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1 Section of Vascular Medicine, The present
study assessed whether impaired aerobic capacity previously observed in
hypercholesterolemic mice is reversible by exercise training.
Seventy-two 8-wk-old female C57BL/6J wild-type (+,
n = 42) and apolipoprotein E-deficient
(
apolipoprotein E-deficient mice; atherosclerosis; nitric oxide; oxygen uptake; vascular reactivity
WE SHOWED PREVIOUSLY (13) in sedentary
mice that both diet-induced and genetically determined
hypercholesterolemia lead to an early impairment of aerobic capacity
during maximal treadmill testing. This impairment in aerobic capacity
significantly correlated with a reduction in endothelium-dependent
relaxation, endothelial nitric oxide (NO) production, and urinary
nitrate excretion. Conversely, there is accumulating evidence that
exercise-induced increase in blood flow induces the expression of mRNA
for NO synthase (NOS), augments NO activity, and enhances
endothelium-dependent vasodilation (6, 11, 14, 24, 27). It was the aim
of this study to examine the effect of exercise training on vascular
reactivity and aerobic capacity in the presence of a broad spectrum of
diet-induced and/or genetically determined cholesterol levels; to
assess whether exercise training could reverse the cholesterol-induced
impairment of aerobic capacity; and to further determine the role of NO
during aerobic adaptation to exercise training in the
hypercholesterolemic state.
Animals.
Eight-week-old female wild-type (n = 42) and apolipoprotein E (apoE)-deficient
(n = 30) C57BL/6J mice (Jackson
Laboratories, Bar Harbor, ME) were entered into experimental protocols
after 1 wk of acclimation in the housing facilities of the Stanford Department of Comparative Medicine. All mice were inspected before the
study by their veterinarians and monitored daily by technicians and
investigators. All experimental protocols were approved by the
Administrative Panel on Laboratory Animal Care of Stanford University
and were performed in accordance with the recommendations of the
American Association for the Accreditation of Laboratory Animal Care.
Mice were housed three to four per cage under standard conditions in
conventional cages. They were maintained on a 12:12-h light-dark cycle
and given unlimited access to food and water for the duration of the
study. All mice were handled daily and taught to run on a treadmill
with shock plate incentive (Exer-4 Treadmill, Columbus Instruments,
Columbus, OH) but were otherwise confined to cages for the duration of
the study.
ABSTRACT
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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, n = 30) mice were assigned
to the following eight interventions: normal chow, sedentary (E+,
n = 17;
E
,
n = 8) or exercised
(E+ex, n = 13; Eex, n = 7) and high-fat chow, sedentary
(E+chol,
n = 6;
Echol,
n = 8) or exercised
(E+chol-ex, n = 6;
Echol-ex,
n = 7). Mice were trained on a
treadmill 2 × 1 h/day, 6 days/wk, for 4 wk. Cholesterol
levels correlated inversely with maximum oxygen uptake
(r = 0.35;
P < 0.02), which was blunted in all
hypercholesterolemic sedentary groups (all
P < 0.05). Maximum oxygen uptake
improved in all training groups but failed to match
E+ex (all P < 0.05). Vascular reactivity and nitric oxide (NO)
synthesis correlated with anaerobic threshold
(r = 0.36;
P < 0.025) and maximal distance run
(r = 0.59;
P < 0.007). We conclude that
genetically induced hypercholesterolemia impairs aerobic capacity. This
adverse impact of hypercholesterolemia on aerobic capacity may be
related to its impairment of vascular NO synthesis and/or vascular
smooth muscle sensitivity to nitrovasodilators. Aerobic capacity is
improved to the same degree by exercise training in normal and
genetically hypercholesterolemic mice, although there remains a
persistent difference between these groups after training.
INTRODUCTION
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
METHODS
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
Experimental protocol.
Wild-type mice and apoE-deficient mice were randomized at
8 wk of age to eight groups with the following diet and
exercise interventions (Fig. 1): wild-type
mice on normal mouse chow, sedentary (E+,
n = 17) or exercised
(E+ex, n = 13); wild-type mice on a high-fat chow, sedentary
(E+chol,
n = 6) or exercised
(E+chol-ex,
n = 6); apoE-deficient mice on a
normal mouse chow, sedentary (E,
n = 8) or exercised
(Eex,
n = 7); and apoE-deficient mice on a
high-fat chow, sedentary (Echol,
n = 8) or exercised
(Echol-ex,
n = 7).
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Assessment of aerobic capacity. At the beginning of the study and after 4 wk of dietary and exercise intervention, treadmill testing was performed on all mice. Each mouse was placed on a treadmill at a constant 8° angle enclosed by a metabolic chamber capable of measuring oxygen and carbon dioxide outflow once every minute (model CT-2, Columbus Instruments, Columbus, OH). After a 15-min period of acclimation, basal measurements were obtained over 7 min. The treadmill was then started at 10 m/min, and the speed was incrementally increased 1 m/min every minute until the mouse reached exhaustion. Exhaustion was defined as spending time on the shocker plate without attempting to reengage the treadmill. Data on maximal oxygen uptake, carbon dioxide production, respiratory exchange ratio, and distance run to exhaustion were collected (Oxymax software, Columbus Instruments).
Exercise parameters. Maximal oxygen uptake is defined as the plateau in oxygen uptake despite increasing work intensity. In a few cases when a plateau was not reached, the maximum oxygen uptake was approximated by the peak oxygen uptake attained by the animal before exhaustion.
The respiratory exchange ratio is the carbon dioxide production/oxygen uptake at any given time and, at exercise intensities above anaerobic threshold, is used as an indirect indicator of lactic acid production. At high work rates, anaerobic work supplements aerobic work. Lactic acid, produced from anaerobic metabolism, is buffered by serum bicarbonate, resulting in a stoichiometric increase in carbon dioxide output over oxygen uptake (32). Thus the respiratory exchange ratio begins to rise after anaerobic threshold is attained and continues to rise with increasing workload until exhaustion (28). The anaerobic threshold for each individual mouse is expressed in units of oxygen uptake and was determined from computer analysis of carbon dioxide production/oxygen uptake plots by the V-slope method of Beaver et al. (2). In situations when the slope of carbon dioxide production/oxygen uptake did not increase at higher work rates, the maximum oxygen uptake was taken as the anaerobic threshold (2). Distance run until exhaustion was measured during maximal treadmill testing. The change in distance run to exhaustion between baseline and end of the study (distance run until exhaustion at 12 wk distance run until exhaustion at 8 wk) is taken as an approximate
measure of the change in overall work performance during the study course.
Aerobic work capacity was determined by the summation of minute oxygen
uptake above the basal rate over the course of treadmill running until
exhaustion. This was multiplied by the constant 20 J/ml
O2 to convert oxygen uptake to
aerobic work (29).
Vascular reactivity.
One 7-mm segment of thoracic aorta (measured proximal from the
diaphragm) was dissected free of connective tissue and immediately placed in cold physiological saline solution (PSS) composed of (mM) 118 NaCl, 4.7 KCl, 2.5 CaCl2, 1.2 MgSO4, 25 NaHCO3, 0.026 Na2EDTA, 11.1 dextrose, and 0.1 L-arginine. Aortic segments were quickly mounted on wire stirrups, hung from force transducers, and
submerged in oxygenated PSS at 37°C. Over the course
of 60 min, the segments were progressively stretched to the optimum point of their length-tension relationship (determined previously to be
3 g). Subsequently, the EC50 of
norepinephrine (NE) was determined by exposing the segments to
increasing concentrations of NE (in half-log increments from
109 to
104 M). Once a maximal
response was obtained, the segments were washed repeatedly with fresh
PSS for 60 min until the tension returned to the previous baseline
value. Responses to the vasodilators nitroglycerine and acetylcholine
were studied after precontracting the segments with the
EC50 of NE. After a stable
contraction was obtained, the segments were exposed to increasing doses
of vasodilator.
Measurement of nitrogen oxides.
A 7-mm segment from the abdominal aorta (measured proximal from the
iliac bifurcation) was removed and placed in ice-cold PSS. After the
removal of connective tissue, the segment was bisected longitudinally
and incubated in 300 µl of HEPES-buffered saline solution medium
(Irvine Scientific, Santa Ana, CA) containing calcium ionophore A-23187
(final concn of 106 M) and
L-arginine (100 µM) at
37°C. After 120 min, the medium was centrifuged at
15,000 rpm for 5 min and the supernatant was stored at 80°C
for measurement of nitrogen oxides (NOx). NOx in the incubation medium
was measured with a commercially available chemiluminescence apparatus
(model 2108, Dasibi, Glendale, CA) as previously described (25). The
samples (100 µl) were injected into boiling acidic vanadium(III)
chloride. This technique utilizes acidic vanadium(III) chloride at
98°C to reduce both NO2 and
NO3 to NO, which is then detected by
the chemiluminescence apparatus after reacting with ozone. Signals from
the detector were analyzed by computerized integration of curve areas.
Standard curves for
NaNO2/NaNO3
were linear over the range of 50 pM to 10 nM. In these small segments
of tissue, there is significant variability, which is a limitation of
this technique.
Hematology and biochemistry.
Blood samples were collected at the time of death. These were
immediately centrifuged at 3,000 rpm for 15 min. The serum was separated and stored at 80°C until analysis. Total serum and high-density lipoprotein cholesterol were analyzed using an enzymatic method (1).
Tissue preparation.
At death the heart was excised and placed in PSS, pH 7.2, for 5 min. It
was then embedded in optimum cutting temperature compound (Fischer
Chemical, Santa Clara, CA), snap-frozen on dry ice, and kept at
80°C until being cryosectioned.
Histochemistry.
Sectioning and lesion evaluation was performed following the protocol
of Paigen et al. (18). The basal portion of the heart and the proximal
ascending aorta were sectioned transversely into 10-µm-thick slices.
Serial sections were collected on polylysine-coated slides and stored
at 80°C. Lipid deposits were identified by use of oil red O
with hematoxylin and light green counterstain (18). For each animal,
five sections separated by 50 µm (12) were quantified. The first and
most proximal section to the heart was taken 80 µm beyond the distal
extent of the aortic sinus. Histologic cross-sections were viewed by
light microscopy with ×10 magnification and quantitated by using
a grid in the eyepiece. The area of oil red O staining in each section
was determined by an experienced observer blinded to the treatment
group, and the mean lesion area per section per animal was calculated
for each individual and group of animals.
Scanning electron microscopy.
The base of the heart with the attached aorta was fixed without
distension in 1.5% glutaraldehyde buffered to pH 7.2 and then dissected longitudinally to allow visualization of the luminal surface
of the aorta and the aortic sinus (Fig. 2).
Samples were dehydrated in graded ethanol, dried by the critical point
method using carbon dioxide, spatter coated with gold and examined with a ISI 40 scanning electron microscope (International Scientific Instruments, Santa Clara, CA) operating at 10 kV with ×500
magnification for morphological features of the endothelium.
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Drugs.
All solutions were prepared in distilled water except for oxaloacetic
acid (OAA) and 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB), which
were prepared in 0.1 M and 1 M Tris · HCl,
respectively. Acetyl coenzyme A, DTNB, OAA, norepinephrine bitartrate,
acetylcholine, calcium ionophore A-23187,
N
-nitro-L-arginine, and
L-arginine were purchased from
Sigma Chemical (St. Louis, MO), whereas nitroglycerin was obtained from
DuPont Chemicals (Wilmington, DE).
Statistical analyses.
For all statistical tests, differences were considered statistically
significant if the two-sided probability of the observed result under
the null hypothesis was <0.05. Results are expressed as means ± SD. All calculations were performed using SPSS (SPSS, Chicago, IL). For
statistical evaluation nonparametric tests (Wilcoxon signed-rank test
for intraindividual comparisons within groups and the Mann-Whitney
U-test for interindividual changes
between groups) and 
-square test (for nominal variables) were used.
ANOVA was performed to identify a significant difference among the mean values of a variable measured in more than two groups. When ANOVA was
significant, comparisons of the mean values were made by paired Student's t-test with Fisher's exact
test correction. Comparisons of multiple means from repeated-measures
experiments were made by multivariate one-way ANOVA. Correlation
coefficients were calculated by Pearson product-moment correlations.
Comparisons of multiple covariate-adjusted means were made by
one-factor univariate one-way analysis of covariance (ANCOVA).
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RESULTS |
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Body weight and serum cholesterol.
At 8 wk of age baseline body weight was comparable in wild-type and
apoE-deficient mice (19.1 ± 0.6 vs. 19.9 ± 0.6 g) (Table 1). After 4 wk of study, apoE-deficient
mice on a high-fat diet had greater body weight in comparison to all
other groups (all P < 0.05).
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Basal aerobic capacity. We previously reported (13) that at the age of 8 wk wild-type and apoE-deficient mice showed comparable exercise performance. In particular, there were no significant differences in maximum oxygen uptake, respiratory exchange ratio, anaerobic threshold, or aerobic work capacity. Only distance run until exhaustion was 27% greater in the apoE-deficient mice.
Aerobic capacity after exercise training.
After 4 wk of study, sedentary wild-type mice on a normal chow ran
farther than at baseline (8 wk of age), whereas corresponding values
remained unchanged in E+chol mice and
decreased significantly in
E mice
(P < 0.05) (Table
2, Fig. 3).
Maximal running distance to exhaustion improved in all training groups,
reaching statistical significance in
E+chol-ex,
Eex, and
Echol-ex mice (all
P < 0.05). Changes in maximal
running distance between baseline and 4 wk of study were inversely
correlated to total serum cholesterol
(r = 0.75,
P < 0.0001).
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1 · kg1,
P = 0.07) and a significant reduction
in apoE-deficient mice on normal (103 ± 1 vs. 98 ± 6, P < 0.004) as well as high-fat diets
(103 ± 1 vs. 97 ± 6; P < 0.0006). In this study, exercise training led to significant improvement in all groups, but values reached by trained apoE-deficient mice on normal as well as high-fat diets were not above those of sedentary wild-type mice.
Highest values for anaerobic threshold were documented in sedentary and
trained wild-type mice on normal chow. Although apoE-deficient mice on
either chow still showed significant improvement over values reached by
their sedentary littermates (all P < 0.05), results were significantly worse than those observed in
E+ex (P < 0.05). In addition, respiratory exchange ratio was significantly higher in apoE-deficient mice than in wild-type mice
(P < 0.05), and values did not
change with exercise training.
Exercise training led to significantly higher aerobic work capacity in
all training groups compared with their respective sedentary groups
(P < 0.05). Nevertheless, mice in
the training groups that received high-fat diets reached significantly
lower levels of aerobic work capacity than mice on normal chow
(P < 0.05).
Aerobic work capacity may be influenced by cardiac mass. However,
cardiac mass was slightly higher in apoE-deficient mice compared with
wild-type mice (all P < 0.05), so
this cannot explain the lower aerobic work capacity in the
apoE-deficient mice.
Because body weight is the denominator for anaerobic threshold, aerobic
work capacity, and maximum oxygen uptake, ANCOVA was performed.
Significance remained when anaerobic threshold, aerobic work capacity,
and maximum oxygen uptake of 1) all
mice and 2) exercised mice only were
adjusted for body weight, suggesting that increasing body weight is not
the cause for declining aerobic capacity.
Vascular reactivity.
Maximal vasoconstriction to NE and
EC50 was not different between
groups (data not shown). Endothelium-dependent vasorelaxation was
impaired in E and
Echol mice (Fig.
4). When apoE-deficient mice underwent
exercise training, endothelium-dependent relaxation in
Eex was comparable to
E+ and
E+ex, whereas vasorelaxation in
Echol-ex was not different from
Echol.
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0.44,
P < 0.005), dietary fat
content (r = 0.35,
P < 0.027), and body weight
(r = 0.33,
P < 0.044).
NO release was significantly higher in all wild-type mice compared with
apoE-deficient mice (P < 0.05); the
difference in NO release between wild-type and apoE-deficient mice was
not abolished by exercise training
(P = NS). NO release
correlated inversely with total serum cholesterol levels
(r = 0.42,
P < 0.001) and respiratory exchange
ratio (r = 0.49,
P < 0.002), whereas it correlated
positively with anaerobic threshold (r = 0.36, P < 0.025).
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DISCUSSION |
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ABSTRACT
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The salient findings of this study are that 1) genetically induced hypercholesterolemia impairs NO-mediated vasodilation and vascular NO elaboration; 2) the impairment of vasorelaxation is associated (and correlated) with an impairment of aerobic exercise capacity; 3) the impairment of endothelium-dependent vasorelaxation and aerobic exercise capacity induced by genetically determined hypercholesterolemia is partially reversed by exercise training; and 4) exercise training caused a similar percentage increase in maximum oxygen uptake of all groups, although a persistent difference remained between the normal and genetically hypercholesterolemic groups.
Metabolic studies. It was previously reported that hypercholesterolemia is strongly associated with an impairment of endothelium-mediated increases in coronary blood flow and that this is found even in the early stages of atherosclerosis (4, 21, 31). To study the effects of exercise training on vascular reactivity in the hypercholesterolemic state, we chose the mouse model because apoE-deficient mice have been shown to develop the entire spectrum of atherosclerotic lesions similar to those seen in humans and are considered a suitable model for the study of atherogenesis (20). To assess changes in vascular reactivity before formation of obstructive atherosclerotic lesions, mice were studied at the young age of 8-12 wk. The overall number as well as extent of lesions visualized by oil red O staining were too modest to allow quantitative comparison between groups. With scanning electron microscopy occasional endothelial detachment was detected in apoE-deficient mice only, which was more pronounced in those on a high-fat diet. No qualitative difference was detected between sedentary and trained groups (Fig. 2).
As expected, high-fat diet and/or apoE deficiency led to increased levels of total serum cholesterol that remained essentially unchanged despite 4 wk of training. High-density lipoprotein cholesterol levels were not significantly different between groups. The observed increase in total serum cholesterol levels was caused by non-high-density lipoprotein cholesterol (i.e., very low-density lipoprotein plus immediate-density lipoprotein fraction; Ref. 20). Although exercise training leads to an increase in high-density lipoprotein cholesterol in humans (30), this effect was not observed in the mice.Aerobic exercise capacity. During exercise the rate at which oxygen is consumed and carbon dioxide is produced in the muscle is greatly increased. The capacity of the heart and lungs to respond to the stress of physical exercise is often used as a measure of their physiological health. Of the various gas exchange measures obtained during exercise testing, maximum oxygen uptake is the most accurate, reproducible, and thus most commonly used measure of cardiopulmonary function. However, other variables including anaerobic threshold, aerobic work capacity, and distance run until exhaustion derived from exercise testing with gas exchange measurements can provide valuable additional information regarding the capacity of the heart and lungs to deliver oxygen to the working muscle during exercise (15). We reported previously (13) that diet-induced or genetically induced hypercholesterolemia induced a decline in aerobic work capacity, anaerobic threshold, distance run until exhaustion, and maximum oxygen uptake. In the present study, exercise training led to improvement of these measures in hypercholesterolemic mice compared with their sedentary littermates. However, values reached failed to equal those of sedentary normocholesterolemic mice, and in the genetically induced hypercholesterolemic mice, measures of aerobic capacity remained significantly worse than those of normocholesterolemic trained mice. Maximum oxygen uptake and anaerobic threshold were inversely correlated to total serum cholesterol, suggesting an inhibitory effect of cholesterol.
In the sedentary groups, apoE-deficient mice experienced the largest decline in running distance over the 4-wk study period. Conversely, apoE-deficient mice that were trained improved their running distance to a similar extent as wild-type mice. Because apoE-deficient mice showed the largest decline in maximum oxygen uptake and anaerobic threshold despite a similar increase in distance run until exhaustion, it may be assumed that they initiated anaerobic metabolism (reached anaerobic threshold) early, so that there was a greater contribution of anaerobic metabolism to the overall work capacity. It is well known that maximum oxygen uptake, anaerobic threshold, and aerobic work capacity increase with exercise training (8). Because body mass is the denominator for these variables, it could be speculated that simply the increase in body weight during the study period is responsible for the attenuated exercise performance. However, ANCOVA revealed that body weight was not a significant determinant of the group difference in aerobic capacity.Vascular reactivity. A strong correlation has been reported between total serum cholesterol and the impairment of endothelium-mediated increases in coronary blood flow in hypercholesterolemic animals and humans (26, 31). We hypothesized that a training-induced increase in blood flow and thus laminar shear stress could overcome the detrimental effect of hypercholesterolemia and then result in improved endothelium-dependent vasorelaxation via increased endothelial NO synthesis. Indeed, training-induced changes in vascular reactivity have been observed in the coronary arteries of dogs after 8 wk of exercise (3). Also, in healthy young men (5) as well as patients with congestive heart failure (9), an enhanced endothelial function has been demonstrated in the brachial artery after chronic exercise training even in the presence of cardiovascular risk factors (5). These findings are consistent with observations from animal studies in which exercise increased the mRNA expression of NOS, augmented NO activity, and enhanced endothelium-dependent vasodilation in coronary arteries (14, 24, 27). The mechanism by which flow augments the expression of NOS probably involves shear stress responsive elements within the promoter region of the gene encoding NOS (23).
In keeping with current literature, in this study total serum cholesterol was inversely correlated with endothelium-dependent vasorelaxation and with NO release. These data suggest that hypercholesterolemia exerts an NO-antagonizing effect that leads to endothelial dysfunction, which could possibly result in an impaired oxygen transport capacity. Additionally, there was also an impairment of endothelium-independent vasorelaxation to nitroglycerin, indicating an impaired sensitivity of the vascular smooth muscle to NO. Although endothelium-dependent relaxation was improved with exercise, response to nitroglycerin was not. Because maximum oxygen uptake is in part determined by the ability to direct blood flow to the active muscles (15), these alterations in vascular reactivity could lead to a subsequent reduction in aerobic capacity. Increases in blood flow may also effect the elaboration of prostacyclin, which has not been assessed in this study. Koller et al. (11) demonstrated in a rat model that the sensitivity of gracilis muscle arterioles to wall shear stress was upregulated after short-term daily exercise, which resulted in an augmented dilator response, probably caused by an increased release of both endothelium-derived NO and prostacyclin. Hecker et al. (7) observed continuous release of NO and prostacyclin from the endothelium that was enhanced by an increase in shear stress. However, in conduit arteries the contribution of prostacyclin to flow-mediated vasodilation appears negligible because NO plays the major role (10). In summary, the present study shows that 4 wk of exercise training enhances aerobic capacity in normal mice. Aerobic capacity is attenuated by genetically induced hypercholesterolemia and only partially restored by exercise training. The training-induced improvement in aerobic capacity is associated with an improvement in endothelial vasodilator function. Hypercholesterolemia-induced impairment of NO-mediated vasodilation may play a role in the lipid-induced attenuation of aerobic capacity.| |
ACKNOWLEDGEMENTS |
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This work was supported in part by National Heart, Lung, and Blood Institute Grant 1RO1-HL-58638 and was done during the tenure of a Grant-in-Aid Award from the American Heart Association and Sanofi Winthrop. J. Niebauer is a recipient of a stipend award from the Deutsche Forschungsgemeinschaft, Bonn, Germany (Ni 456/1-1). A. J. Maxwell is the recipient of a Bugher Foundation Fellowship of the American Heart Association. J. P. Cooke is an Established Investigator of the American Heart Association.
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FOOTNOTES |
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Address for reprint requests: J. P. Cooke, Section of Vascular Medicine, Div. of Cardiovascular Medicine, Stanford Univ. School of Medicine, 300 Pasteur Dr., Stanford, CA 94305-5246 (E-mail: john.cooke{at}stanford.edu).
Received 10 December 1997; accepted in final form 17 November 1998.
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DISCUSSION
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P < 0.05 vs.
E+chol;
§ P < 0.05 vs.
E
