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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 6 2946-2950
Copyright © 2004 by The Endocrine Society

Lipoprotein Remnants and Endothelial Dysfunction in the Postprandial Phase

Franco Maria Maggi, Sara Raselli, Liliana Grigore, Laura Redaelli, Simona Fantappiè and Alberico Luigi Catapano

Department of Pharmacological Sciences (F.M.M., A.L.C.), University of Milan, 20133 Milan, Italy; and Center for the Study of Atherosclerosis (F.M.M., S.R., L.G., L.R., S.F., A.L.C.), Bassini Hospital Cinisello Balsamo, Milan, 20092 Italy

Address all correspondence and requests for reprints to: Professor Alberico L. Catapano, Department of Pharmacological Sciences, University of Milan, Via Balzaretti, 9 20133 Milan, Italy. E-mail: alberico.catapano{at}unimi.it.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
The objective of this work was to study whether changes in remnant lipoprotein (RLP) plasma levels during the postprandial phase relate to alterations of the endothelial function.

Fasted patients (15 moderately dyslipidemic men) were given an oral fat load (OFL), and blood samples were collected before the OFL ingestion (T0) and 2, 4, 6, and 8 h (T2, T4, T6, T8) thereafter. Endothelial function, determined as flow-mediated dilatation (FMD) of the brachial artery, was assessed at the same time points.

Triglyceridemia peaked between T4 (5.48 ± 0.64 mmol/liter) and T6 (5.34 ± 0.89 mmol/liter) and decreased at 8 h (4.36 ± 0.87 mmol/liter) after the OFL. FMD decreased significantly 6 h after the OFL consumption (from 16.03 ± 1.32% to 11.53 ± 1.42%, P < 0.01). Cholesterol in RLPs increased steadily up to 6 h and decreased at 8 h (T0 0.53 ± 0.10, T6 0.81 ± 0.11, T8 0.73 ± 0.13 mmol/liter). Fasting levels of triglycerides and cholesterol-RLPs (C-RLPs) correlated significantly with FMD at baseline. The decrease in endothelial function at 6 h also significantly correlated with the area under the curve of triglycerides (R = 0.53, P = 0.04). Postprandial C-RLPs (area under the curve), however, showed the best correlation with the decrease of FMD (R = 0.63, P = 0.012). The correlation persisted in a multivariate analysis.

We concluded that C-RLPs contribute significantly to the endothelial dysfunction occurring during the postprandial lipemia.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
ATHEROSCLEROSIS IS AN inflammatory disease involving the presence of both intra- and extracellular lipid deposits in arteries. More than 20 yr ago, Zilversmith (1) hypothesized that processes that occur during the postprandial phase are proatherogenic. Several clinical and experimental data suggest, in fact, that elevated postprandial lipemia is related to the presence of coronary artery disease (CAD) (2) and is an independent risk factor for coronary atherosclerosis (3). The role of the endothelium in the pathogenesis of cardiovascular diseases is well recognized (4). A close correlation exists between the presence of cardiovascular risk factors and a decrease of the endothelial vasodilator function (5). Endothelial function is reduced in patients with CAD (6, 7) or myocardial ischemia (8, 9). Furthermore, endothelial dysfunction predicts the recurrence of cardiovascular events (4, 10, 11) and progression of atherosclerotic disease (10).

The control of the main risk factors improves endothelial function. In fact, total cholesterol fasting levels (12, 13) are inversely related to the endothelial function; this condition is rapidly improved upon cholesterol reduction as best illustrated by the dramatic changes occurring after low-density lipoprotein (LDL) apheresis in familial hypercholesterolemia patients (14).

The endothelial function is transiently reduced in normocholesterolemic and hypercholesterolemic subjects during postprandial lipemia (15, 16, 17, 18). The lipoprotein fraction(s) that may be involved in determining such an effect are unknown. Fasting remnant lipoprotein (RLP) plasma levels correlate directly with the endothelial dysfunction in peripheral (19) and coronary arteries (20), and changes in the postprandial phase correlate with the fasting endothelial function (21). Furthermore, RLP levels are strongly associated with angiographically verified progression of focal coronary atherosclerosis (22), and their lowering with gemfibrozil prevents vein graft stenosis (22). In addition, RLP levels are significantly increased after a fat loading (23).

This burden of evidence prompted us to investigate whether changes in RLP levels during the postprandial phase affect endothelial function.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

Fifteen patients, all males, were recruited into the study. The inclusion criteria were age 30 to 70 yr; body mass index less than 30 kg/m2; a fasting lipid profile typical of moderate dyslipidemia; and absence of hypertension, diabetes, or a personal or familiar history of CAD (Table 1Go). No subjects were taking cardiovascular active drugs or antioxidant supplements. The presence of secondary forms of dyslipidemia such as kidney disease, diabetes, hypothyroidism, chronic liver disease, or the use of ß-blockers were excluded. The study was performed in a period of 3 months.


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  		TABLE 1. Inclusion criteria

 
Written informed consent was obtained from all patients before the study. The ethics committee of the center approved the study. The investigation conforms to the principles outlined in the Declaration of Helsinki.

Experimental procedures

Fasted patients consumed in the morning an oral fat load (OFL) (caloric composition: 82% fats, 9% proteins, 9% carbohydrates) with a total caloric intake of 693 kcal and 446 mg cholesterol per square meter of body surface. The meal was semisolid and subjects were allowed 10 min to consume it (cholesterol 890 mg), and blood samples were collected in test tubes containing NaEDTA (0.1 mg/ml) before the OFL ingestion (T0) and 2, 4, 6, and h (T2, T4, T6, T8) thereafter. The OFL protocol is a modification of the test proposed by Patsch et al. (24). During the OFL only water was allowed. The time schedule of blood drawing also was used for the flow-mediated dilatation (FMD) test, performed on the controlateral arm.

Endothelial function was evaluated noninvasively by B-mode ultrasonography (Biosound Au4 idea, Indianapolis, IN; with a 10-MHz linear array transducer) on the brachial artery, as previously described by our group (25). Briefly, each subject was requested to lie at rest for 10 min in a temperature-controlled room (21 C + 1), and the first scan was taken. This was followed by inflation of a standard pneumatic tourniquet placed around the upper arm at a pressure of 250 mm Hg, followed by deflation after 4.5 min. Electrocardiography was monitored continuously during the study and measurements were taken at the diastole. The reproducibility of the assay was determined by repeating the measurement on 15 subjects on consecutive days by the same observer. The coefficient of variation of the assay was 7%. During each test, vessel images were taken at rest and during reactive hyperemia: FMD was calculated as the percentage in variation between the basal diameter and the maximum diameter 90–210 sec after the deflation of a pneumatic tourniquet. This method has previously been shown to be accurate and reproducible for measurement of small changes in arterial diameter (26, 27), with low interobserver error (26, 27). Endothelial function tested by this method in the brachial artery is due predominantly to nitric oxide release by the endothelium (28). The test was performed by one of the authors (S.R.); she was unaware of the laboratory measurements that were performed in a blinded fashion. Lipid profiles (total cholesterol, high-density lipoprotein cholesterol) in the fasting condition and plasma triglycerides (TG), fasting, and 2-, 4-, 6-, and 8-h samples after OFL consumption were evaluated by colorimetric test (ABX for Cobas Mira Plus, Montpellier, France) using standardized procedures. Apolipoprotein (Apo) AI and Apo B fasting plasma levels were measured by a turbidimetric assay (ABX for Cobas Mira Plus). Cholesterol in RLPs was assessed at the same time points using the JIMRO-II kit (Japan Immunoresearch Laboratories, Takasaki, Japan) based on the immunoprecipitation of ApoB/ApoA1-containing particles followed by determination of the cholesterol concentration in the supernatant (29, 30, 31, 32).

Statistical analysis

All data were expressed as mean ± SE; the limit of significance was set for P < 0.05. Statistical analysis was performed using CSS Statistica software (Statsoft, Tulsa, OK): the Student’s t test for repeated determinations was used to evaluate the mean changes in TG, FMD, and RLPs in postprandial phase, compared with fasting values. The Pearson’s correlation analysis was used to evaluate the relations between FMD and all other variables. All significant correlations at T0 or T6 were entered in a forward stepwise correlation analysis using the same software.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Characteristics and the fasting lipid profile of the patients enrolled into the study are reported in Table 1Go. The patients were of middle age, and moderately overweight plasma lipids profile is consistent with the presence of moderate mixed dyslipidemia.

The changes of plasma TG during the postprandial phase are depicted in Fig. 1AGo. Plasma TG peaked between 4 and 6 h and began to decrease 8 h after OFL, although the TG did not return to baseline levels (2.44 ± 0.37 mmol/liter at T0, 3.90 ± 0.48 mmol/liter at T2, 5.48 ± 0.64 mmol/liter at T4, 5.34 ± 0.89 mmol/liter at T6, 4.36 ± 0.87 mmol/liter at T8, respectively). The increases of TG plasma levels were significant at all times (P < 0.01).



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  		FIG. 1. Postprandial change in plasma lipids (A and B) and FMD (C). The variables were determined after an OFL at the indicated times. Points represent the mean ± SE of 15 patients. For experimental details, see Patients and Methods. *, P < 0.05; **, P < 0.01 with the Student’s paired t test.

 
The changes in RLPs-cholesterol (C-RLPs) during the postprandial phase are also shown in Fig. 1BGo: C-RLPs increased significantly and continuously up to 6 h and decreased slightly at 8 h (from 0.53 ± 0.10 mmol/liter at T0, to 0.60 ± 0.10, 0.73 ± 0.09, 0.81 ± 0.11, and 0.73 ± 0.13 mmol/liter at T2, T4, T6, and T8, respectively). In the postprandial phase, the vasodilatation of brachial artery during hyperemia (FMD) decreased significantly after 6 h (11.53% vs. 16.03%, P < 0.01; Fig. 1CGo).

Of all parameters tested at T0, only two related with FMD: fasting plasma TG and fasting remnant cholesterol levels (Table 2AGo, P = 0.033 and 0.040, respectively).


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  		TABLE 2. Correlations among variables at time (T) 0 and FMD at T0 (A) and correlations among postprandial variables and changes in FMD at T6 (B)

 
Postprandial lipemia, measured as plasma TG levels area under the curve (AUC), significantly correlated with the decrease of endothelial function at 6 h after the OFL (Table 2BGo, P < 0.04). Postprandial C-RLPs (AUC) also correlated with the changes on the endothelial function (Table 2BGo, P < 0.007).

We then analyzed the data in a multivariate analysis in a stepwise fashion. The only parameter that related to the FMD at T0 was the fasting plasma TG levels (P < 0.033), whereas in the postprandial phase, the only parameter whose correlation persisted with the delta in FMD was the AUC for the remnants (P < 0.027).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Endothelial dysfunction is believed to be a proatherogenic condition (6, 7, 9) and predicts cardiovascular events (4, 10, 11). All major coronary risk factors (e.g. LDL, TGs, hypertension, smoking, diabetes, elevated homocysteine) can affect endothelial function (12, 13, 14, 25, 26, 33, 34). It has been reported that fasting levels of lipoprotein remnants predict endothelial dysfunction (21). We confirmed and expanded the latter finding because both fasting RLPs (R = –0.53 P = 0.040) and fasting plasma TG (R = –0.55; P = 0.033) correlate with the basal level of FMD. However, in a multivariate analysis, fasting plasma TG was the only variable able to predict endothelium-mediated vasodilatation. Funada et al. (21) recently described a good correlation between remnant levels and endothelial function in normolipidemic individuals, whereas plasma TG fasting levels, although correlated at the univariate analysis, were excluded in a multiple regression model. This difference may be due to the subject studied, i.e. normo- vs. hyperlipidemic. Furthermore, we found no correlation for total cholesterol and LDL cholesterol. This is at variance with previous observations (12, 13); however, the small number of patients in our study (beta error) as well as the presence of hypertriglyceridemia might explain these differences.

In addition to the above-mentioned chronic conditions, a variety of acute stimuli such as mental stress (35), circulating levels of estrogen and progesterone (36), smoking (37), acute changes in glucose and insulin (38), oxidative stresses occurring during hemodialysis (39), and postprandial hyperlipemia (15, 16, 17, 18) acutely influence endothelial function. In the present study, we confirmed that postprandial hyperlipemia affects endothelial function, resulting in a marked impairment of FMD.

Raitakari et al. (40) suggested that the basal diameter of the brachial artery and blood flow were significantly increased during the postprandial phase, whereas FMD was not impaired. We also detected a change in basal arterial diameter during postprandial lipemia (4.509 ± 0.279 vs. 4.849 ± 0.345 mm, P < 0.005). In our experimental setting, however, a severe impairment of FMD also occurred during the postprandial phase, not related to the changes in basal arterial diameter (r = 0.09, P = ns), suggesting that different mechanisms are responsible for these findings. Perhaps the different type of fat load, or difference in patients (healthy vs. hyperlipidemic), might have resulted in different arterial dilatory responses. It should be noted, however, that the FMD measured by Raitakari et al. is fairly low, compared with data reported by us (25) and others (7, 14, 26).

The main purpose of our study was to evaluate whether lipoprotein remnants play a role in determining the endothelial dysfunction that occurs during postprandial lipemia. The levels of lipoprotein remnants increased during the postprandial phase (about 50%), peaking at 6 h, in agreement with previous observations (41), and the C-RLPs peaked at 6 h after the fat load exactly at the same time at which maximal endothelial function impairment occurred. In addition, the AUC (representing the amount of circulating remnants to which the endothelium is exposed) highly correlates with the degree of endothelial dysfunction (P = 0.007). This finding indicates that the burden of remnant may impact on endothelial function. Plasma level remnants remain significantly related to changes of FMD in a multivariate analysis (Table 2Go). Vogel et al. (16) suggested that the degree of endothelial dysfunction during the postprandial phase relates to the postprandial hypertriglyceridemia. Our results are in line with this finding. However, the correlation of TG plasma level at T2, T4, and T6 with FMD at T6 are of borderline significance, whereas the plasma levels of C-RLPs at the same time points are significantly related to the changes of FMD at T6 (Table 2Go). The AUC for the TG was significantly related to the changes of FMD (R = 0.53, P = 0.04). The AUC for C-RLPs, however, showed a better correlation (R = 0.66, P = 0.007) that in a multivariate analysis was the best predictor of endothelial dysfunction.

Concerning the mechanisms by which RLPs induce endothelial dysfunction, very little is known: our data are consistent with observations by Doi et al., who demonstrated that lipoprotein remnants induce, in vitro, endothelial dysfunction in arterial rings (42). Whether this finding relates to an increased oxidative stress, a mechanism that decreases nitric oxide bioavailability (18), or to other mechanisms is unknown.

An increased flux of free fatty acids to endothelial cells by remnants may induce oxidative stress; alternatively, these lipoproteins may be the preferential carrier for oxidized lipids during the postprandial phase. Oxysterols are absorbed, are proatherogenic (43), and modify several cell functions (44). It is also tempting to speculate that RLPs may be particularly sensitive to oxidation. The understanding of the mechanisms by which RPLs induce endothelial dysfunction clearly requires further work.

A limitation of our study is that we enrolled only male patients with hyperlipidemia phenotype IIb; therefore, our data cannot be extended to the whole population. Preliminary data from our laboratory, however, suggest that postprandial changes in RLPs also determine endothelial dysfunction in other groups of male patients including normolipidemic subjects. Further studies are requested to address this issue as well as the possible gender-related specificity of the response (45).

In summary, we have shown, for the first time to our knowledge, that during the postprandial phase, the degree of endothelial function impairment is related to changes of RLP levels. Given the prognostic value of endothelial dysfunction for future coronary heart disease, our finding argues in favor of a proatherogenic role for these lipoproteins. The identification of dietary or pharmacological interventions, such as the use of statins (41), which modulate RLP levels, may provide effective tools for controlling endothelial dysfunction and, therefore, atherosclerosis and cardiovascular disease.


   Footnotes
 
This work was supported in part by a grant from the Ministero Università e Ricerca (to A.L.C.).

Abbreviations: Apo, Apolipoprotein; AUC, area under the curve; CAD, coronary artery disease; C-RLP, cholesterol remnant lipoprotein; FMD, flow-mediated dilation; LDL, low-density lipoprotein; OFL, oral fat load; RLP, remnant lipoprotein plasma; TG, triglyceride(s).

Received November 13, 2003.

Accepted March 7, 2004.


   References
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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