Effect of low-fat, fermented milk enriched with plant sterols onserum lipid profile and oxidative stress in moderatehypercholesterolemia1Ϫ3
Boris Hansel, Catherine Nicolle, Florent Lalanne, Franc¸oise Tondu, Taous Lassel, Yves Donazzolo, Jean Ferrières,Michel Krempf, Jean-Louis Schlienger, Bruno Verges, M John Chapman, and Eric BruckertABSTRACT
reduce plasma concentrations of LDL cholesterol by Ȃ10% (1). Background: Plant sterol (PS)-enriched foods have been shown to
Thus, a daily intake of PSs in the range of 1-2 g/d is now recom-
reduce plasma LDL-cholesterol concentrations. In most studies,
mended for hypercholesterolemic patients (2). Indeed, the hypo-
however, PSs were incorporated into food products of high fat
cholesterolemic effect of PSs is additive to that of other dietary
measures, such as a reduction in saturated fat intake (3). PSs,
Objective: We examined the effect of daily consumption of PS-
which closely resemble cholesterol in their molecular structure,
supplemented low-fat fermented milk (FM) on the plasma lipid
exert their hypocholesterolemic effect primarily through com-
profile and on systemic oxidative stress in hypercholesterolemic
petitive inhibition of cholesterol micellar solubilization and,
hence, of the intestinal absorption of both dietary and biliary
Design: Hypercholesterolemic subjects (LDL-cholesterol concen-
trations ͧ130 and ͨ 190 mg/dL; n ҃ 194) consumed 2 low-fat
In most previous studies, PSs were incorporated into high-fat
portions of FM in the same meal daily for 6 wk. Subjects were
foods, such as dressings, margarines, or spreads, to facilitate their
randomly assigned to 2 groups: low-fat FM enriched with 0.8 g PS
solubility. In a recent meta-analysis, the consumption of 2 g/d
ester per portion or control FM. Plasma concentrations of lipids,
of PS-enriched fat food products reduced LDL-cholesterol con-
oxidized LDL, -carotene, -sitosterol, campesterol, and high-
centrations by 0.33-0.54 mmol/L (5). Furthermore, it has been
sensitivity C-reactive protein were measured during the trial.
suggested that the dispersion of PSs in different food forms may
Results: Plasma LDL-cholesterol concentrations were reduced by
substantially affect the degree of LDL cholesterol reduction
9.5% and 7.8% after 3 and 6 wk, respectively, in the 1.6-g/d PS group
achieved (1). However, few studies have examined the hypocho-
compared with the control group, whereas plasma triacylglycerol
lesterolemic effect of PS supplementation in low-fat dairy prod-
and HDL-cholesterol concentrations were not significantly affected.
ucts such as milk (6, 7), yogurt (6, 8 –11), and other beverages
In addition, there were no significant changes in serum -carotene on
normalization to LDL cholesterol during the study period in bothgroups, whereas plasma concentrations of oxidized LDL were re-
Atherosclerosis underlies most forms of cardiovascular dis-
duced significantly in the PS group compared with the control group
ease, and both chronic low-level inflammation and oxidative
(Ҁ1.73 compared with 1.40 U/L, respectively; P 0.05). Plasma
stress are prominent features of its pathophysiology. Oxidative
sitosterol concentrations were increased by 35% (P 0.001 com-
stress results from an imbalance between tissue prooxidants (free
pared with control); however, campesterol concentrations did not
From the Service d’Endocrinologie-Métabolisme, AP-HP, Hôpital de la
Conclusion: Daily consumption of 1.6 g PS in low-fat FM effi-
Pitié, Paris, France (BH and EB); Institut National de la Santé et de laRecherche Médicale (INSERM) Unité 551 “Dyslipidemia and Atheroscle-
ciently lowers LDL cholesterol in subjects with moderate hypercho-
rosis” and University Pierre and Marie Curie, Hôpital de la Pitié, Paris,
lesterolemia without deleterious effects on biomarkers of oxidative
France (BH, MJC, and EB); Danone Vitapole, Centre de Recherche Daniel
Am J Clin Nutr 2007;86:790 – 6.
Carasso, Nutrivaleur, Palaiseau, France (CN, FL, FT, and TL); OPTIMED,Gieres, France (YD); Service de Cardiologie, AP-HP, Centre Hospitalier
KEY WORDS
Plant sterol, hypercholesterolemia, oxidative
d’Endocrinologie et Nutrition, Hôpital hôtel Dieu, Nantes, France (MK);Service de Médecine Interne, CHU de Hautepierre, Strasbourg, France(J-LS); and Service Endocrinologie, Diabétologie et Maladies Métaboliques,
INTRODUCTION
Hôpital du Bocage, Dijon, France (BV).
Elevated concentrations of plasma LDL cholesterol are rec-
Supported by a grant from Danone Research (Palaiseau, France).
ognized as a major risk factor for the development of premature
Address reprint requests to B Hansel, Service d’Endocrinologie-
Métabolisme, Pavillon Benjamin Delessert, Hôpital de la Pitié, 83 boulevard
cardiovascular disease. Therapeutic strategies aimed at reducing
de l’Hôpital, 75651 Paris Cedex 13, France. E-mail: boris.hansel@
LDL cholesterol focus on dietary recommendations as an initial
step. Among these recommendations, the daily consumption of
dietary constituents enriched in plant sterols (PSs) was shown to
Accepted for publication May 10, 2007. Am J Clin Nutr 2007;86:790 – 6. Printed in USA. 2007 American Society for Nutrition
LOW-FAT PLANT STEROLS IN HYPERCHOLESTEROLEMIA
radicals or oxygen reactive species) and antioxidants (enzymes
and vitamins; 14). LDL is preferentially deposited in the vascular
Clinical and biological characteristics of the subjects at baseline1
wall at sites of endothelial dysfunction early in the course of the
development of atherosclerotic lesions, where it is oxidized as a
consequence of oxidative stress. Numerous in vitro or animalmodels of human atherosclerosis suggest that oxidized lipids
derived from LDL (oxLDL) possess proinflammatory activity
and play a major role not only at early stages of atherogenesis, but
equally at late stages involving plaque rupture with ensuing clin-
ical events (15). Recently, plasma concentrations of oxLDL were
shown to be a strong predictor of acute coronary heart disease
events (16). The potential effect of daily consumption of PS on
the level of oxidative stress remains to be established. It could be
speculated that dietary PS supplementation, which can mediate
reduction in plasma concentrations of fat-soluble vitamins (5),
may lead to global impairment of antioxidative defenses and thus
to enhanced oxidative stress. In contrast, because dietary PS
consumption leads to a reduction in the plasma concentrations of
LDL cholesterol, thereby reflecting a decrease in the number of
circulating LDL particles that are susceptible to oxidation, the
formation of atherosclerotic lesions is potentially attenuated.
The objectives of the present study were 1) to examine the
1 PS, plant sterol, SBP, systolic blood pressure; DBP, diastolic blood
effect of daily consumption of 1.6 g PS in low-fat fermented milk
pressure; FBG, fasting blood glucose. Comparisons between the PS-enriched
(FM) on the plasma lipid profile in hypercholesterolemic sub-
group and the control group were performed by using ANOVA for contin-
jects, 2) to quantify the influence of daily intake of PS-
uous data or chi-square tests for qualitative data.
supplemented FM on oxidative stress (as assessed by plasma
2 x Ȁ SD (all such values).
concentrations of -carotene and oxLDL) and on inflammation
3 Significantly different from control, P 0.05.
[as assessed by high-sensitivity C-reactive protein (hs-CRP)],and 3) to evaluate the influence of PS consumption on circulating
biological characteristics of all subjects (n ҃ 194) are shown in
Study design SUBJECTS AND METHODS
This double-blind, multicenter (5 centers), parallel (enriched
product compared with control), randomized study was stratified
Subjects
by statin treatment and consisted of a 4-wk run-in period (general
Subjects were recruited from the patient registries at special-
dietary recommendations for moderate hypercholesterolemic
ized lipid clinical units in several hospitals in France and via
patients, exclusion of enriched PS products, and consumption of
publicity in local newspapers. The study protocol was carefully
2 low-fat yogurts per day) and a 6-wk experimental phase. At the
explained to all subjects before they provided written informed
end of the run-in period, the subjects were randomly assigned to
consent. The study protocol was approved by the ethics commit-
1 of 2 experimental groups: low-fat FM enriched with 0.8 g PS
tee of the Comite Consultatif pour la Protection des Personnes se
ester per portion or control FM. Subjects were requested to fol-
pretant la Recherche Biomedicale (CCPPRB no. 50-04) in 2004.
low the same dietary recommendations for the next 6 wk and to
Subjects were eligible if they were between the ages of 18 and
consume 2 low-fat portions of FM daily with the same meal. The
75 y (inclusive), whether they were taking statins (but not other
subject flow through the study is shown in Figure 1.
hypocholesterolemic drugs), or whether they were following a
Routine laboratory measurements were conducted at the
prescribed diet. To be included in the study, subjects had to have
screening visit of the study to ensure normal health status. Fasting
a serum LDL-cholesterol concentration of 130 –190 mg/dL
blood samples were taken 1) at the beginning of the run-in period
(3.35– 4.9 mmol/L), a serum triacylglycerol concentration of
(day 28) of low-fat FM consumption (day 14), 2) at the beginning
250 mg/dL (2.86 mmol/L), and not have diabetes; normal liver,
of the experimental period (day 0), and 3) after 3 and 6 wk (days
kidney, and thyroid function and a body mass index (in kg/m2)
21 and 42) of product consumption. Potential side effects were
between 19 and 30 were all inclusion criteria. Exclusion criteria
were as follows: pregnancy or lactation, change of oral contra-ceptive formulation, the presence of severe disease able to influ-
Administration of FM
ence the results (nephritic syndrome or cholestasis), a history of
The PS-enriched FM and control FM were produced and pre-
cardiovascular disease or chronic inflammatory disease, soy al-
pared by Danone Research Center (Palaiseau, France). The com-
lergy, and hypersensitivity to milk proteins. On the basis of these
positions of the PS-enriched and control products are presented
criteria, 365 subjects were eligible; of these, 194 subjects were
in Table 2. PSs were extracted from tall oil and were esterified
included in the study and were randomly assigned. One subject
with rapeseed oil. The PS-enriched FM contained mainly
did not complete the study for personal reasons linked to adverse
-sitosterol (75%) and campesterol (8.4%). One serving of FM
events not related to the study product. The baseline clinical and
supplied 0.8 g PS equivalent as free sterol. Subjects consumed 2
194 randomly assigned ITT population 191 no deviations or minor deviations PP population FIGURE 1. Clinical trial profile. PS, plant sterol; ITT, intention-to-treat; PP, per protocol.
servings to provide a daily dose of 1.6 g PS equivalent as free
Descriptive statistics are presented as means Ȁ SDs or as
medians and quartiles (with 95% CIs) for continuous data or asa percentage for qualitative variables. Comparisons between the
Blood sampling
active group and the control group were performed with statis-
Venous blood samples were obtained after the subjects had
tical descriptive tests by using a significance level of 5% (2-
fasted overnight. Samples were drawn from the forearm vein into
sided) with appropriate methods according to the distribution
EDTA-treated and plain tubes. Plasma samples were analyzed
(parametric or nonparametric or both). The hypocholesterolemic
enzymatically for total cholesterol and HDL cholesterol after
effect of PS was assessed after 3 and 6 wk of product consump-
precipitation of apolipoprotein B– containing lipoproteins (en-
tion. Comparisons between 2 groups of continuous data were
zymatic colorimetric assay, catalog no. 11491458; Roche Diag-
analyzed by using a mixed analysis of variance model (or appro-
nostics, Basel, Switzerland); LDL cholesterol was calculated
priate nonparametric analysis). Analysis of variance was per-
with the use of the Friedewald equation. Plasma concentrations
formed on raw data for cholesterol markers and on other markers
of -carotene were measured by reversed-phase HPLC. Plasma
if departure from normality was not established. In other cases,
-sitosterol and campesterol concentrations were measured by
statistical analyses were performed on transformed data (loga-
gas chromatography–mass spectrometry. The limits of detection
rithmic transformation as usually recommended for triacylglyc-
and quantification, respectively, ranged from 0.1 and 0.4 g/mL
erols or hs-CRP) or on rank data for other markers. Comparisons
for sitosterol, from 0.4 and 1.2 g/mL for campesterol, and from
between 2 groups of qualitative data were analyzed by using a
0.2 and 0.6 g/mL for lathosterol. hs-CRP concentrations were
chi-square or Fisher’s exact test, logistic regression analysis with
measured by a particle-enhanced immunoturbidimetric assay
a binary response, or a Cochran-Mantel-Haenzel test. For each
(Roche). OxLDL was measured with the use of an enzyme im-
subject and at each level of stratification, the change from base-
munoassay (Mercodia, Uppsala, Sweden). The resultant color
line was calculated and expressed in absolute or relative change
reaction was read spectrophotometrically at 450 nm.
or both. Statistical analyses were performed on the individualdata by using a general linear model with study product and
Compliance
stratification factors (center and statin level). Data analyses wereperformed by using SAS software (version 8.2; SAS Institute Inc,
Compliance with the study product was evaluated by inter-
viewing the subjects and by counting the unopened and uncon-sumed product packages returned to the clinic. Compliance wasrecorded as the percentage of the scheduled servings consumed.
Noncompliance was defined as the consumption of 80% of the
Composition of control and plant sterol (PS)-enriched fermented milk
scheduled servings during the study period. Statistical analyses
The number of subjects was calculated by taking into account
a critical difference in LDL cholesterol of 0.32 Ȁ 0.732 mmol/L
between the active and the control groups with ␣ ҃ 5% and a
power of 80%. Given these constraints, 84 evaluable subjects per
group to 168 in total were required. To take into account possible
premature withdrawal and block size, a total of 200 subjects was
planned to be included for random assignment.
LOW-FAT PLANT STEROLS IN HYPERCHOLESTEROLEMIA
TABLE 3 Serum lipid concentrations at baseline and at 3 and 6 wk of intake of the Study participants
plant sterol (PS)-enriched or control fermented milk and the absolutechange between baseline and the end of the trial (week 6 Ҁ baseline)1
Of the 194 subjects, 3 subjects presented major protocol de-
viations (one withdrew prematurely, one had a randomization
error, and one had a nonfasting plasma sample at inclusion).
None of the subjects were taking medications that could have
affected the results. Given the large number of subjects and the
very small number of subjects with major protocol deviations,
the analyses were performed on all subjects in the intention-to-
There were no significant differences between the PS and the
control groups at baseline in age, BMI, systolic and diastolic
blood pressures (Table 1), alcohol consumption (46.3% com-
pared with 49.5%), and smoking habits (13.7% compared with
14.0%). Men and women were equally distributed in both groups
(65% compared with 35% in the active group and 69% compared
with 31% in the control group, respectively). Subjects were se-
lected on the basis of screening values for mean fasting LDL-
cholesterol concentrations between 130 and 190 mg/dL (3.35
and 4.90 mmol/L) and mean triacylglycerol concentrations
250 mg/dL (2.86 mmol/L). The mean plasma concentrations of
LDL cholesterol were greater in the group consuming the PS-
enriched product than in the control group (158.1 Ȁ 13.4 com-
pared with 151.8 Ȁ 15.9 mg/dL, respectively; P 0.05). Neither
biological criteria nor dietary habits differed significantly at
1 All values are x Ȁ SD.
baseline. Only 14% and 15% of the control and PS groups,
2 Interaction of study product ҂ time was significant, P 0.001.
respectively, received statin treatment; none of those subjects
3 Comparison between PS-enriched fermented milk group and control
discontinued statin treatment during the study. There were no
group was performed by using ANOVA on raw data.
significant changes in the dietary habits or levels of physical
Significantly different from control: 4P 0.001, 6P 0.01. 5 Absolute change from baseline was calculated for each subject as the
activity in either of the groups (data not shown).
end of trial value (week 6) minus baseline value. 7 Interaction of study product ҂ time was not significant: for HDL, P ҃
Compliance and side effects during the study
0.70; for triacylglycerol, P ҃ 0.73.
Compliance for the product enriched in PS and for the control
Comparison between PS-enriched fermented milk group and control
FM (defined as consumption of 80% of the scheduled servings
group was performed on log-transformed data by using ANOVA on raw data.
during the study period) was highly satisfactory (95.5%) after 3wk of consumption and attained 97.7% after 6 wk. All subjects
and 0.8 Ȁ 1.2%, respectively). The same patterns were observed
followed the dietary recommendations. No adverse events re-
lated to the consumption of the product occurred during the
Plasma total cholesterol concentrations were significantly
lower after PS consumption than after consumption of the controlFM (Table 3): Ҁ6.2% reduction at the intermediate visit (P
Serum lipid profile
0.001 between groups) and Ҁ4.7% at the end of the intervention
The mean plasma lipid concentrations at baseline and after 3-
period (P 0.001 between groups). HDL-cholesterol and
and 6-wk consumption of the control FM and of the PS-
plasma triacylglycerol concentrations were not significantly af-
supplemented FM are shown in Table 3. Most of the reduction
fected by the consumption of the PS-enriched FM (Table 3).
in plasma LDL-cholesterol concentrations was achieved after 3wk. The reduction in LDL cholesterol during the first 3 wk was
Plasma plant sterols
9.5% greater in the PS group than in the control group, and it
Variation in plasma PS concentrations during the study re-
corresponded with a 14.5-mg/dL decrease in LDL cholesterol
flected the degree of absorption and transport of PSs in the sys-
(P 0.001 between groups). After daily consumption of PS for
temic circulation (Table 4). The increase in plasma -sitosterol
3 additional weeks, LDL-cholesterol concentrations were 8.4%
concentrations in the PS group was 35% greater than that in the
and 0.7% lower than baseline in the PS and control groups,
control group at the end of the intervention period (0.81 com-
respectively. The mean reduction of LDL cholesterol after daily
pared with 0.06 mg/L). There was no significant change in
intake of 1.6 g PS was 12.4 mg/dL greater than that in the control
plasma campesterol concentrations during the intervention.
group (P 0.001 between groups). After 3-wk consumption of
Plasma concentrations of -sitosterol plus campesterol increased
the PS-enriched FM, statin-treated and -untreated subjects had
significantly more in the PS group (14.5% compared with the
LDL-cholesterol concentrations that were reduced by 8.0 Ȁ
control group, P 0.001) after the 6-wk intervention period.
2.1% and 8.4 Ȁ 1.2%, respectively. Very little change was ob-
Lathosterol is assumed to be a marker of endogenous choles-
served in the LDL-cholesterol concentrations of the statin-
terol synthesis. Plasma lathosterol concentrations did not differ
treated and -untreated subjects in the control group (2.3 Ȁ 3.7%
significantly between the 2 groups during the study (Table 4):
Plasma plant sterol (PS) and lathosterol concentrations at baseline (week
Plasma concentrations of -carotene (absolute and LDL
0) and at the end of the trial (week 6) and the absolute change between
cholesterol–adjusted serum concentrations), high-sensitivity C-reactive
baseline and the end of the trial (week 6 Ҁ baseline)1
protein (hs-CRP), and oxidized LDL (oxLDL) at baseline and at the end ofthe trial (week 6) and study product effect (week 6 Ҁ baseline)11 All values are x Ȁ SD. 2 Comparison between PS-enriched fermented milk group and control
group was performed by using ANOVA of rank data. 2 Comparison between the PS-enriched fermented milk group and the
3 Absolute change from baseline was calculated for each subject as
control group was performed by using ANOVA of rank data of absolute
follows: end of trial value (week 6) Ҁ baseline value.
change. The mean of % change for all subjects is presented. 4 Significantly different from control, P 0.001. 3 x Ȁ SD (all such values). 4, 8 Significantly different from control: 4P 0.001, 8P 0.05. 5 Chi-square test on absolute change, classified into 2 levels: “decreas-
Ҁ0.08 compared with Ҁ0.02 mg/L between baseline and week 6
ing” and “stable or increasing.” The mean of % change for all subjects is
in the PS and the control groups, respectively; NS. 6 ANOVA of transformed data using logarithmic transformation. The
Oxidative stress and inflammation criteria
mean of absolute change for all subjects is presented. 7 Median; lower and upper quartiles in parentheses (all such values).
Absolute and LDL-cholesterol–adjusted -carotene concen-
trations are reported in Table 5. The reduction in plasma
-carotene concentrations was 12% greater in the PS group than
products (17, 18). A meta-analysis (5) showed that daily con-
in the control group (P 0.001). However, after standardization
sumption of 2 g PS in margarines, mayonnaise, butter, or olive
for LDL cholesterol, variation in -carotene concentrations dur-
oil can reduce LDL-cholesterol concentrations by 0.33-0.54
ing the study did not differ significantly between the 2 groups.
mmol/L in hypercholesterolemic subjects. Few data, however,
Plasma concentrations of oxLDL were reduced significantly
are available on the plasma cholesterol–lowering properties of
more in the group consuming PS (Ҁ1.73 compared with 1.40
nonfat or low-fat PS-enriched foods. Daily consumption of a
U/L; P 0.05; Table 5), but the decrease was not significant after
relatively low-fat (2%) yogurt containing 1 g PS ester signifi-
standardization for LDL cholesterol. hs-CRP was unchanged
cantly lowered total cholesterol and LDL-cholesterol concentra-
after 6 wk of product consumption, and variation in this variable
tions (8); however, in this study, the control FM led to a decrease
did not differ significantly between the 2 groups during the study
in total cholesterol and LDL-cholesterol concentrations, and
comparisons with controls were not available. In a subsequentstudy conducted by Jones et al (13), daily ingestion of 1.8 g freePS in a low-fat beverage failed to decrease LDL-cholesterol
DISCUSSION
concentrations in moderately hypercholesterolemic subjects.
In this large, double-blind randomized controlled (PS-
The authors hypothesized that the content of fat was not high
enriched product compared with control) multicenter study,
enough to adequately solubilize phytosterols in the small intes-
daily consumption of 1.6 g PS in low-fat FM led to reductions in
tine. On the contrary, other studies suggested that relatively low-
plasma LDL-cholesterol concentrations of 9.5% and 7.8% in
fat dairy products may be an adequate vehicle for the delivery of
moderately hypercholesterolemic subjects after 3 and 6 wk,
esterified PS to effectively lower plasma cholesterol concentra-
tions (6, 9 –11, 19 –21). The LDL-cholesterol reduction found in
In previous studies with products naturally containing fat, PSs
our study with PS-enriched FM agrees with the latter data. How-
were most frequently incorporated in fat-rich vehicles such as
ever, in these studies, the vector used to deliver PS was distinct
spreads and dressings. Two studies used a naturally fat-free or-
(6, 9 –11, 19 –21). First, in the studies of Mensink et al (9) and of
ange juice as a vehicle for phytosterol ester and showed an LDL-
Doornbos et al (11), the experimental group received a daily
cholesterol–lowering effect similar to that of PS-enriched fat
intake of 3 g plant stanol esters, ie, about twice the dose of PS
LOW-FAT PLANT STEROLS IN HYPERCHOLESTEROLEMIA
ingested in our study. In other studies, 2 g PS esters were con-
concentrations relative to those of LDL cholesterol, we observed
sumed daily. Thus, the dose of PS administered in our protocol
that the small decrease in plasma -carotene concentrations did
was the lowest among these studies to show a significant de-
not reach statistical significance after standardization for LDL-
crease in LDL cholesterol when incorporated in a low-fat dairy
cholesterol concentrations. These observations are consistent
product. Another characteristic of the product tested in the
with previous studies (7, 10, 29, 30).
present study is its very low fat content. In previous studies of
Oxidative stress, defined as an imbalance between anti- and
“low-fat” dairy products (6, 10, 20), the fat content of the prod-
prooxidant factors, is implicated in the development of numerous
ucts tested was often relatively low but higher than that in the present
chronic pathologies, including atherosclerosis. It has been sug-
study. The main dietary recommendation for patients with hyper-
gested that even a minor decrease in -carotene concentrations
cholesterolemia is to limit their intake of saturated fats, including
may be proatherogenic. However, antioxidants include numer-
those of dairy products. In addition, patients may be reluctant to
ous substances or enzymes and liposoluble vitamins that may
consume margarine either because they are not in the habit of
interact synergistically. Thus, analysis of one component inde-
using margarine or because of its taste. Thus, the use of a very-
pendently of the others may not accurately reflect their combined
low-fat food to administer plant sterols at a sufficient dose is of
action and may not, therefore, properly estimate systemic oxi-
particular interest in patients with hypercholesterolemia.
dative stress. Thus, we measured the effect of PS on the level of
Compliance is obviously a key aspect of therapeutic strategies,
oxLDL, an integrative marker of systemic oxidative stress. In all
which aim to treat chronic asymptomatic abnormalities. In the
likelihood, plasma oxLDL concentrations may depend on the
present study, compliance was excellent (reaching 97.7% at the
capacity of in vivo antioxidants to protect LDL particles against
end of the study), and FM consumption did not give rise to any
oxidation in the arterial wall. Plasma concentrations of oxLDL
were shown to be a strong predictor of acute coronary heart
PS administered in food usually lowers plasma concentrations
disease events (16). Interestingly, we report in the present study
of LDL cholesterol within a short period of time. In the present
that consumption of PS was associated with a significant de-
study, the maximum change in LDL cholesterol (Ҁ9.5% com-
crease in the plasma concentrations of oxLDL as compared with
pared with control) occurred after 3 wk of consumption of PS-
the consumption of a control dietary product (P ҃ 0.03). Such a
enriched FM. No additional decrease in plasma LDL-cholesterol
decrease paralleled the LDL-cholesterol–lowering effect. Thus,
concentrations occurred after this period. Nguyen et al (22) re-
we interpreted our data to suggest that the slight decrease in
ported a similar pattern of response to a spread enriched in plant
systemic antioxidant concentrations reported with PS intake did
stanol esters, with a maximum change after 2 wk.
not affect LDL oxidation. Our results confirm those of Homma
It is well known that lipid and lipoprotein responses to a dietary
et al (31), who reported a 20% decrease in oxLDL concentrations
change and particularly to sterol- or stanol-enriched products are
in patients consuming 2-3 g/d plant stanol in enriched spreads, as
heterogeneous (23–25). In our study, 67% of the patients in the
sterol group showed a 5% decrease in LDL cholesterol. This
Another emergent question concerning the therapeutic use of
finding suggests that most patients may exhibit a clinically rel-
PS has to do with the possibility that their accumulation in plasma
evant LDL cholesterol reduction derived from daily consump-
may be atherogenic. In our study, plasma PS concentrations,
tion of PS-enriched FM in addition to traditional diet recommen-
notably, -sitosterol, significantly increased with PS-FM con-
sumption (35% compared with control). However, the absolute
The effect of PS-enriched margarine in patients taking statins
changes in campesterol and -sitosterol concentrations were of a
has been shown to be additive rather than synergistic (26). It is
small magnitude, and the values in the experimental group were
generally assumed that dietary PS esters produce an additional
not significantly different from those in patients consuming a
reduction in LDL cholesterol of Ȃ6 – 8% (27); the design of our
plant food– based diet. For example, in a population of healthy
study did not allow us to accurately quantify this additive effect.
pure vegetarians, the plasma concentrations of -sitosterol plus
However, the 7.8% LDL-cholesterol–lowering effect of PS-
campesterol were similar (6.0 mg/L) to those in patients con-
enriched FM was consistent in the subgroup of subjects treated
suming PS in our study (5.7 mg/L; 32). Moreover, these values
with a statin. Concordantly, we did not observe any interaction
are at least one-tenth to one-twentieth those typical of
between statin therapy and PS consumption. In line with previous
-sitosterolemia, which is characterized by elevated plasma con-
results obtained with the use of margarines, the magnitude of the
centrations of -sitosterol and accelerated atherosclerosis.
additional decrease in LDL cholesterol is slightly greater than
The main weakness of our study is its short duration. However,
that to be expected by doubling the dose of statin (28). Unlike PS,
a large body of evidence now indicates that reductions in plasma
statins inhibit the synthesis of hepatic cholesterol but equally
cholesterol induced by PS consumption are sustained over the
increase its intestinal absorption. These complementary effects
long term, especially when compliance is maintained. In addi-
suggest, therefore, that it may be of special interest to combine
tion, the low level of adverse effects suggests that PS consump-
statin-mediated inhibition of cholesterol synthesis with the inhi-
tion is safe over a relatively long period of time (33, 34). Finally,
bition of cholesterol absorption by PS in the same subject.
the decrease in hs-CRP observed in patients treated with PS-
One of the major concerns with respect to dietary PS supple-
enriched FM was not significant, which can be explained by the
mentation involves the possibility that fat-soluble vitamin ab-
large variability in hs-CRP at baseline and thus a lack of statis-
sorption is reduced (5). Because plasma lipoproteins (mainly
VLDL and LDL) are the major transport vehicles for lipid-
In summary, the present study showed that daily consumption
soluble antioxidants, a reduction in LDL concentrations may
of 1.6 g PS ester in a very-low-fat PS-enriched FM resulted in an
result in a decrease in fat-soluble vitamin concentrations. Fewer
LDL-cholesterol–lowering effect in mildly hypercholester-
lipoprotein particles may, therefore, be available to carry caro-
olemic subjects. Moreover, an absolute decrease in the plasma
tenoids. Because it is common practice to express carotenoid
concentration of oxLDL was equally observed in both the group
consuming PS and the control group. Subjects did not report any
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We kindly thank I Seksek, L Verseil, S Doat, and B Rumo for their
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La rivolta del contadini scoppiata nel comune di San Salvatore Monferrato, in provincia di Alessandria, nei giorni 24 e 25 ottobre 1898 si concluse in un bagno di sangue nel conflitto con i carabinieri inviati dal prefetto a protezione delle squadre antifil-losseriche incaricate di eseguire l’esplorazione dei vigneti della zona, per accertare se questi fossero stati colpiti dalla fillossera.
Lymphoedema Management. Involving the patient in treatment choice and implementation of care. Denise Renshaw, MCSP, SRP, Vodder Lymphoedema Therapist. Independent practitioner. Previously employed as a Macmillan Lymphoedema Specialist Physiotherapist at St Ann’s Hospice running a Clinic seeing both cancer related and non-cancer related lymphoedemas. Introduction Lymphoed