© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Distribution of ApoA-I–Containing HDL Subpopulations in Patients With Coronary Heart Disease
From the Lipid Metabolism Laboratory, Jean Mayer USDA Human Nutrition Center on Aging at Tufts University, and the Division of Endocrinology, Metabolism, Diabetes, and Molecular Medicine (B.F.A., J.R.M., K.V.H., E.J.S.), New England Medical Center, Boston, Mass; the Physiology Department (P.S.R.), Louisiana State University Medical Center, New Orleans; the Division of Cardiology (R.L.M.), Alton Ochsner Hospital, New Orleans, La; and Pennington Biomedical Research Center (M.L.), Baton Rouge, La.
Correspondence to Bela F. Asztalos, PhD, JM-USDA/HNRC at Tufts University, Lipid Metabolism Laboratory, 711 Washington St, Boston, MA 02111. E-mail belaasztalos{at}yahoo.com
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Abstract |
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Abstract—High density lipoproteins (HDLs) and their subspecies play a role in the development of coronary heart disease (CHD). HDL subpopulations were measured by 2-dimensional nondenaturing gel electrophoresis in 79 male control subjects and 76 male CHD patients to test the hypothesis that greater differences in apolipoprotein (apo)A-I–containing HDL subpopulations would exist between these 2 groups than for traditional lipid levels. In CHD subjects, HDL cholesterol (HDL-C) was lower (-14%, P<0.001), whereas total cholesterol and the low density lipoprotein cholesterol/HDL-C ratio were higher (9% [P<0.05] and 21% [P<0.01], respectively) compared with control levels. No significant differences were found for low density lipoprotein cholesterol, triglyceride, and apoA-I levels. In CHD subjects, there were significantly (P<0.001) lower concentrations of the large lipoprotein (Lp)A-I
1 (-35%),
pre-1 (-50%),
pre-2 (-33%), and
pre-3 (-31%) subpopulations, whereas the
concentrations of the small LpA-I/A-II 3
particles were significantly (P<0.001) higher (20%).
Because 1 was decreased more than HDL-C and
plasma apoA-I concentrations in CHD subjects, the ratios of HDL-C to
1 and of apoA-I to
1 were significantly
(P<0.001) higher by 36% and 57%, respectively,
compared with control values. Subjects with low HDL-C levels (
35
mg/dL) have different distributions of apoA-I–containing HDL
subpopulations than do subjects with normal HDL-C levels (>35 mg/dL).
Therefore, we stratified participants according to HDL-C concentrations
into low and normal groups. The differences in lipid levels between
controls and HDL-C–matched cases substantially decreased; however, the
significant differences in HDL subspecies remained. Our research
findings support the concept that compared with control subjects, CHD
patients not only have HDL deficiency but also have a major
rearrangement in the HDL subpopulations with significantly lower
1 and pre-1–3
(LpA-I) and significantly higher 3
(LpA-I/A-II) particles.
Key Words: HDL subpopulations • coronary heart disease • lipids • lipoproteins • apolipoproteins
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Introduction |
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Coronary heart disease (CHD) remains the leading cause of death and disability in the United States. Approximately 14 million people have CHD, and 1.5 million individuals experience a myocardial infarction annually, leading to
500 000 deaths per
year.1
Atherosclerosis is a multifactorial disease affected by
lifestyle and genetic
factors.2 Independent
risk factors for CHD as defined by the National Cholesterol
Education Program (NCEP) Adult Treatment Panel II include the
following: age, sex, hypertension, smoking, diabetes, family history of
premature CHD, elevated plasma levels of LDL cholesterol
(LDL-C 
160 mg/dL), and low levels of HDL (HDL-C <35
mg/dL).3 4 5 6 7 8 9 10
The NCEP panel classified an HDL-C level 60 mg/dL (>1.55
mmol/L) as protective against the development of
CHD.3 Many prospective
epidemiological studies have indicated that a decreased HDL-C level is
a significant independent risk factor for heart
disease.5 6 7 9 11 12
HDL is found in human plasma at a density of 1.063 to 1.21
g/mL and contains 50% protein, 25% phospholipid, 20%
cholesterol (mainly esterified), and 5%
triglycerides by weight. The 2 major protein constituents
are apoA-I and apoA-II. A variety of methods, including analytical
ultracentrifugation, differential precipitation,
immunoaffinity chromatography, and nondenaturing 1D and
2D gel electrophoresis, have been developed to separate HDL into
different subclasses. These HDL subpopulations differ in apolipoprotein
and lipid composition, as well as in size and charge, and probably have
different physiological
functions.13 14 15 16
Separation of HDL subclasses on the basis of charge and size
by 2D nondenaturing gel electrophoresis was developed in the late
1980s14 and later was
adopted by
others.16 17 18
By use of this method, the majority of apoA-I in plasma has
mobility. These HDL particles have been classified as
1, 2, and
3, with sizes of 11.2, 9.51, and 7.12 nm,
respectively.18 Small
amounts of HDL particles containing apoA-I with pre-ß mobility
(pre-ß1 and pre-ß2)
have been detected as well. We have standardized the 2D nondenaturing
gel electrophoresis methodology and have reported 12 apoA-I–containing
HDL subpopulations, including 4 new subpopulations with pre-
mobility containing only
apoA-I.18 19
ApoA-II is present in 2 and
3 HDL
subpopulations.19
Subjects with low HDL-C levels have significant decreases in the large
LpA-I HDL particles, 1 and
pre-1.19
The precise function and the metabolic nature of the apoA-I–containing and/or other apolipoprotein-containing HDL subfractions remain to be elucidated. There are a number of epidemiological studies on the relationship between CHD and HDL subspecies with conflicting results. Most investigators report an overall reduction in HDL-C and apoA-I in CHD subjects compared with control subjects.20 Depending on the methodology used, however, some scientists report significantly lower levels of HDL2 or LpA-I in CHD subjects,21 22 23 24 25 and others report reductions in HDL3, in HDL2 and HDL3, or in LpA-I and LpA-I/A-II.23 26 27 28 29 30 Using immunoaffinity chromatography and nondenaturing gel electrophoresis, Cheung et al31 reported significant differences in the size of HDL particles between CHD patients and control individuals. They found that the presence of CHD was more strongly associated with HDL particle size distribution than with a low HDL-C level. The discrepancy between studies may be due to sample size and/or subject selection. Alternatively, the difference in results between studies may be explained by the fact that HDL2, HDL3, LpA-I, and LpA-I/A-II are heterogeneous fractions and contain a variety of different HDL subspecies. These issues require resolution with larger sample sizes and with more complete characterization of HDL subspecies.
Our goal was to determine and compare HDL subpopulations, as defined by 2D nondenaturing gel electrophoresis, in healthy male controls and male subjects with CHD. The present study provides additional information about the potential role of HDL subpopulations in the risk for CHD.
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Methods |
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Study Population
Fasting plasma samples were obtained from 79 healthy male subjects, aged 30 to 82 years. Participants were selected to have total plasma cholesterol and LDL-C levels between the 10th and 90th percentile, HDL-C levels >25 mg/dL or below the 95th percentile, and triglycerides below the 95th percentile. Lipid cutoff points were selected to eliminate subjects with lipid disorders. Exclusion criteria included the presence of cardiovascular, renal, hepatic, endocrine, gastrointestinal, or other systemic disease, body mass index >32 kg/m2, and hypertension. During screening visits, physical examinations, blood chemistry, lipid profiles, and urinalyses were performed.
Fasting plasma samples were also obtained from 76 male
patients, aged 33 to 81 years, with established CHD, as documented by
history of prior myocardial infarction, coronary artery bypass
grafting, percutaneous transluminal coronary
angioplasty, documented disease on coronary angiography (>50%
stenosis in 1 coronary artery), or the presence of
angina pectoris with a positive stress test. Exclusion criteria
included triglyceride values >400 mg/dL, body mass index
>35 kg/m2, secondary causes of
hyperlipoproteinemia, diabetes, any systemic
disease interfering with lipoprotein metabolism,
lipid-lowering medications, and/or myocardial infarction, and/or
coronary artery bypass graft within the last 12
weeks.
Lipid and Lipoprotein Analysis
Fasting blood samples were collected into tubes
containing 1.5 g/L EDTA and centrifuged at
3000g for 20 minutes at 4°C to obtain plasma.
Aliquots of each plasma sample were stored at -80°C or in liquid
nitrogen until use. Total cholesterol, HDL-C, and
triglycerides were determined by use of automated enzymatic
assays. HDL-C was determined after precipitation of the non-HDL
fraction by the dextran sulfate
method.32 LDL-C was
calculated by use of the Friedewald
equation.33 ApoA-I
was measured in plasma by automated immunoturbidometric assay (Wako
Inc). Coefficients of variation for all assays between and within runs
were <10%.
HDL Subpopulation Analysis
Separation of HDL subpopulations was carried out
similarly as previously described in
detail.18 19
Plasma samples stored at -80°C were placed into liquid nitrogen for
30 minutes before thawing at 37°C to avoid any alterations in the
physicochemical composition of the particles. The effects of storage
and thawing conditions were carefully investigated
(Table 1
). No significant differences in the percent
distribution of the apoA-I–containing HDL subpopulations were detected
(at 95% CI) when fresh plasma and stored plasma samples (up to 1 year)
were compared.
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In the first dimension, we separated HDL according to charge
into pre-ß, , and pre- mobility particles. Four microliters of
plasma was applied to 0.7% LE SeaKem agarose gels (3 mm thick)
and electrophoresed in a vertical slab gel electrophoresis unit
(Pharmacia GE 2/4 recirculating apparatus) in 25
mmol/L Tris-tricine buffer at pH 8.6 (10°C) at 250 V until the
albumin (the blue band) reached 3.5 cm. Gel strips were cut
out, placed, and sealed (with 65°C agarose) on the top of the
nondenaturing 3% to 34% concave gradient polyacrylamide gels,
followed by electrophoresis in the second dimension. Gels (3 mm
thick) were prepared in a Hoefer gel-caster (SE-600). Electrophoresis
was carried out in a Hoefer SE-600 electrophoresis
apparatus (Amersham Pharmacia Biotech) for 24 hours at 250
V in buffer containing 90 mmol/L Tris, 80 mmol/L boric acid,
and 2.5 mmol/L EDTA, pH 8.3.
125I-labeled molecular weight standard
proteins (Pharmacia High Molecular Weight Standard) were applied in the
middle of each polyacrylamide gel. Electrotransfer onto
nitrocellulose membranes (BA-S83, 0.2 µm, Schleicher & Schuell) was
carried out at 30 V for 24 hours at 10°C. Posttransfer membrane
operations included fixing with 0.3% glutaraldehyde in
PBS for 10 minutes, rinsing with Tris-buffered PBS (PBST), blocking
with 5% dry milk for 10 minutes, and incubating with monospecific
polyclonal goat anti-human apoA-I sera for 6 hours. Unbound antibody
was removed by washing 3 times for 3 minutes each with PBST, followed
by incubation with 125I-labeled rabbit
anti-goat Fa(b)2 IgG fragment overnight.
Membranes then were washed 3 times for 3 minutes each with PBST, dried,
and placed in cassettes for overnight exposure. Quantification was
carried out in a PhosphorImager with the use of an ImageQuant software
package (Molecular Dynamics). After the peaks were determined by
integrating the designated
areas,18 each HDL
subpopulation was delineated. The program automatically measured the
volume of each area and the percent distribution of each of the
encircled HDL subpopulations. Data were expressed as pixels linearly
correlated with the disintegrations per minute of the
125I bound to the antigen-antibody
complex.34 Absolute
concentrations (in milligrams apoA-I per deciliter plasma) were
calculated by multiplying the plasma total apoA-I concentration
(milligrams per deciliter) by the percentile value of each
subpopulation.
For further analysis, nonnormally distributed data were transformed by use of the natural logarithm to approach a gaussian distribution. To test the hypothesis of no difference in mean levels of given variables between categories, ANOVA was used with the Stat Most statistical software package.
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Results |
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Information about age, concentrations of plasma lipids and apoA-I, and the ratio of LDL-C to HDL-C for control subjects (n=79) and CHD patients (n=76) is presented in Table 2
. The CHD group was significantly
(P<0.001) older (8.4 years) than the control group.
Other significant differences between the control and CHD groups were
as follows: HDL-C (-14%, P<0.001), total
cholesterol (9%, P<0.05), and the ratio
of LDL-C to HDL-C (23%, P<0.01). Concentrations of
LDL-C and triglycerides were higher in the CHD group by 5%
and 18%, respectively, but the differences were not significant,
whereas apoA-I concentrations were similar in the 2 groups. When the
apoA-I–containing HDL subpopulations were compared between the 2
groups
(Table 3), we found significantly lower concentrations of
1 (-35%), pre-1
(-50%), pre-2 (-33%), and
pre-3 (-31%, P<0.001) in
CHD patients. In contrast, the 3 HDL
subpopulation was significantly higher (20%,
P<0.001) in the case patients, whereas differences in
2, pre-ß1, and
pre-ß2 were not significantly different
between the 2 groups. We calculated the ratios of apoA-I to
1 and of HDL-C to 1
and found that both ratios were significantly
(P<0.001) higher in the CHD group (by 57% and 36%,
respectively) than in the control group.
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To test the hypothesis that HDL-C concentration has an
influence on the values of the above-measured parameters,
both groups were further separated according to HDL-C level into low
(HDL-C 35 mg/dL) and normal (HDL-C >35 mg/dL) groups. There were 24
control (30.4%) and 37 CHD (48.7%) subjects in the low HDL-C group
and 55 control (69.6%) and 39 CHD (51.3%) subjects in the normal
HDL-C group. In the low HDL-C group, CHD subjects had significantly
higher total cholesterol (20%, P<0.05)
and significantly lower HDL-C (-6%, P<0.05)
concentrations compared with HDL-C–matched control subjects
(Table 4). LDL-C, triglyceride, and apoA-I
levels were higher by 13%, 15%, and 5%, respectively, but these
differences were not significant. In the normal HDL-C group, only the
average HDL-C concentration was significantly different (-9%,
P<0.05) in CHD patients compared with control
subjects. The ratios of LDL-C to HDL-C were higher in CHD patients in
the low (21%) and normal (9%) HDL-C groups, but these differences
were not significant
(Table 4).
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When the apoA-I–containing HDL subpopulations were compared
between control and CHD subjects, very similar patterns were found in
low and normal HDL-C groups
(Table 5), and the differences resembled those obtained when
all CHD patients were compared with all control individuals. In CHD
patients with low HDL-C levels compared with control subjects,
1, pre-1,
pre-2, and pre-3
subpopulations were significantly lower (P<0.001), by
-30%, -48%, -33%, and -32%, respectively, whereas
pre-ß1 and 3 were
significantly higher by 40% (P<0.05) and 21%
(P<0.01), respectively
(Table 5). Levels of pre-ß2
(-7%) and 2 (8%) were not significantly
different between cases and controls with low HDL-C levels. In patients
with normal HDL-C levels, the 1,
pre-1, pre-2, and
pre-3 subpopulations were also significantly
(P<0.001) lower by -29%, -44%, -29%, and
-29%, respectively, whereas 3 was
significantly higher by 21% (P<0.001), and the
concentrations of pre-ß1,
pre-ß2, and 2 were
not significantly different when CHD cases were compared with the
appropriate controls. The ratios of apoA-I to
1 and of HDL-C to 1
were significantly higher in CHD patients in the low and normal HDL-C
groups by 57%, 37%, and 44%, 33%, respectively, compared with
ratios in the appropriate control groups.
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The 1 and
2 HDL subpopulations were strongly correlated
with HDL-C in control subjects (r=0.756 and
r=0.714, respectively) and CHD subjects
(r=0.774 and r=0.575, respectively).
Concentration of the 3 subpopulation did not
correlate with HDL-C. In addition, a very strong positive correlation
was found between the 1 and
2 subpopulations and apoA-I levels in control
subjects (r=0.832 and r=0.852,
respectively) and CHD subjects (r=0.600 and
r=0.798, respectively). The concentration of the
3 subpopulation was weakly correlated with
apoA-I values in both groups. In control and CHD groups, the
1 subpopulation correlated negatively with
the plasma triglyceride level (r=-0.476
and r=-0.517, respectively), whereas the
3 subpopulation correlated positively with
the plasma triglyceride level (r=0.380 and
r=0.230, respectively). No correlation was found
between the -mobility HDL subpopulations and either total
cholesterol or LDL-C. In
Figure 1, we present the regression lines and the 95%
CIs around the regression lines for the various -mobility
subpopulations versus HDL-C and plasma total apoA-I for control
subjects superimposed with the x-y scatterplot of the same
parameters for CHD subjects. The majority of data points
for CHD subjects of 1 versus HDL-C (66%) and
apoA-I (86%) were below the 95% CIs calculated for control
individuals. The majority of data points on CHD subjects with regard to
3 versus HDL-C (67%) and apoA-I (78%) were
above the 95% CIs calculated for control individuals. Data points of
cases on 2 subpopulations versus HDL-C (42%)
and 2 versus apoA-I (38%) also showed a
trend for values above the 95% CIs of control subjects.
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Because earlier studies on the relation of HDL subspecies
and CHD used ultracentrifugally separated subfractions, we compared the
2 methodologies. Ultracentrifugally separated
HDL2 (density [d]<1.125) and
HDL3 (d=1.125 to 1.24) were subjected to 2D
nondenaturing gel electrophoresis
(Figure 2). The majority of HDL2 was
found in the 1 and
pre-1 positions, whereas
HDL3 was a composite of the smaller
2, 3,
pre-2, pre-3, and
pre-ß1 subpopulations. All of the
pre-ß2 and some apoA-I from the other
particles were found in the d>1.21 g/mL fraction in accordance with
our previous
observation.18
Because it is known that ß-blockers can affect lipoproteins, we
examined HDL subspecies in CHD patients on and off ß-blockers and saw
no significant effects.
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Discussion |
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The inverse association between the incidence of CHD and HDL has been known for decades.7 8 16 20 21 22 23 24 25 26 27 28 29 30 31 35 36 37 38 HDL is heterogeneous, containing multiple subpopulations differing in size, density, flotation rate, lipid and apolipoprotein composition, and functional properties.19 39 40 41 42 In the last 2 decades, many laboratories have tried to assess whether any of these subpopulations have a stronger relationship with risk for CHD than others.20 21 22 23 24 25 26 27 28 29 30 31 35 36 37 Despite conflicting data, as Silverman et al43 reviewed in 1993 and Montali et al30 summarized in 1994, many investigators believe that measuring HDL subfractions may provide additional information about atherosclerotic risk as well as about the underlying physiological mechanism responsible for that risk.
In the present study, we investigated the relationship
between plasma lipid levels and the apoA-I–containing HDL
subpopulations, separated by nondenaturing 2D gel electrophoresis, and
CHD. Data generated in the present study support earlier
observations that a low HDL-C level, even in the presence of a normal
LDL-C concentration, is a potential risk factor for
CHD43 44
(Table 2
). Our results indicate that in the CHD group, the
lower concentration of HDL-C (-14%) rather than the higher LDL-C
level (5%) was mainly responsible for the significantly increased
ratio of LDL-C to HDL-C (23%).
We have previously published that subjects with low HDL-C
levels (35 mg/dL) have different HDL subpopulation profiles than do
subjects with normal levels of HDL-C (>35
mg/dL).19 Therefore,
we further partitioned both groups into low and normal HDL-C subgroups.
Comparing the HDL-C–matched CHD and control groups, we found 20%
(P<0.05) higher total cholesterol levels
in the low HDL-C CHD subjects versus only 3% higher total
cholesterol values in CHD subjects in the normal HDL-C
group
(Table 4). Therefore, CHD subjects in the low HDL-C group
were responsible for the significantly higher total
cholesterol in the combined CHD group compared with the
combined control group. Similar to total cholesterol,
differences in the concentrations of LDL-C and
triglycerides and the ratio of LDL-C to HDL-C were greater
in low HDL-C cases than in cases with normal HDL-C levels compared with
the appropriate control groups. Because the ratios of LDL-C to HDL are
dependent on HDL-C concentrations, this ratio gives more precise
information about risk for CHD when CHD patients are compared with
HDL-C–matched control individuals. In contrast, HDL-C 1 ratio did
not show this discriminative difference between groups with different
HDL-C levels and was significantly lower in CHD cases in the low and
normal HDL-C groups.
As we discussed earlier, the major HDL constituents, apoA-I
and HDL-C, did not differ strikingly between control and CHD subjects.
However, a major reorganization of the apoA-I–containing HDL
subpopulations was observed in CHD patients compared with control
individuals
(Tables 3 and 5). The 1 and all of
the pre- subpopulations were significantly lower, whereas the
3 subpopulation was significantly higher in
CHD subjects compared with control subjects. The differences in the
concentrations of the 2 and the pre-ß
mobility subpopulations were not significant between the 2 groups. It
has to be noted that there were significantly higher
pre-ß1 HDL subpopulations in CHD subjects than
in control subjects when percent distribution was calculated. These
data suggest that in CHD subjects the lipid-poor
pre-ß1 maturation into larger discoidal HDL
particles (probably 1) is impaired. Because
85% of apoA-I is in mobility particles, our focus was on
differences in these particles. Previously, we have reported that
neither the 1 nor the pre–-mobility HDL
subpopulations contain apoA-II; therefore, they are LpA-I
particles.19 LpA-I
particles appear to play a pivotal role in reverse
cholesterol transport and in the development of
CHD.23 Our finding of
decreased large LpA-I particles, including 1
and pre-1, in CHD subjects versus control
subjects supports recently published observations of Decossin et
al.45
We have also demonstrated that subjects with low (35
mg/dL) and normal (>35 mg/dL) HDL-C levels have very different
distributions of apoA-I–containing HDL subpopulations. Therefore, we
examined whether the differences in the HDL subpopulation profiles
between control and CHD subjects are only reflections of the
differences in HDL-C levels. The subgroup analyses proved that
the differences in HDL subpopulation profile between the control and
CHD groups are still significant after the HDL-C level is taken into
account. The 1 subpopulation is decreased by
41% in the low HDL-C groups compared with the normal HDL-C groups and
is further decreased by about another 30% in CHD individuals compared
with HDL-C–matched control subjects
(Table 5).
Our results indicate that despite the decrease in apoA-I and
HDL-C, the extensively decreased 1 (-35%)
resulted in increased ratios of apoA-I to 1
(57%) and HDL-C to 1 (36%) in CHD
individuals
(Table 2). The differences in these ratios were still
significant between controls and cases after subgrouping individuals
into low and normal HDL-C groups
(Table 5). The lower 1 and higher
3 concentrations in CHD subjects were also a
characteristic for the group and independent of HDL-C level
(Figure 1). These results indicate that some patients have
CHD caused by factors that do not alter the lipid and HDL subpopulation
profile. However, the majority of normolipidemic CHD patients have an
altered distribution of HDL subpopulations.
On the basis of our results, we may be able to explain the
discrepancies among laboratories on the possible role of HDL subclasses
in the development of CHD. By our 2D analysis, the majority of
HDL2 is in the 1 and
pre-1 positions
(Figure 2). Earlier, we demonstrated that
1 and pre-1 consist
of LpA-I particles. Data generated by
ultracentrifugation, immunoaffinity
chromatography, or nondenaturing gel electrophoresis
indicate lower levels of these particles in CHD individuals compared
with control
subjects.21 22 23 31
These findings are understandable, inasmuch as
1 is a homogeneous subpopulation
and shows a very strong positive correlation with HDL-C and apoA-I
concentrations, which are usually lower in CHD subjects. However, the
picture is more complicated for HDL3, because it
consists of many different HDL subspecies (mainly
2 and 3) of varying
sizes and apolipoprotein composition
(Figure 2). The concentration of these particles is
differentially altered (2 decreases, whereas
3 increases) in CHD individuals compared with
control subjects.
Data generated in the present study on normolipidemic
subjects support our hypothesis that the apoA-I–containing HDL
subpopulation profile, obtained by 2D nondenaturing gel
electrophoresis, is significantly different between control and CHD
individuals. These differences were not influenced significantly by
HDL-C or apoA-I concentrations. Our research findings support the
concept that compared with control subjects, CHD patients not only have
HDL deficiency but also have a major rearrangement in the HDL
subpopulations with significantly lower 1 and
pre-1–3 (LpA-I) and significantly higher
3 (LpA-I/A-II)
particles.
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Acknowledgments |
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This research was supported by a grant from Parke Davis, Morris Plain, NJ, and by the National Institutes of Health/National Heart, Lung, and Blood Institute (HL-56160). The authors wish to thank Dana Bass for her excellent help in collecting medical histories on CHD patients.
Received April 26, 2000; accepted September 21, 2000.
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