© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
The Metabolic Syndrome, LDL Particle Size, and Atherosclerosis
The Atherosclerosis and Insulin Resistance (AIR) Study
From the Wallenberg Laboratory for Cardiovascular Research (J.H., J.W.) and the Department of Medicine (L.B., B.F.), Sahlgrenska University Hospital, Göteborg University, Gothenburg, Sweden.
Correspondence to Johannes Hulthe, MD, PhD, the Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden. E-mail johannes.hulthe{at}wlab.wall.gu.se
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Abstract |
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Abstract—An operative definition of the metabolic syndrome has been suggested by a working group associated with the World Health Organization in 1998. The aim of this study was to examine whether small, low density lipoprotein (LDL) particle size was associated with the metabolic syndrome and with subclinical atherosclerosis as measured by ultrasound in the carotid and femoral arteries. The study was performed in a population-based sample of clinically healthy men (N=391), all 58 years old and not undergoing any treatment with cardiovascular drugs. Exclusion criteria were cardiovascular or other clinically overt diseases or continuous medication with cardiovascular drugs. The results showed that subjects characterized by the metabolic syndrome (n=62) had a thicker mean intima-media complex (IMT) in both the carotid and femoral arteries (0.86 versus 0.77 mm, P<0.001, and 1.03 versus 1.00 mm, P=0.022, respectively) and also lower mean values for LDL particle size (25.78 versus 26.80 nm, respectively, P<0.001) compared with subjects with no risk factors (n=77). The group with the metabolic syndrome (n=62) also had higher mean values for serum cholesterol and heart rate. In the whole study group (N=391), there were significant but weak negative relationships between small LDL particle size, increasing IMT, and increasing cross-sectional intima-media area of the carotid and femoral arteries and also negative relationships between LDL particle size and plaque occurrence and size in the carotid and femoral arteries. In summary, this is the first large-scale study to demonstrate a relationship between the clustering of risk factors that constitute the metabolic syndrome and a small LDL particle size pattern and the occurrence of preclinical atherosclerosis in the carotid and femoral arteries, as assessed by the ultrasound technique, in healthy 58-year-old men recruited from the general population.
Key Words: metabolic syndrome • atherosclerosis • ultrasound • LDL particle size
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Introduction |
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The observation that insulin resistance is associated with a clustering of risk factors for cardiovascular disease has led to the suggestion of a syndrome, which has been given different names, eg, the metabolic syndrome or the insulin resistance syndrome.1 However, it is still unclear how this proposed syndrome should be delineated and how the underlying mechanisms affect the cardiovascular disease process.1 Central to the hypothesis is the concept that insulin resistance leads to a multitude of perturbations that in the end may cause atherosclerotic disease.1 Also, other risk markers have been associated with the metabolic syndrome, such as heart rate,2 3 which seem to be associated with increased sympathetic nervous activity in combination with decreased vagal tone. Earlier studies have indicated an association between insulin resistance and variables related to atherosclerotic disease among whites.4 5 6 However, the definition of the metabolic syndrome has not yet been fully clarified. An operative definition of the metabolic syndrome has been suggested by a working group associated with the World Health Organization in 1998.7
The dyslipidemia associated with insulin resistance is characterized by hypertriglyceridemia and a low concentration of serum HDL cholesterol.8 9 10 The hepatic synthesis of lipoproteins and the degradation of circulating lipoproteins are, to a large extent, dependent on insulin action.11 12 13 The size and composition of the lipoproteins may consequently be related to insulin resistance. Hence, it is generally believed that small LDL particle size may be associated with insulin resistance.14 15 16 17 However, there are also several reports that have failed to confirm a relationship between LDL particle size and insulin resistance.18 19 Small LDL particle size has also been suggested to be associated with the development of atherosclerosis as measured by coronary angiography,20 21 22 23 but again, this is not a consistent finding.24 25 26 27 28 Taken together, available data show that it is still unclear whether small LDL particle size is related to the insulin resistance syndrome and to the atherosclerotic disease process.
A negative relationship between LDL particle size and intima-media thickness (IMT) has been found in a previous study by Skoglund-Andersson et al.29 In that study, only subjects homozygous for the apoE3 allele were included. Furthermore, subjects with a high body mass index (BMI >32 kg/m2) and plaque occurrence were excluded. In a subsample of subjects (n=36) recruited from the present study, the reproducibility of LDL particle size determination has been studied.30 In this pilot study, we also showed a negative relationship between plaque occurrence in the carotid artery and small LDL particle size.30 However, the study only included 36 subjects and did not address the relationships between small LDL particle size and atherosclerosis in the femoral artery or the carotid bulb, the latter of which is possibly a segment more closely related to coronary atherosclerosis than are common carotid IMT and femoral IMT.31
Taken together, there has been no previous large-scale study investigating the relationship between the metabolic syndrome, LDL particle size, and atherosclerosis in a population-based sample of clinically healthy subjects. Accordingly, the present study was designed with the aim of examining whether small LDL particle size is associated with the metabolic syndrome and with preclinical atherosclerosis, as measured by ultrasound in the carotid and femoral arteries. The study was performed in a population-based sample of clinically healthy men (N=391), all 58 years old and who were not undergoing any treatment with cardiovascular drugs.
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Methods |
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Study Group
The subjects were randomly selected from among 58-year-old men listed in the county council register of Gothenburg, Sweden. Our power calculation indicated that we needed 800 subjects. An invitation letter was sent to 1728 men, of whom 1188 gave a positive reply. After a telephone interview and a screening examination, 314 subjects fulfilled the exclusion criteria, 19 subjects refused to participate in the study, and 37 subjects could not be reached for the telephone interview. Hence, 818 men were finally recruited to the Atherosclerosis and Insulin Resistance (AIR) study. To keep the sociocultural components within a limited range, inclusion criteria were 58 years of age, Swedish ancestry, and living in Gothenburg, Sweden. Exclusion criteria were cardiovascular or other clinically overt diseases (eg, malignancy or psychiatric disease) and continuous medication with cardiovascular drugs (ie, antidiabetic, lipid-lowering, antihypertensive, and heart failure drugs or drugs for angina pectoris). Among these 818 included subjects, 38 (5%) were found to have a blood glucose level
6.1 mmol/L at the time of screening.
However, none of the subjects had overt diabetes mellitus. In connection with the screening examination, the subjects were divided into quintiles of a BMI/blood glucose score, which allowed immediate stratification and selection for further studies. The following equation was used: BMI/blood glucose score=46.22 -1.27(BMI) -0.84(whole-body glucose). This algorithm was based on a previous study of clinically healthy men of similar age who had undergone a euglycemic hyperinsulinemic clamp examination.32 The correlation coefficient between the BMI/blood glucose score and observed insulin sensitivity was 0.81. In the present population sample, this score was significantly correlated with insulin sensitivity measured with the euglycemic hyperinsulinemic clamp method, when expressed as insulin-mediated glucose uptake adjusted both for body weight and for fat-free mass (r=0.69, P<0.001 and r=0.59, P<0.001, respectively; n=104). In a score reproducibility study of 60-year-old men obtained from the background population (n=32) examined at an interval of 2 weeks, this parameter showed a coefficient of variation of 3.39% and a correlation coefficient of r=0.99 between the 2 examinations. All subjects in quintiles 1 and 5 and every fifth subject in quintiles 2 through 4 were invited to participate in future cross-sectional and prospective studies of insulin metabolism and ultrasound examinations of the carotid and femoral arteries (N=391). All men received both written and oral information before consenting to participate in the study. The study was approved by the ethics committee at Sahlgrenska University Hospital.
Fasting Glucose and Insulin Resistance
Glucose intolerance was defined as a fasting blood glucose level
5.6 mmol/L. Insulin resistance was defined as a fasting plasma
insulin level 14.86 mU/L. This definition was obtained by using the
euglycemic hyperinsulinemic clamp method to
define glucose uptake below the lowest quartile for the population
under investigation in a representative sample of 50
subjects from the present study. The plasma insulin level
corresponding to the lowest quartile for glucose uptake was calculated
and used as a cutoff point when defining insulin resistance. The
positive and negative predictive values of this plasma insulin cutoff
point were 0.88 and 0.86, respectively, in 52 subjects from the same
background population who had undergone a clamp examination and who
were not included in the first calculation above.
Definition of the Metabolic Syndrome
The definition suggested by a working group consulted by the
World Health Organization in 19987 was used. The
metabolic syndrome is defined as glucose intolerance and/or
insulin resistance together with 2 or more of the following risk
factors: (1) raised arterial
(systolic/diastolic) pressure 160/90 mm Hg
(either value); (2) raised triglycerides (1.7
mmol/L) and/or low HDL cholesterol (<0.9 mmol/L); (3)
central body obesity (waist-to-hip ratio >0.90) and/or BMI >30
kg/m2; and (4) microalbuminuria
(urinary albumin excretion rate 20 µg/min or
albumin-to-creatinine ratio 20 mg/g). In the
present study, subjects with a dipslide reading of 1+ were also
included in this category, whereas those with a dipslide reading of
1+ or a urinary excretion rate >208 µg/min were excluded from this
category.
For analyses of ultrasound and LDL particle size variables, the study group (N=391) was divided into 3 subgroups: (1) subjects fulfilling the criteria for the metabolic syndrome (n=62); (2) subjects with at least 1 risk factor (n=252); and (3) subjects with no risk factors (n=77). This latter group was used as a reference group for subjects with the metabolic syndrome.
LDL Particle Size Determination
Gradient Gel Electrophoresis
LDL particle size was assessed on commercially available,
nondenaturing 2% to 16% polyacrylamide gradient gels (Alamo
Inc) as previously described.30
Standards
A pooled plasma standard (kindly supplied by R.M. Krauss,
Lawrence Berkeley Laboratory, University of California, Berkeley) with
3 peaks of known size at 31.69±0.22, 27.77±0.18, and 25.06±0.14 nm
was used along with apoferritin (12.2 nm) to calibrate a standard serum
developed at the Wallenberg Laboratory from 1 patient with 3 distinct
peaks (30.58±0.14, 26.33±0.11, and 25.38±0.09 nm). This standard
serum was then used in the present study.
Measurement Procedure
The coefficient of variation (same serum run on different gels
on different days) for LDL peak particle size was 0.3%, with a
correlation coefficient of r=0.99. To minimize the reading
error from the gels, each lane was scanned twice. Mean values from the
2 readings are used in the present study. It is possible to choose
which variables are to be studied. For the present study, the
main variables studied were (1) LDL peak particle size (in
nanometers); (2) the percentage of particles under the curve
with a size <25.5 nm, called B%; and (3) the percentage of particles
under the curve with a size between 27.5 and 30 nm, called IDL% (ie,
intermediate density lipoprotein).
Ultrasonography
IMT, Lumen Diameter, and Cross-Sectional Area
The ultrasound images were analyzed in an automated,
computerized analysis system.33 IMT was defined as
the distance from the leading edge of the lumen-intima interface of the
far wall to the leading edge of the media-adventitia interface of the
far wall. Lumen diameter was defined as the distance between the
leading edges of the intima-lumen interface of the near wall and the
lumen-intima interface of the far wall. Both the left and right carotid
arteries were scanned at the level of the bifurcation, and images for
IMT measurements were recorded from the far wall in the common
carotid artery, the carotid artery bulb, and the right femoral artery.
The software program gives the average thickness of the intima-media
complex (ie, IMT). Measurements in the common femoral artery were made
in a similar way to those in the carotid artery but along a 15-mm-long
section proximal to the bifurcation.34
An estimate of the mean cross-sectional area of the IMT was calculated
for both the carotid and femoral arteries as the difference between the
total area inside the adventitia and the lumen area35 :
[lumen
diametermean/2+IMTmean]2-[lumen
diametermean/2)2.
Assessment of Plaque Occurrence
The carotid and femoral arteries were scanned both
longitudinally and transversely to assess the occurrence of
plaques.34 A plaque was defined as a distinct area with an
IMT >50% thicker than that of neighboring sites (as judged visually).
A semiquantitative subjective scale was used to grade the size of
plaques into the following categories: (1) grade 1, 1 or more small
plaques (less than 
10 mm2); (2) grade 2,
moderate to large plaques (The differentiation between grades 1 and 2
was made subjectively in most cases, and quantitative measurements were
made by the computerized system36 only when the correct
classification was not obvious to the observer.); and (3) grade 3,
plaques producing flow disturbances.34 In the
present study, no plaque of grade 3 was found in the femoral
artery, but 3 subjects had plaques of grade 3 in the carotid artery.
Therefore, plaques of grades 2 and 3 were merged into 1 group of
moderate to large plaques. This analysis included plaques in
the near wall as well as the far wall of the vessel. Analyses
of plaques were performed in both the right and left carotid arteries.
The largest plaque in either artery was used in the present
analysis. Reproducibility studies of a blinded rereading of
plaque occurrence in 53 male subjects showed that plaque size was
assessed in the same way on both occasions in 95% of the cases.
Measurements
Established questionnaires were used to evaluate each subject’s
history of previous and current disease and smoking. Body weight was
measured on a balance scale with the subject dressed in underwear.
Measurements of waist and hip ratios were performed while the subjects
were in the supine position. Blood pressure was measured twice after
the subject had been resting in the supine position for 5 minutes with
the use of an appropriate cuff size in relation to arm size.
Diastolic blood pressure was determined as Korotkoff phase
V. A 12-lead standard ECG was recorded. Heart rate was recorded
from the ECG. Blood samples for serum cholesterol, serum
triglycerides, and lipoprotein fractions were drawn after a
fasting period of 10 to 12 hours and were thereafter frozen in aliquots
at -70°C within 4 hours. Twelve-hour urine samples were collected
overnight on 2 consecutive occasions. Information on smoking habits was
obtained by a self-administered questionnaire. The total number of
years of smoking was multiplied by the number of cigarettes smoked
daily. The product was called "cigarette-years." This
variable was calculated only for subjects classified as present
or past smokers.
Biochemical Analysis
Cholesterol and triglyceride levels were
determined by fully enzymatic techniques.37 38 HDL was
determined after precipitation of apo B–containing lipoproteins with
MnCl2 and dextran sulfate. LDL
cholesterol was calculated as described by Friedewald et
al.39 Apo A-I and apo B concentrations were measured by a
rate nephelometric method.40 Blood glucose was measured
with the glucose oxidase technique. Plasma insulin was determined in
all subjects with a radioimmunoassay (Pharmacia Insulin RIA, Pharmacia
Diagnostics). All lipid analyses were performed at
the Wallenberg Laboratory.
Statistical Analysis
All statistics were performed by using SPSS for
Windows 7.5 (SPSS, Inc). Nonparametric Spearman’s rank
correlation test was used in the correlation analysis, with the
relationship illustrated by Pearson’s correlation coefficient
(r). The Mann-Whitney U test was used when
comparing mean values for ultrasound and LDL particle size
variables in subjects with the metabolic syndrome and
subjects with no risk factors. Furthermore, a t-distributed
variable was used to calculate 95% confidence intervals (CIs) for
differences. Comparisons between groups for anthropometric data, blood
pressure, triglycerides, HDL cholesterol, BMI,
blood glucose, and plasma insulin were not formally tested for
significance because subjects with the metabolic syndrome
were selected on the basis of these variables. Mantel’s test for
linear association was used to test the relationship between LDL
particle size and plaque occurrence and size in the carotid and femoral
arteries. Because of technical reasons there were missing data for IMT
in the common carotid artery in 3 subjects and for LDL particle size in
11 subjects. These subjects were not excluded from the results
presented in Table 1
.
P<0.05 (2-sided) was regarded as statistically
significant.
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Results |
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Prevalence of Risk Factors in the Study Group
No subjects had overt diabetes mellitus. A blood glucose value
6.1 mmol/L was found in 22 subjects (5.6%). Eighty-one subjects
had a fasting blood glucose level 5.6 mmol/L and/or insulin
resistance (20.7%). There were 96 (25%) subjects who had raised
systolic and/or diastolic arterial
blood pressure; 127 (33%) subjects had raised triglyceride
or low HDL levels; 293 (75%) subjects had central obesity or a raised
BMI; and 46 (12%) subjects had microalbuminuria. Sixty-two
subjects (16%) fulfilled the criteria for the metabolic
syndrome according to the definition given above; 252 (64%) subjects
had at least 1 risk factor (but not the full syndrome); and 77 (20%)
subjects had no risk factors.
Anthropometric Data, Blood Pressure, Heart Rate, Serum Lipids and
Lipoproteins, and Smoking Habits in Subjects With the
Metabolic Syndrome Compared With Subjects With No Risk
Factors
Subjects with the metabolic syndrome had, as expected,
higher BMI, blood pressure, serum triglycerides, blood
glucose, and plasma insulin and also lower HDL levels compared with
subjects with no risk factors (not tested for statistical significance
because of the selection criteria; Table 1
). Furthermore,
subjects with the metabolic syndrome had significantly
higher mean values for heart rate, serum total cholesterol,
and apo B compared with subjects with no risk factors (Table 1).
There were no differences in mean LDL cholesterol
concentrations or cigarette-years between the 2 groups.
IMT, Lumen Diameter, Cross-Sectional Area, Plaque Occurrence, and
LDL Particle Size in Subjects With the Metabolic Syndrome
Compared With Subjects With No Risk Factors
Subjects with the metabolic syndrome had significantly
higher mean values for common carotid artery and carotid artery bulb
IMT and cross-sectional intima-media area in the carotid artery
compared with subjects with no risk factors (Figure 1). Mean value for lumen diameter in the
carotid artery was significantly higher in subjects with the
metabolic syndrome compared with subjects with no risk
factors (6.38±0.67 and 6.01±0.44 mm, respectively,
P=0.001). No significant difference in lumen diameter was
seen in the femoral artery. Mean values for IMT and cross-sectional
intima-media area of the common femoral artery were significantly
higher in subjects with the metabolic syndrome compared
with subjects with no risk factors (1.03±0.33 versus 1.00±0.57
mm and 32.6±11.6 versus 28.4±12.6 cm2,
P=0.022 and P=0.006, respectively). There were no
significant differences in plaque occurrence and size in the carotid or
femoral arteries between the 2 study groups. Furthermore, subjects with
the metabolic syndrome had significantly smaller LDL
particles and a smaller proportion of IDL particles compared with
subjects with no risk factors (Figure 2).
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LDL Particle Size in Relation to Metabolic and
Ultrasound Variables
Numbers of subjects characterized by pattern B (small, dense LDL
particles) and pattern A (large particles) were 62 and 318,
respectively. Subjects with pattern B had significantly higher mean
values for BMI, systolic and diastolic blood
pressures, heart rate, serum cholesterol,
triglyceride levels, and plasma insulin and lower HDL
levels compared with subjects with pattern A (Table 2). Subjects with pattern B also had a
higher prevalence of moderate to large plaques in the carotid artery
compared with subjects with pattern A (Table 2). There were no
significant differences between the 2 groups in LDL
cholesterol, blood glucose, smoking habits, IMT, lumen
diameter, or plaque occurrence in the femoral artery (Table 2).
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LDL Peak Particle Size in Relation to IMT, Plaque Occurrence, and
Cross-Sectional Area
Decreasing LDL peak particle size was significantly associated
with increasing IMT of the common carotid artery, the carotid artery
bulb, and the common femoral artery (Figure 3). There was a statistically significant
association between plaque occurrence and size and the LDL peak
particle diameter in both the carotid and femoral arteries (Figure 4). Thus, smaller LDL particle size was
associated with the occurrence of moderate to large plaques. LDL
particle size was weakly and negatively associated with cross-sectional
area in both the carotid and femoral arteries (r=-0.14 and
r=-0.16, P=0.008 and P=0.004,
respectively).
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Discussion |
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The results of the present study showed that clinically healthy, 58-year old men with a clustering of risk factors typical of the metabolic syndrome had small LDL particles and an increased thickness of the IMT of the common carotid artery, the carotid artery bulb, and the common femoral artery. The mean value for lumen diameter in the carotid artery but not in the femoral artery was higher in the subjects with the metabolic syndrome compared with the subjects with no risk factors. Furthermore, there was also a weak and negative relationship between LDL particle size and IMT of the common carotid artery, the carotid artery bulb, and the common femoral artery.
These results were obtained in a
population-representative sample of 58-year-old, white,
untreated men who were selected to minimize the effect of confounding
factors such as race, sex, age, and treatment with different drugs for
cardiovascular disease. A suggested operative
definition of the metabolic syndrome was used because there
is today no generally established definition of this
syndrome.7 This definition was based on the combination of
impaired fasting glucose or insulin resistance and the presence of at
least 2 of the factors that are characteristics of the
metabolic syndrome.7 We modified this
algorithm by using fasting plasma insulin as a measure of insulin
resistance, after having defined a cutoff limit corresponding to the
lowest quartile of insulin-mediated glucose uptake during a
hyperinsulinemic euglycemic clamp
examination performed in a random sample of the background population.
This cutoff point was also validated in an independent sample from the
same background population. In patients with established diabetes
mellitus, circulating insulin levels may not reflect low insulin
sensitivity, as among nondiabetics, due to insufficiency of the
pancreatic ß-cells to increase the secretion of
insulin.15 However, we did not include any patients
with clinically overt diabetes and those with a blood glucose level
6.1 mmol/L demonstrated insulin levels >90th percentile.
The components included in this definition of the metabolic syndrome were high blood pressure, general or upper-body obesity, and dyslipidemia with hypertriglyceridemia or low HDL levels, apart from a disturbed glucose and insulin metabolism. These variables were consequently not tested for statistical significance. The group with the metabolic syndrome also had higher mean values for serum cholesterol and apo B as well as a higher heart rate compared with subjects with none of the risk factors constituting the metabolic syndrome. Both an elevated serum cholesterol and high heart rate are recognized risk factors for cardiovascular disease and may thus have contributed to the ultrasound findings indicating more pronounced atherosclerosis in the group with the metabolic syndrome.2 41 The higher heart rate may be associated with an increased sympathetic nervous system activity, perhaps in combination with vagal withdrawal, that is associated with obesity.3
When we used the aforementioned approach to divide the subjects into those with small versus large LDL particles, a consistent picture emerged: ie, subjects with small LDL particles (pattern B) had higher BMI, blood pressure, heart rate, triglycerides, and plasma insulin and also lower HDL cholesterol levels compared with subjects characterized by larger LDL particles (pattern A). In addition, the occurrence and size of plaques in the carotid artery were also associated with small LDL particle size. Subjects with pattern B also had a tendency toward a thicker IMT in the common carotid artery and the carotid artery bulb compared with subjects with pattern A (P=0.10; 95% CI, -0.064 to 0.006 and P=0.10; 95% CI, -0.184 to 0.016, respectively). This is the first study to examine healthy, unmedicated subjects from the general population who have a clustering of risk factors constituting the metabolic syndrome in a preclinical stage of atherosclerosis development. Our results are in line with the findings from other studies, showing that small LDL particles are related to such components of the metabolic syndrome as insulin resistance, dyslipidemia, and perturbations in glucose metabolism.15 16 17 The results from the present study also give support to those previous studies that have shown a relationship between small LDL particles and atherosclerotic disease. The ultrasound technique used in the current study allows measurement of atherosclerosis development at an early stage of the disease process, and IMT of the common carotid artery42 and the carotid artery bulb31 has also previously been shown to be associated with coronary atherosclerosis.
An association between small LDL particle size and angiographically defined coronary artery disease has thus been found in several studies.20 21 22 23 Patients with small, dense LDL particles have also been shown to have a 3-fold increased risk of myocardial infarction, independent of age, sex, and relative weight.43 Small LDL particle size has also been suggested to be an additional risk factor for coronary artery disease.23 In other studies, however, no certain relationship has been found between atherosclerotic disease and LDL particle size.24 25 26 27 28 A negative relationship between LDL particle size and IMT of the common carotid artery has recently been shown in subjects who are homozygous for the apoE3 allele.29 However, in that study subjects with a high BMI (>32 kg/m2) and plaque occurrence were excluded. The results are therefore not directly comparable to the results obtained in the present study.
The mechanisms underlying the development of small LDL particles are not fully known. Insulin resistance is associated with an influx of fatty acids from the splanchnic circulation to the liver, causing an increased production of VLDL particles.11 12 13 The concomitant reduction in lipoprotein lipase action in the peripheral tissues and the liver is believed to lead to the production of small LDL particles. The proposed proatherogenic properties of small LDL particles may relate to their ability to penetrate the arterial wall,44 to bind more easily to arterial proteoglycans,45 46 and thus be more susceptible to oxidation,47 a key event in the atherosclerotic process.
Our interpretation and conclusion of these data are that the clustering of factors that constitute the metabolic syndrome is associated with a small LDL particle size pattern and to atherosclerosis in the carotid and femoral arteries, as assessed by the ultrasound technique. To summarize, this is the first study to demonstrate a relationship between preclinical atherosclerosis, LDL particle size, and the metabolic syndrome in healthy middle-aged men recruited from the general population.
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Acknowledgments |
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This work was supported by grants from the Swedish Heart-Lung Foundation, the Swedish Medical Research Council (12270, 10880), King Gustav V and Queen Viktoria Foundation, and Astra Hässle, Möndal, Sweden We thank laboratory technologists Eva-Lena Alenhag, Anna Frödén, Caroline Schmidt, and Aira Lidell for excellent research assistance. We also thank Stefan Agewall and Göran Lindstedt at the Departments of Cardiology and Clinical Chemistry, respectively, Sahlgrenska University Hospital, for their assistance in assessing urinary albumin excretion.
Received October 21, 1999; accepted March 31, 2000.
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