Elevated Remnant-Like Particles in Heterozygous Familial Hypercholesterolemia and

Response to Statin Therapy

Pernette R. W. de Sauvage Nolting, Marcel B. Twickler, Geesje M. Dallinga-Thie, Rudolf J.A.
Buirma, Barbara A. Hutten and John J.P. Kastelein

Circulation. 2002;106:788-792; originally published online July 8, 2002;

doi: 10.1161/01.CIR.0000025586.89221.4B
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2002 American Heart Association, Inc. All rights reserved.
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 Elevated Remnant-Like Particles in Heterozygous Familial
Hypercholesterolemia and Response to Statin Therapy
Pernette R.W. de Sauvage Nolting, MD; Marcel B. Twickler, MD; Geesje M. Dallinga-Thie, PhD;
Rudolf J.A. Buirma, MD; Barbara A. Hutten, PhD; John J.P. Kastelein, MD, PhD; for the Examination of
Probands and Relatives in Statin Studies with Familial Hypercholesterolemia (ExPRESS) Study Group

Background—Remnant lipoproteins (RLP-C) are considered important in atherogenesis. Hence, this study was designed
to assess RLP-C levels and the effect of statin therapy in patients with familial hypercholesterolemia (FH). Elevated
RLP-C levels have been associated with the presence and progression of atherosclerotic disease, and their presence in
FH patients has been proposed but never established in a large cohort, nor has their response to statin therapy been
confirmed.
Methods and Results—FH patients were recruited from 36 lipid clinics. After a washout period of 6 weeks, all patients
were started on monotherapy with 80 mg of simvastatin for 2 years. RLP-C levels were assessed by an immune-
separation assay. In 327 FH patients, RLP-C measurements could be performed before and after treatment. Mean total
cholesterol (10.55⫾2.17 mmol/L), mean LDL cholesterol (8.40⫾2.13 mmol/L), and median RLP-C (0.47 mmol/L)
levels were all severely elevated at baseline. After treatment, RLP-C levels were reduced by 49% (0.24 mmol/L;
P⬍0.0001). Even patients with normal triglyceride levels had elevated RLP-C levels at baseline, and those with high
RLP-C levels were generally characterized by a very atherogenic lipoprotein profile.
Conclusions—Baseline RLP-C levels are severely elevated in FH patients and are reduced by simvastatin but do not return
to normal. These elevated RLP-C levels could be the consequence of impaired function of the LDL receptor in FH.
RLP-C levels in FH contribute to an atherogenic lipoprotein profile and could identify patients who require additional
treatment. (Circulation. 2002;106:788-792.)
Key Words: hypercholesterolemia 䡲 lipids 䡲 lipoproteins 䡲 atherosclerosis

F amilial hypercholesterolemia (FH) is an autosomal dom-

inant disorder of lipoprotein metabolism.1 Mutations in
the LDL receptor gene are the cause of this disease and lead
progression and cardiac events. Recently, Nakajima et al8 –10
developed a simple technique to analyze RLP cholesterol
(RLP-C) using an immune-affinity gel containing anti-
to a reduction in the clearance of LDL cholesterol (LDL-C), apolipoprotein (apo) A-I and anti-apoB100 monoclonal anti-
which causes a rise in LDL-C levels and predisposes to the bodies. This unique anti-apoB100 monoclonal antibody was
development of atherosclerosis.2 Therefore, FH patients are at shown to recognize apoB100 in LDL and most VLDL but not
great risk of developing premature coronary artery disease. in apoE-enriched VLDL, whereas anti-apoA-I recognizes and
However, there is a wide variation of coronary risk among FH binds all HDL particles. This technique isolates apoE-rich
patients.3 VLDL particles containing apoB100 together with chylomi-
Increasing experimental and clinical evidence suggests that cron remnants containing apoB48, neither of which binds to
triglyceride (TG)-rich lipoproteins, and in particular remnant- the immunoaffinity gel. Increased levels of these remnant
like particles (RLPs), contribute to atherogenesis and conse- particles have been associated with the presence and progres-
quently to cardiovascular disease progression. High levels of sion of cardiovascular disease and with endothelial dysfunc-
remnant lipoproteins of both hepatic (VLDL) and intestinal tion.11–18 However, these previous results were examined in
(chylomicron) origin are associated with the progression of non-FH patients. Evidently, these patients have a different
coronary atherosclerosis.4 –7 In a study by Phillips et al,7 it lipid profile from the extremely elevated LDL-C levels seen
was found that neither LDL-C nor TG levels correlate well in FH patients. Therefore, this association between elevated
with lesion progression or clinical events. TG-rich lipoprotein levels of RLP-C and cardiovascular disease cannot be extra-
remnant levels, however, did correlate with both lesion polated to FH patients as such.

Received February 22, 2002; revision received May 21, 2002; accepted May 23, 2002.
From the Department of Vascular Medicine, Academic Medical Center (P.R.W.d.S.N., B.A.H., J.J.P.K.), Amsterdam, the Netherlands; Department of
Vascular Medicine, University Medical Center (M.B.T., G.M.D.-T.), Utrecht, the Netherlands; and Merck, Sharp and Dohme (R.J.A.B.), Clinical
Research, Haarlem, the Netherlands.
Correspondence to P.R.W. de Sauvage Nolting, MD, Academic Medical Center, G1-114. Meibergdreef 9, 1105AZ Amsterdam, Netherlands. E-mail
[email protected]
© 2002 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org DOI: 10.1161/01.CIR.0000025586.89221.4B

788
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 de Sauvage Nolting et al RLP-C in FH Patients and Simvastatin 789

Levels of remnant particles could be relevant for the wald formula.22 ApoA-I and apoB were determined by an immuno-
understanding of the heterogeneity in coronary risk among logic rate-nephelometric procedure with a polyclonal goat anti-
human antibody (Array protein system, Beckman Coulter).23
FH patients. RLP-C levels have thus far not been assessed in
The RLP fraction was prepared by use of an immune-separation
a large FH population. To date, only 2 small studies (in 15 technique described by Campos et al8 and Nakajima and colleagues.9
and 7 FH patients, respectively) reported RLP-C levels of FH Briefly, 5 ␮L of serum was added to 300 ␮L of mixed immunoaf-
patients and did indeed show increased RLP-C levels.19,20 In finity gel suspension containing monoclonal anti-human apoA-I
the present study, we aimed to assess accumulation of RLP-C (H-12) and anti-human apoB100 (JI-H) antibodies (Immunoresearch
Laboratories). The reaction mixture was gently shaken for 120
and also to evaluate whether RLP-C levels would be lowered
minutes at room temperature. After the supernatant was left standing
by statin therapy in a large, well-defined cohort of FH for 15 minutes, 200 ␮L was withdrawn for the assay of RLP-C.
patients. Cholesterol in the RLP fraction (coefficient of variation ⬍3%) was
measured by an enzymatic assay on a Cobas Mira S autoanalyzer
Methods (ABX Diagnostics). ApoE genotyping was performed as described
by Reymer et al.24
FH Subjects
The present study is a substudy of the ExPRESS FH (Examination of Statistical Analysis
Probands and Relatives in Statin Studies with Familial Hypercho- Data are expressed as mean⫾SD. Skewed data distributions are
lesterolemia) study, in which efficacy, safety, and pharmacogenom- presented as median and interquartile range. Mean and median
ics of simvastatin 80 mg were assessed in 526 heterozygous FH cholesterol levels in FH patients compared with controls were tested
patients. For this open-label, multicenter study, FH patients were by the independent-sample t test and the Mann-Whitney test,
recruited from 36 lipid clinics in the Netherlands. Patients were respectively. Mean values in lipids and lipoproteins before and after
included if they met the following criteria: all patients had to have treatment were compared with the paired-sample t test. TG and
either a molecular diagnosis for FH or were diagnosed with definite RLP-C levels were compared by nonparametric Wilcoxon test
FH and had to have 6 or more points, according to an algorithm (to because they had a skewed distribution. Mean values in baseline
allow standardization of the diagnosis of FH based on clinical characteristics and lipids for the different groups were compared
findings, personal and familial clinical history, and biochemical with 1-way ANOVA. Parameters with a skewed distribution (TG,
parameters)21; all patients were at least 18 years of age; and patients RLP-C, and RLP reduction) were compared with the Kruskal-Wallis
with a history of myocardial infarction, CABG, or PTCA could be test. ␹2 tests were applied for comparison of distributions of
included if the physician thought it was medically allowed for the dichotomous data (sex, presence of diabetes, and apoE2 levels). All
patient to have a washout period. Patients were excluded if they were statistical analyses were performed with the SPSS package (version
pregnant or nursing women or premenopausal women not using 10.0.7, United Kingdom). A probability value of ⬍0.05 was consid-
adequate contraceptives; had acute liver disease, hepatic dysfunction, ered statistically significant.
or persistent elevations of serum transaminases; had hypersensitivity
or intolerance to simvastatin or any of its components; had hyper-
lipidemia type I, III, IV, or V or homozygous FH; had a recent Results
history of alcohol or drug abuse; had secondary hypercholesterol- Among the 526 patients who participated in the ExPRESS FH
emia due to any cause; had inadequately controlled diabetes, unsta- study, blood samples were stored for 327 patients. Conse-
ble angina, or intermediate coronary syndrome, or clinically signif- quently, these patients were available for RLP-C analyses and
icant ventricular arrhythmia at study entry, or myocardial infarction composed our study group. This group did not differ from the
within the past 3 months; were concurrently using erythromycin and
similar drugs that affect the cytochrome P450 enzyme; or had a source population with regard to baseline characteristics and
history of cancer. lipid parameters. Age ranged from 18 to 80 years. Mean age
was 47.4 years (SD ⫾13.2). Slightly more men (54%) than
Controls women (46%) were included. Mean body mass index (BMI)
Controls for the 327 FH patients in whom RLP-C levels were was 25.8 kg/m2 (SD ⫾3.6). Lifestyle and physical character-
measured were recruited post hoc from their families and matched istics such as dietary adherence, BMI, alcohol intake, and
for age and sex. From these 77 individuals, we obtained demographic
characteristics, lipid levels, and lipoprotein levels. physical exercise did not change over the course of the trial.
Mean lipid, lipoprotein, and RLP-C levels at baseline and
Study Design 1 year after therapy with simvastatin 80 mg are shown in
After a washout period of 6 weeks, patients were started on Table 1. As expected, mean total cholesterol levels
monotherapy with simvastatin 80 mg. No other lipid-lowering (10.55⫾2.17 mmol/L) were severely elevated in FH patients
medication was allowed. Medical history, physical examination, and
compared with their family controls (4.58⫾0.77 mmol/L;
additional risk factors for cardiovascular disease, as well as labora-
tory analysis of lipid and lipoprotein levels and routine safety P⬍0.0001), and this could largely be attributed to elevated
parameters, were obtained from all patients. The biochemical anal- LDL-C levels (8.40⫾2.13 mmol/L). Mean HDL-C levels
yses of lipid levels and safety parameters were performed in the were lower in FH patients than in controls (1.25⫾0.35 versus
hospitals themselves and were standardized by a virtual central 1.39⫾0.38 mmol/L; P⫽0.04), whereas median TG levels
laboratory. The apo determinations were performed in the Academic
Medical Center in Amsterdam and the RLP determinations in the
were elevated compared with controls (1.80 versus
University Medical Center in Utrecht. The ethics committees of all 0.97 mmol/L; P⬍0.0001). Median RLP-C levels
36 centers approved the protocol, and written informed consent was (0.47 mmol/L) were severely elevated in FH patients. Median
obtained from all participants. RLP-C levels in controls were 0.20 mmol/L, which indicates
that FH patients had a 2-fold elevation of RLP-C levels
Biochemical Analysis (P⬍0.0001). After simvastatin treatment, plasma cholesterol,
Blood samples were taken in the morning after an overnight fast.
Total cholesterol, HDL cholesterol (HDL-C), and TG levels were LDL-C, TG, and apoB levels decreased, and HDL-C and
routinely determined in the different laboratories and standardized by apoA-I levels increased, all significantly. RLP-C levels de-
a virtual central laboratory. LDL-C was calculated with the Friede- creased significantly from a median of 0.47 to 0.24 mmol/L
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790 Circulation August 13, 2002

TABLE 1. Lipid, Lipoprotein, and RLP-C Levels in Controls and RLP-C levels, median TG levels were normal (1.10 mmol/L),
in FH Patients at Baseline and After 1 Year of Therapy whereas in that third, median RLP-C levels were still above
Baseline Simvastatin 80 mg normal (0.32 mmol/L). Moreover, significantly more patients
Variable (n⫽327) (n⫽327) P in the highest RLP-C tertile had an apoE2 allele compared
TC, mmol/L 10.55⫾2.17 6.36⫾1.37 ⬍0.0001 with the 2 lower tertiles (P⫽0.001). Finally, RLP-C levels
were more reduced in the highest tertile than in the lower
LDL-C, mmol/L 8.40⫾2.13 4.32⫾1.30 ⬍0.0001
tertiles. Because pretreatment and posttreatment measure-
HDL-C, mmol/L 1.25⫾0.35 1.39⫾0.39 ⬍0.0001
ments of the variable of interest were, in general, not perfectly
TG, mmol/L 1.80 (1.20–2.40) 1.20 (0.90–1.73) ⬍0.0001
correlated, the evaluation of treatment effects must be ad-
ApoA-I, g/L 1.24⫾0.22 1.36⫾0.24 ⬍0.0001 justed for regression to the mean. Chen et al25 proposed 4
ApoB, g/L 1.97⫾0.45 1.19⫾0.31 ⬍0.0001 models, which included either or both additive and multipli-
RLP-C, mmol/L 0.47 (0.34–0.80) 0.24 (0.20–0.31) ⬍0.0001 cative effects. We applied this model to evaluate RLP-C
TC indicates total cholesterol. changes. The model that included both additive and multipli-
All values are given as mean with SD except that TG and RLP-C are given cative effects fit better than that with only additive effects
as median with interquartile range. (regression to the mean) for RLP-C change (P⬍0.0001).
Therefore, changes in RLP-C could not be attributed to
(P⬍0.0001), which is consistent with a 49% median reduc- regression to the mean only but indeed exhibited a relation-
tion. At baseline, only 5 FH patients (1.5%) had normal ship with baseline levels. Of FH patients in the highest versus
RLP-C levels (ⱕ0.20 mmol/L); in contrast, after simvastatin the lowest third of RLP-C levels, 53 (48.6%) had cardiovas-
therapy, 84 patients (25.7%) were below this RLP-C level. cular disease versus 30 (27.5%) of the cases (␹2⫽10.5,
In Table 2, baseline RLP-C levels are divided into 3 equal P⫽0.005). However, on multiple logistic regression analysis
groups by the 33rd and 66th percentiles. FH patients in the with age, sex, BMI, and major lipids in the model, this
highest third were older, were more often male, had a higher relation was no longer statistically significant (P⫽0.32).
BMI, and more often had diabetes. To address whether FH Table 3 shows the data stratified according to baseline TG
patients with type 2 diabetes were outliers in terms of levels in quartiles. Patients in the lowest quartile had com-
remnant accumulation and caused significant shifts of the pletely normal median baseline TG levels (0.90 mmol/L);
medians in the different groups, we calculated median RLP-C however, the corresponding RLP-C levels were already
levels with these individuals included or excluded. However, strongly elevated (0.32 mmol/L), whereas plasma LDL-C
results indicated no significant changes in the medians of levels were similar in all groups (P⫽0.09).
these 3 groups (data not shown). In addition, the statistically
significant increase in total cholesterol, LDL-C, and TG
levels and the decrease in HDL-C illustrate the association
Discussion
between plasma RLP-C and the presence of a severe athero- RLP-C Increase at Baseline
genic lipoprotein profile. RLP-C levels were also correlated In the present study, we observed that median RLP-C levels
with HDL-C levels; the Spearman rank correlation coefficient in FH patients were severely elevated compared with their
was r⫽⫺0.37 at P⬍0.0001. In the lowest third of baseline siblings (0.47 versus 0.20 mmol/L; P⬍0.0001). Elevated

TABLE 2. Lipids, RLP, ApoE2, and Clinical Features in FH Patients With Baseline RLP-C
Levels Divided in 3 Equal Groups
RLP-C⬍0.39 mmol/L 0.39ⱕRLP-C⬍0.65 mmol/L RLP-Cⱖ0.65 mmol/L
Variables (n⫽109) (n⫽109) (n⫽109) P
Age, y 44.0⫾14.2 46.6⫾13.2 51.5⫾11.0 ⬍0.0001
Male, n (%) 41 (45.0) 47 (51.4) 60 (65.1) 0.009
BMI, kg/m2 24.6⫾3.7 25.6⫾3.2 27.3⫾3.5 ⬍0.0001
Diabetes, n (%) 0 (0) 1 (0.9) 5 (4.6) 0.029
TC, mmol/L 9.50⫾1.70 10.68⫾2.08 11.47⫾2.23 ⬍0.0001
LDL-C, mmol/L 7.58⫾1.63 8.64⫾2.13 8.99⫾2.32 ⬍0.0001
HDL-C, mmol/L 1.37⫾0.36 1.29⫾0.35 1.09⫾0.27 ⬍0.0001
TG, mmol/L 1.10 (0.90–1.50) 1.80 (1.30–2.05) 2.80 (2.10–3.60) ⬍0.0001
ApoA-I, g/L 1.28⫾0.21 1.25⫾0.24 1.18⫾0.19 0.004
ApoB, g/L 1.74⫾0.35 2.00⫾0.39 2.17⫾0.49 ⬍0.0001
RLP-C, mmol/L 0.32 (0.26–0.34) 0.47 (0.43–0.53) 1.06 (0.79–1.62) ⬍0.0001
RLP reduction, % 29.0 (14.9–41.0) 50.5 (39.8–57.7) 67.5 (57.2–76.8) ⬍0.0001
ApoE2 allele, n (%) 5 (4.6) 4 (3.7) 17 (15.6) 0.001
TC indicates total cholesterol.
All values are given as mean with SD or n (%), except that TG, RLP-C, and RLP-C reduction are given as median
with interquartile range.

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 de Sauvage Nolting et al RLP-C in FH Patients and Simvastatin 791

TABLE 3. Lipids and RLP-C Levels in FH Patients With Baseline TG Levels Divided in Quartiles
TGⱕ1.10 mmol/L 1.10⬍TGⱕ1.80 mmol/L 1.80⬍TGⱕ2.40 mmol/L TG⬎2.40 mmol/L
(n⫽80) (n⫽91) (n⫽76) (n⫽80) P
LDL-C 8.03⫾1.90 8.81⫾2.17 8.48⫾2.30 8.23⫾2.07 0.09
TG 0.90 (0.80–1.00) 1.50 (1.30–1.70) 2.10 (1.90–2.20) 3.25 (2.73–4.10) ⬍0.0001
RLP-C 0.32 (0.25–0.41) 0.42 (0.33–0.49) 0.52 (0.42–0.75) 1.16 (0.79–1.80) ⬍0.0001
LDL-C is given as mean with SD; TG and RLP-C are given as median with interquartile range.

RLP-C levels were reported before in FH patients, albeit in levels of LDL-C are severely elevated, as are levels of
very small cohorts. Twickler et al20 measured RLP-C levels in RLP-C. Moreover, these elevated RLP-C levels are signifi-
7 FH patients and found significantly elevated mean RLP-C cantly reduced by simvastatin treatment. Statins likely im-
levels compared with 7 controls (42.10 mg/dL [1.09 mmol/L] prove RLP clearance by upregulating LDL receptors and by
versus 7.49 mg/dL [0.19 mmol/L]; P⬍0.01). Dane-Stewart et decreasing hepatic VLDL synthesis.32,33 Both mechanisms
al19 also found elevated median RLP-C levels in 15 FH lead to less competition for the clearance mechanisms shared
patients compared with 15 controls (16.2 mg/dL [0.42 mmol/L] by chylomicrons and VLDL.34 The reductions in apoB and
versus 8.5 mg/dL [0.22 mmol/L]; P⫽0.003). In the present LDL-C were very consistent with those of RLP-C, as is
cohort, mean age and BMI increased from the lowest to the anticipated, because by upregulating the LDL (apoB, E)
highest RLP-C tertiles. Why RLP levels rise with age is receptor, all apoB (LDL)- and apoE (RLP-C)-containing
unknown, but older people have higher BMIs, often com- lipoproteins will be reduced in essentially similar proportions.
bined with higher TG levels. This association points to The raised TG levels in the higher RLP-C tertiles support
increased synthesis of VLDL, which could lead to higher the accumulation of TG-rich lipoproteins. The conclusion
RLP levels.26 We also found a higher prevalence of apoE2 could therefore be drawn that TG levels measured in FH
allele carriers in the highest RLP-C tertile. ApoE is the major patients primarily reflect atherogenic remnant lipoproteins.
ligand for hepatic lipoprotein receptors and mediates chylo- However, even patients with normal TG levels had elevated
micron and VLDL remnant uptake.27 ApoE2 is 1 of the 3 E RLP-C levels. This observation was also made previously.20
isoforms and exhibits a very low affinity to the LDL All these data indicate the presence of remnant particle
receptor.28 It is therefore not unexpected to find more apoE2 accumulation in FH patients, irrespective of concomitant TG
alleles in the highest third of RLP-C levels. The apoE allele elevation. Likewise, stratification of the data according to
distribution was in Hardy-Weinberg equilibrium (␹2⫽3.59, baseline TG into quartiles resulted in an association between
P⬎0.1) in our FH sample, but the frequency of the ⑀-2 allele TG and RLP-C levels, but LDL-C levels were equally
was lower than previously reported in the general Dutch elevated in all quartiles. This suggests that despite the fact
population (0.047 and 0.082, respectively).29 It is therefore that plasma LDL-C levels are strongly elevated in FH
unlikely that an overrepresentation of the ⑀-2 allele of the patients, RLP-C levels could further contribute to the athero-
apoE gene contributed to our findings. genic lipoprotein profile over and above LDL-C measure-
These elevated RLP-C levels might play an important role, ments. We therefore hypothesize that remnant accumulation
in addition to elevated LDL-C levels, in the acceleration of in FH might be explained by a combination of factors, such as
atherosclerosis in FH. This idea is supported by the findings
the LDL-receptor mutation; VLDL production associated
of Karpe et al,17 who did not find an association between
with advancing age, central obesity, and glucose intolerance;
LDL-C and new lesions in vein grafts in 395 patients with
carriership of an ⑀-2 allele of the apoE gene; and possibly
coronary artery disease but did find a strong trend for higher
defective LDL-receptor related protein function. These find-
RLP-C concentrations.
ings may raise the need to prescribe combination therapy with
simvastatin 80 mg and either nicotinic acid or fenofibrate or
RLP-C Reduction After Statin Intervention
RLP-C levels are significantly decreased by simvastatin. to prescribe more powerful statins to lower the risk associated
Median RLP-C levels almost returned to normal but remained with the residual remnant increase.
slightly elevated. This observation was reported previously in In conclusion, baseline RLP-C levels are severely elevated
7 FH patients.20 Recently, 2 studies in patients with combined in FH patients. Treatment with high-dose simvastatin resulted
dyslipidemia showed similar results.30,31 Stein et al30 found in a strong reduction of RLP-C, but in the majority of
that median elevated RLP-C levels of 0.34 mmol/L were patients, RLP-C levels remained elevated. RLP-C levels in
reduced by simvastatin 20 mg (6.0%) and by atorvastatin 10 FH contribute to an atherogenic lipoprotein profile and could
mg (25.9%) but not by pravastatin 40 mg in 22 patients in a identify patients who require additional treatment.
crossover study. In addition, Sasaki et al31 found that atorva-
statin 10 to 20 mg reduced RLP-C levels from 0.31 to Acknowledgment
0.16 mmol/L. These studies also illustrate a treatment effect The ExPRESS study was sponsored by Merck, Sharp, and Dohme,
the Netherlands.
of statins on the RLP-C fraction.
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