(Circulation. 1999;99:1959-1964.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Evidence for a New Pathophysiological Mechanism for Coronary Artery Disease Regression
Hepatic Lipase–Mediated Changes in LDL Density
From the Department of Medicine, Division of Metabolism, Endocrinology and Nutrition (A.Z., J.E.H., J.D.B.) and Division of Cardiology (G.B.), University of Washington, Seattle, Wash.
Correspondence to Dr Alberto Zambon, Department of Medicine, Box 356426, University of Washington, Seattle, WA 98195-6426.
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Abstract |
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Background—Small, dense LDL particles are associated with coronary artery disease (CAD) and predict angiographic changes in response to lipid-lowering therapy. Intensive lipid-lowering therapy in the Familial Atherosclerosis Treatment Study (FATS) resulted in significant improvement in CAD. This study examines the relationship among LDL density, hepatic lipase (HL), and CAD progression, identifying a new biological mechanism for the favorable effects of lipid-altering therapy.
Methods and Results—Eighty-eight of the subjects in FATS with
documented coronary disease, apolipoprotein B levels 
125
mg/dL, and family history of CAD were selected for this study. They
were randomly assigned to receive lovastatin (40 mg/d) and
colestipol (30 g/d), niacin (4 g/d) and colestipol, or conventional
therapy with placebo alone or with colestipol in those with elevated
LDL cholesterol levels. Plasma hepatic lipase (HL),
lipoprotein lipase, and LDL density were measured when subjects were
and were not receiving lipid-lowering therapy. LDL buoyancy increased
with lovastatin-colestipol therapy (7.7%;
P<0.01) and niacin-colestipol therapy (10.3%;
P<0.01), whereas HL decreased in both groups (-14%
[P<0.01] and -17% [P<0.01] with
lovastatin-colestipol and niacin-colestipol, respectively).
Changes in LDL buoyancy and HL activity were associated with changes in
disease severity (P<0.001). In a
multivariate analysis, an increase in LDL
buoyancy was most strongly associated with CAD regression, accounting
for 37% of the variance of change in coronary stenosis
(P<0.01), followed by reduction in apolipoprotein Bl
(5% of variance; P<0.05).
Conclusions—These studies support the hypothesis that therapy-associated changes in HL alter LDL density, which favorably influences CAD progression. This is a new and potentially clinically relevant mechanism linking lipid-altering therapy to CAD improvement.
Key Words: stenosis • lipoproteins • lipids • atherosclerosis
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Introduction |
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Elevated LDL cholesterol (LDL-C) is associated with increased risk of coronary artery disease (CAD).1 2 Numerous primary and secondary CAD prevention trials have convincingly demonstrated that LDL-C reduction is associated with a decrease in clinical cardiac events.3 Emerging evidence also shows that lowering LDL-C is probably only part of the coronary heart risk story.4 In particular, LDL subclasses, characterized by different size, density, and lipid composition, have important clinical significance for CAD.5 Both cross-sectional6 7 8 9 10 and prospective studies11 12 13 demonstrate an association between LDL size6 7 8 9 11 12 13 14 or density9 10 and CAD. Recent clinical trials indicated that (1) subjects with small, dense LDL at baseline are more responsive to pharmacologically induced CAD improvement than individuals with large, buoyant LDL particles15 16 and (2) the on-treatment LDL density is inversely related to progression of coronary artery lesions.17
In cross-sectional studies, high hepatic lipase (HL) activity is associated with an increase in small, dense LDL particles and a decrease in HDL2 cholesterol (HDL2-C).18 19 20 21 No convincing epidemiological data are available on the association between HL and CAD. Furthermore, the effect of intensive lipid-lowering therapy on HL activity and its bearing on LDL density are not known.
The present study investigated the effect of intensive lipid-lowering therapy on changes in LDL density and CAD regression in the Familial Atherosclerosis Treatment Study (FATS).22 Moreover, the pathophysiological mechanism linking therapy to LDL density has been studied, with focus on the effect of intensive treatment on HL activity.
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Methods |
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Patients
Of 1198 men
62 years old with CAD who were screened for
inclusion in FATS,22 42% had apolipoprotein B (apoB)
levels 125 mg/dL and would qualify for the FATS protocol.
Eighty-eight sequential subjects of the 120 who completed the FATS
protocol had HL measured and were included in the present study.
Details of randomization and therapies have been published
previously.22 Subjects received an American Heart
Association step II diet and were randomly assigned to
lovastatin (40 mg daily) and colestipol (30 g daily) or
niacin (4 g daily) and colestipol, defined as intensive lipid-lowering
therapy, or conventional treatment by diet alone (placebo) or diet and
colestipol if the subject's LDL-C was 90th percentile for his or her
age. Blood samples were obtained for lipid analysis at
baseline, during 2.5 years of therapy, and 6 weeks after treatment, as
described previously.22 At the 2.5-year time point and 6
weeks aftertreatment, samples for HL activity and LDL buoyancy were
obtained. Samples for LDL buoyancy were available from 83 of 88
subjects.
Blood Collection
Blood was collected in EDTA after a 12- to 14-hour fast for LDL
buoyancy and plasma lipid measurements. Ten minutes after an
intravenous heparin bolus (60 IU/kg), blood was collected
in lithium-heparin for HL activity. Blood was immediately
centrifuged at 4°C and stored at -70°C.
Lipid and Lipoprotein Determinations
Plasma, LDL, HDL, HDL2, and
HDL3-C, triglycerides (TG), apoB,
apoA-I, and apoA-II were measured as previously
described.22 Lipoprotein(a) levels were determined with a
double monoclonal antibody-based ELISA.23
Density Gradient Ultracentrifugation
Lipoprotein particles were separated by flotation
rate24 optimized for apoB-containing
lipoproteins25 on the basis of strategies previously
described.26 A gradient of 1 mL of plasma adjusted to a
density of 1.08 g/mL (total volume, 5 mL) and 12 mL of a 1.006 g/mL
concentration of NaCl was formed in a Sorvall TV-865B tube
(DuPont) and centrifuged at 65 000 rpm for 90 minutes at
10°C. Tubes were fractionated, and cholesterol was
measured in 38 fractions by enzymatic kit (Sigma Chemical Co). LDL
relative flotation (LDL-Rf) was calculated as the fraction of the major
peak of LDL divided by the total number of fractions. The coefficient
of variation of LDL-Rf is 0.2%.18 All samples were
assayed within 600 days. LDL-Rf and LDL size are strongly
correlated,5 and LDL-Rf is different in subjects
classified by LDL subclass phenotype.27 The
physical principles behind this density gradient
ultracentrifugation are similar to the analytical
ultracentrifugation.28
Post–Heparin Plasma Lipase Activity
Lipolytic activity was measured in plasma as previously
described.29 Glycerol
tri[1-14C]oleate and lecithin were incubated
with postheparin plasma for 60 minutes at 37°C, and
liberated C14 free fatty acids were extracted and
counted. HL activity, in nanomoles of fatty acids released per
minute per milliliter of plasma (nmol ·
min-1 · mL-1), is
defined as the activity after incubation with a monoclonal antibody
that inhibits lipoprotein lipase (LPL).30 A bovine milk
LPL standard was included to adjust for interassay variation. A human
postheparin control sample included in each assay had a
coefficient of variation of 13.3% and no significant change over 600
days. All samples were assayed within this period of time.
Coronary Angiography
Quantitative coronary angiography was performed, and
angiograms were analyzed as previously
described.22 31 For each arterial lesion,
lumen diameter was measured at the point of greatest narrowing (minimum
diameter) and at a nearby point of normal diameter. In each subject, we
obtained an estimate of percentage proximal disease severity (%Sprox)
by averaging the severity of the worst lesion found in each of the 9
standard proximal coronary segments.22 Disease
changes (
%Sprox) were calculated as the difference between %Sprox
at baseline and after treatment.
Statistical Analyses
Values are mean±SD. On- and off-treatment effects within the
same group were analyzed with the paired Student t
test. Analyses between different treatment groups used the
unpaired Student t test. Either the Wilcoxon signed
rank or Mann-Whitney rank sum test was used when data were not normally
distributed.
Relationships between quantitative variables were tested by linear regression. Changes in LDL-Rf were linearly adjusted to the mean change in TG levels.
Multiple regression of changes in coronary stenosis (dependent variable) used a step-up procedure of risk variables that maximizes the predictive value of the model (R2).32 We calculated changes in blood pressure, body weight, lipids, and apolipoproteins by subtracting baseline values from on-treatment values. Significance was assumed at P=0.05.
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Results |
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Of the 88 sequential FATS subjects studied, 31 received lovastatin and colestipol, 26 niacin and colestipol, and 31 conventional therapy (18 as diet alone and 13 as diet and colestipol) (Table 1
). These treatment groups
were not statistically different from the treatment groups of the
original FATS cohort,22 which indicates that this subset
is representative of the larger group initially
studied. Moreover, lipid parameters measured at baseline
were not significantly different from follow-up values, with the
exception of HDL2-C (Table 1).
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Percent coronary stenosis decreased during intensive
lipid-lowering therapy with lovastatin-colestipol
(-1.25%) and niacin-colestipol (-0.7%), whereas an increase in
stenosis was seen with placebo and with placebo and colestipol
(combined mean, 1.87%) (Figure 1).
Coronary stenosis was significantly decreased in
subjects taking lovastatin-colestipol (P<0.01)
or niacin-colestipol (P=0.01) compared with subjects
receiving conventional treatment (whole group: placebo plus
colestipol), as previously reported.22
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P
HL activity significantly decreased by 14% in the
lovastatin-colestipol group (from 206±72 to 178±62
nmol · min-1 ·
mL-1) and by 17% in the niacin-colestipol group
(from 224±75 to 185±82 nmol ·
min-1 · mL-1)
(Table 2; Figure 1
). In patients
taking lovastatin-colestipol and niacin-colestipol, LDL
buoyancy significantly increased by 7.7% (from 0.261±0.04 to
0.281±0.03 Rf) and 10.3% (from 0.252±0.04 to 0.278±0.03
Rf), respectively. On the other hand, patients receiving
colestipol had a 6.8% decrease in LDL buoyancy (from 0.267±0.04 to
0.249±0.03 Rf; P<0.05) associated with a 6.1%
increase in HL activity (from 214±68 to 227±65 nmol ·
min-1 · mL-1). In
subjects receiving placebo, no significant changes in HL activity or
LDL buoyancy were observed. LPL activity did not change in any of the
groups studied (Table 2).
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Changes in LDL buoyancy were associated with changes in
coronary stenosis severity (r=-0.61,
P<0.001) in the whole population (Figure 2A). In subjects receiving intensive
lipid-lowering therapy, LDL buoyancy off therapy was significantly
associated with changes in disease severity (r=0.29,
P<0.05; n=54) such that denser LDL particles off therapy
were associated with better treatment outcome.
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Changes in HL activity and changes in percentage coronary
stenosis with therapy were highly associated
(r=0.57; P<0.001; Figure 2B).
Cross-sectional analysis showed that HL activity and LDL
buoyancy were significantly correlated both off treatment
(r=-0.25, P<0.05) and with lipid-lowering
therapy (r=-0.31, P<0.01). In addition, a
decrease in HL activity was strongly associated with a corresponding
increase in LDL buoyancy (r=-0.79, P<0.001;
Figure 2C). This association remained after adjustment for
changes in LDL buoyancy by changes in plasma TG (r=-0.80,
P<0.001; Figure 2C). A decrease in HL activity was
also associated with an increase in HDL2-C
(r=-0.50, P<0.001).
More than 50% of the changes in coronary stenosis
could be explained by changes in variables measured in this study
(Figure 3). Changes in LDL buoyancy with
drug therapy were the best correlates of changes in coronary
stenosis, accounting for 37% of the variance of changes in
disease severity (P<0.01), with changes in apoB levels
accounting for an additional 5% of the variance (P<0.05).
Changes in plasma TG explained an additional 3.0% of the variance
(P=0.08), with an additional 8.5% explained by the changes
in the remaining variables.
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Discussion |
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This analysis of FATS examines the strengths of LDL density and HL activity relative to other common risk factors as correlates of coronary disease progression. Two strong associations have emerged. These appear promising in that they lead toward new and clinically relevant therapeutic approaches.
First, drug-induced increases in LDL buoyancy are strongly associated
with improvement in coronary stenosis over a 2.5-year
period. By multivariate analysis, this
association of disease change with changes in LDL buoyancy is
considerably stronger than that with changes in LDL-C or apoB levels.
This dominant association is independent of changes in other risk
variables. Thus, changes in coronary disease depend not
only on quantitative changes in the number of LDL particles (ie,
decrease in apoB and LDL-C levels) but, more importantly, on
concomitant changes in lipoprotein composition that influence LDL
buoyancy (Figure 4). This first finding
is consistent with published evidence associating LDL density
with clinical coronary disease risk,7 8 9 10 11 12 13 14 with
angiographic rate of atherosclerosis
progression,15 16 or with subgroups of patients more
likely to benefit from certain lipid-altering
therapies.16 17 In many of these reports, as in the
present report, the risk attributable to LDL density was
independent of other lipoprotein levels or their
changes7 10 13 15 ; in others, the LDL density effects were
significant by univariate analysis but were not
statistically independent of TG9 and HDL-C
levels8 or of total cholesterol and HDL-C
levels12 or their ratio.11 These reports
highlight an issue that confounds statistical attempts to rank
lipoprotein particles according to their atherogenic potential: the web
of metabolic interrelationships among the plasma
lipoproteins, especially the TG-rich particles, HDL-C, and LDL size and
density.33 34 These metabolic
interrelationships violate the fundamental assumption of
multivariate analysis that selected independent
variables are indeed independent. In this setting, statistical
analyses can provide important clues to identify the truly
atherogenic particles, but well-designed experimental and clinical
studies are required to confirm the atherogenic potential of particles
implicated by multivariate analysis. In this
regard, small, dense LDL have been found to penetrate the
arterial wall more readily than buoyant LDL,35
to bind more avidly to arterial wall
proteoglycans,36 and to be more easily modified in an
oxidizing environment.37 Thus, a good case can be made for
the primary atherogenicity of small, dense LDL. Indeed, therapy-induced
changes in LDL-C levels and in LDL buoyancy appear to be largely
independent and may even be directionally opposite responses (ie, the
colestipol effect in the present study). In this regard, a
reasonable explanation for the recent controversy regarding the degree
of LDL-C reduction as a determinant of clinical
benefit38 39 may lie in the unmonitored and variable
effects of LDL density and its response to therapy among phenotypically
diverse individuals in these study populations.
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A second key finding is that HL activity falls significantly in response to intensive lipid-lowering therapy. Furthermore, there is an exceptionally strong (r=-0.80) inverse association between these changes in HL activity and changes in LDL buoyancy. Such evidence generates the hypothesis that the favorable effects on coronary disease severity attributable to increased LDL buoyancy are mediated by a pharmacological reduction in HL activity. HL is responsible for the lipolysis of both VLDL remnant particles40 and large, buoyant LDL, as well as the conversion of larger HDL2 to smaller HDL3 particles.40 41 As yet, the mechanisms for this newly observed therapeutic reduction in HL activity are unclear. However, one consequence of such reduction (namely, an increase in LDL buoyancy) is not unexpected. Studies in subjects with normal lipid levels show that HL levels are inversely correlated with LDL size and buoyancy18 19 and that men have twice the HL levels of women and have smaller, more dense LDL particles.20 A similar cross-sectional relationship between HL activity and LDL density exists among CAD patients.18 Genetic deficiency of HL is associated with large, buoyant, LDL-like particles.25 Recently a polymorphism in the promoter region of the HL gene has been reported that accounts substantially for observed variations in HDL-C42 43 and HL activity.44 45 We have reported that this polymorphism accounts for 20% of the variation in HL activity among normal subjects and for 32% among coronary disease patients and contributes to the modulation of the LDL buoyancy in these 2 groups.45 The present report clearly documents that therapeutic interventions associated with a reduction in HL activity improve LDL buoyancy.
There is some disagreement whether HL activity is proatherogenic or antiatherogenic.46 Although the rare individual with familial HL deficiency develops CAD,47 the present findings support a proatherogenic role for the enzyme HL.
The clinical implications of these findings apply at least to the large percentage (42%) of the coronary disease population who meet FATS lipid entry requirements on routine catheterization laboratory screening.22 First, LDL density appears to be a realistic and rewarding additional therapeutic target for coronary disease prevention. This is particularly true for individuals with borderline-high LDL-C, mildly elevated TG, and borderline-low HDL-C, a lipid phenotype often associated with small, dense LDL.33 As this report indicates, the risk for progressive coronary disease in such individuals, underestimated by the standard lipid measurements, can be reduced substantially by regimens that effectively increase LDL buoyancy. Second, HL activity takes on new importance as a potential therapeutic target by which LDL density and coronary disease risk may be favorably affected. HL activity may be inhibited directly at its site of action or indirectly by modulation of the gene promoter region.
In conclusion, these findings add compelling evidence for the role of increased LDL buoyancy for prevention of coronary disease progression and, by implication, of clinical events.48 49 They also identify HL as a potential key mediator of beneficial therapeutic effects on lipoprotein composition and coronary risk. These insights may help to improve substantially on the 20% to 35% cardiovascular risk reduction seen with treatment strategies focused on LDL-C lowering.50 51 52 53 54
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Acknowledgments |
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This study was supported by NIH grants (HL-30086, HL-19451, and HL-42419). A portion of this study was performed at the Clinical Research Center (NIH MOL 00037) and supported by the Clinical Nutrition Research Unit (NIH DK 35816) and the John L. Locke Charitable Trust, Seattle, Wash. Dr Zambon is a recipient of a fellowship from the American Heart Association, Washington Affiliate.
Received July 27, 1998; revision received December 31, 1998; accepted January 11, 1999.
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