictor of CHD [23,24], while the TG level has a greater, albeit underestimated, predictive power [23,25]. According to our results, hFH men have 82% higher fasting TG levels than hFH women during their third decade, a difference that, to our knowledge, has not been reported in other studies.

An alternative explanation for the increased VLDL levels involves more intense endogenous cholesterol synthesis in hepatic cells due to the lack of exogenous cholesterol uptake, leading to an enhanced hepatic secretion rate of apoB-containing liporpoteins [26]. Since VLDL are rapidly converted to intermediate low-density lipoproteins (IDL) and then to LDL, the increased VLDL production gives rise to increased LDL particles. In addition, small VLDL (Svedberg flotation unit 20 to 60) and IDL (Svedberg flotation unit 12 to 20) are able to cross the endothelial barrier to enter the arterial intima [27]. Both of these these pathways may promote the atherosclerotic process.

The reason why FH patients have increased post-prandial triglyceride levels, compared to normal individuals [15], rests on the fact that TG-rich lipoproteins (chylomicrons, VLDL, and their remnants) are partly catabolized by hepatic LDL receptors, in addition to LDL receptor related protein. Specifically, TG-rich lipoproteins and their remnants compete for the same removal pathway as LDL particles, with chylomicron remnants requiring 4 receptors for binding compared to 1 receptor per LDL particle [28,29]. Furthermore, in FH subjects there is substantial accumulation of small, dense chylomicron particles even in the fasting state [30]. These observations suggest that in LDL receptor-deficient states, postprandial as well as fasting TG levels are prone to increases.

Ageing in women leads to greater variation in fasting TG levels, suggesting that loss of endogenous estrogens is associated with loss of the tight regulation of plasma TG [31]. Little information is available regarding the direct effect of sex hormones on human fatty acid metabolism. The available data suggest that female sex steroids (estrogen and progesterone) may modulate plasma free fatty acid turnover [32,33]. Animal studies indicate that estrogens can improve the clearance of chylomicrons and remnant particles [34]. This estrogen effect has also been described in humans. Thus, van Beek et al [31] assessed the effect of natural menopause on postprandial lipemia comparing the postprandial response of postmenopausal with premenopausal women matched for age and BMI. Even with identical fasting TG levels, incremental TG levels (after subtraction of baseline TG) were different in postmenopausal vs premenopausal women (p = 0.023). Similarly, our group has shown that postmenopausal hFH women have higher baseline TG levels and greater TG-AUC when compared to premenopausal women and they lose their normal postprandial response [14].

Exogenous estrogens can also improve the postprandial lipid response. Jensen et al [35] administered estrogen to postmenopausal women and reported an increase of 10–20% in adipose tissue lipolysis, suggesting that estrogen deficiency is associated with increased plasma free fatty acid availability. Westerveld [36] reported that replacement therapy with 17beta-estradiol improved post-prandial lipid metabolism, increasing the clearance of chylomicron remnants by 41% [36]. Interestingly, during a normal menstrual cycle, the cyclic changes in estrogen and progesterone production have minor, if any, effects on free fatty acid mobilization [37]. During the menopausal transition,, the BMI tends to increase [38].

An overall beneficial effect of estrogens is also evident in the present study with premenopausal hFH women having a better postprandial response to a fatty meal compared to age-matched hFH men. At 2, 4, 6, and 8 hr after the fatty meal, hFH men had significantly delayed and exaggerated TG clearance compared to hFH women.

Acquiring a greater number of subjects with similar baseline TG levels would provide further information regarding the influence of gender and sex hormones on postprandial lipemia. It would be interesting to compare age-matched postmeno-pausal hFH women and hFH men, where less significant differences would be expected, based on this study and our previous data [14,15]. The present open cross-sectional comparison of age-matched hFH men and women has certain limitations. We determined the premenopausal state of our subjects clinically without using any hormone measurements. Furthermore, the mean BMI value was different in our groups, though 95% of the males were not obese (mean BMI <26 (2.3) kg/m2) and the effect of BMI was controlled in multivariate modeling.

In conclusion, this study shows that post-prandial lipemia in hFH subjects must be considered in the context of gender, baseline TG level, and BMI. Premenopausal hFH women appear to be protected from exaggerated postprandial lipemia and female gender is negatively associated with postprandial TG levels. These relationships may in part explain the later onset of CHD in hFH women. As for hFH men, they should further minimize CHD risk factors that affect postprandial lipemia such as BMI. The current study shows that BMI in hFH men should not exceed 25.25 kg/m2 in order for postprandial lipemia to remain within normal ranges. Fasting TG levels may predict an abnormal lipemic response to a fatty meal.


   References
Top
 Abstract
 Introduction.
 Materials and Methods
 Results
 Discussion
 References
 

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Angiology, August 1, 2008; 59(2_suppl): 54S - 57S.
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