(Circulation. 1997;96:3287-3293.)
© 1997 American Heart Association, Inc.
Articles |
Endothelial Dysfunction Is Associated With Cholesterol Levels in the High Normal Range in Humans
From the Indiana University Medical Center and the Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis.
Correspondence to Alain D. Baron, MD, Division of Endocrinology and Metabolism, Indiana University Medical Center, 541 N Clinical Dr, Clinical Bldg 459, Indianapolis, IN 46202-5111. E-mail abaron{at}mdep.iupui.edu
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Abstract |
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Background The purpose of this study was to test the hypothesis that cholesterol levels in the high normal range are associated with impaired endothelium-dependent vasodilation.
Methods and Results We studied leg blood flow (LBF) responses to graded intrafemoral artery infusions of the endothelium-dependent vasodilator methacholine chloride (MCh) or the endothelium-independent vasodilator sodium nitroprusside (SNP) in normal volunteers exhibiting a wide range of total cholesterol levels within the normal range (<75th percentile). LBF increased in a dose-dependent fashion in response to the femoral artery infusions of MCh and SNP (P<.001). LBF responses to MCh were significantly blunted (P<.001) in subjects with high normal cholesterol (195±6 mg/dL, n=13) compared with subjects with low normal cholesterol (146±5 mg/dL, n=20). Maximal endothelium-dependent vasodilation in the high normal group was decreased by nearly 50% compared with the low normal group (146±13% versus 268±34%, P<.01). There was a negative correlation between total cholesterol levels and maximal endothelium-dependent vasodilation (total cholestero,l r=-.41, P<.02; LDL cholesterol, r=-.42, P<.02). On the other hand, LBF responses to the endothelium-independent vasodilator SNP did not differ between groups.
Conclusions These data suggest that an inverse and continuous relationship exists between the prevailing cholesterol level and endothelium-dependent vasodilation. Moreover, cholesterol levels even in the normal range may be associated with endothelial dysfunction, thus potentially contributing to the increased risk of macrovascular disease conferred by cholesterol elevations.
Key Words: cholesterol • endothelium • vasodilation • methacholine • sodium nitroprusside
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Introduction |
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Cholesterol is one of the most well-established risk factors for premature CAD1 2 3 and peripheral vascular disease. Cholesterol levels and CAD risk show a strong and linear relationship.1 Hypercholesterolemia with total cholesterol levels of
260 mg/dL and LDL
cholesterol levels of 200 mg/dL are associated
with impaired endothelium-dependent vasodilation in the
forearm4 5 6 7 and in the coronary
vasculature,8 indicating impaired
endothelial function.
Endothelium-dependent vasodilation is mediated at least
in part through the release of EDNO.9 EDNO, the most
powerful endogenous vasodilator, participates in the
regulation of systemic blood pressure and local vascular tone
regulation.10 Furthermore, EDNO inhibits proliferation and
migration of vascular smooth muscle cells11 12 as well as
lipid oxidation,13 14 which all are involved in the
development and progression of atherosclerotic vascular disease. Thus,
impaired production/release of EDNO under conditions of
elevated cholesterol levels may be an important mechanistic
link between hypercholesterolemia and increased
rates of CAD. Given the similar effect of hypercholesterolemia on endothelial function in both the coronary and the peripheral vascular beds and given the continuous relationship between cholesterol levels and coronary artery risk, we hypothesized that cholesterol levels are continuously related to endothelial function. In other words, cholesterol levels even in the normal range would have a negative effect on endothelial function. To this end, we studied the LBF responses to graded intrafemoral artery infusions of the endothelium-dependent vasodilator MCh or the endothelium-independent vasodilator SNP in two groups of healthy volunteers exhibiting low and high serum cholesterol concentrations in the normal range.
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Methods |
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Subjects
Table 1
gives the demographic
characteristics of the subject groups in each. All study subjects were
healthy and had total and LDL cholesterol levels <75
percentile according to the NHANES III data.15 All
subjects were on no medications and had normal cuff blood pressure
determinations and normal 75-g oral glucose tolerance
tests.16 Studies were approved by the Indiana University
Human Subjects Internal Review Board, and all volunteers gave
informed consent.
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Diet
All subjects were admitted to the Indiana University General
Clinical Research Center 2 days before study and were fed a
weight-maintaining diet the caloric content of which was distributed as
50% carbohydrate, 30% fat, and 20% protein.
Drugs
All infusates were prepared under sterile conditions on the
morning of the study. MCh (Roche Labs) was dissolved in normal saline
to a concentration of 25 µg/mL, and SNP (Roche Labs) was
dissolved in normal saline to a concentration of 7 µg/mL. MCh
or SNP was infused directly into the femoral artery with a Harvard
programmable pump (model 44, Harvard Apparatus).
Protocol
Separate groups of subjects were studied under two distinct
study protocols designed to examine the effect of normal range
cholesterol concentrations on
endothelium-dependent (MCh study) and
endothelium-independent vasodilation (SNP study).
Aspects of the protocol that are common to both studies are
described below.
At 7 AM, after an overnight 14-hour fast, a catheter was
inserted into the antecubital vein. Subsequently, the right femoral
artery and vein were cannulated. A 5F sheath (Cordis Corp) was placed
in the right femoral vein to allow insertion of a custom-designed 5F
double-lumen thermodilution catheter (Baxter Scientific, Edwards
Division) to measure LBF as previously described.17 The
right femoral artery was cannulated with a 5.5F double-lumen catheter
(Arrow International) to allow simultaneous infusion of
substances through the proximal port (most caudad) and invasive blood
pressure monitoring through the distal port (most cephalad). Heart rate
and MAP were monitored continuously via precordial leads and a
pressure transducer connected to a vital signs monitor (VSM 1,
Physiocontrol).
Hemodynamic Measurements
All hemodynamic measurements were obtained with
subjects in the supine position in a quiet, temperature-controlled room
and after the subject had emptied his or her bladder. Baseline
measurements of LBF, MAP, and heart rate were obtained after allowing
30 minutes of rest after insertion of the catheters. Rates of LBF
were determined by injecting 1 mL of iced normal saline into the
femoral vein via the thermodilution catheter. The thermodilution curves
were recorded on a chart recorder and visually inspected for
integrity. LBF was calculated by a cardiac output computer (model
9520A, American Edwards Laboratories) that integrates the area under
the thermodilution curve and displays the flow rate in liters per
minute. During graded intrafemoral artery infusion of drugs (MCh or
SNP), LBF measurements were begun 2 minutes after the onset of each
dose. LBF measurements were performed every 30 seconds for a total
of 10 determinations at each drug dose. Invasively determined MAP and
heart rate were recorded with every other LBF determination.
Endothelium-Dependent Vasodilation (MCh
Study)
To study the effect of normal range cholesterol on
endothelium-dependent vasodilation, we administered
graded intrafemoral artery infusions of MCh at sequential doses of 2.5,
5.0, 7.5, 10.0, and 12.5 µg/min. In this fashion,
dose-response curves for MCh to cause
endothelium-dependent vasodilation were obtained. Each
MCh dose was administered for 8 minutes. The volume of MCh delivered
ranged from 0.1 to 0.5 mL/min.
Endothelium-Independent Vasodilation (SNP
Study)
To study the effect of normal range cholesterol
levels on endothelium-independent vasodilation, graded
intrafemoral artery infusions of SNP were administered at rates of
1.75, 3.5, and 7.0 µg/min. In this fashion, dose-response
curves for the effect of SNP to cause
endothelium-independent vasodilation were obtained.
Each SNP dose was administered for 8 minutes. The volume of SNP
delivered ranged from 0.25 to 1.0 mL/min.
Analytical Methods
Serum total cholesterol and
triglyceride levels were measured on an Ektachem 702
analyzer with an enzymatic method. HDL cholesterol
was measured with the Magnetic HDL kit (Reference
Diagnostics, Inc), and LDL cholesterol was
calculated according to the formula of Friedewald et al.18
Free fatty acids were measured according to the method described by
Novak.19 Body fat content was determined by dual energy
x-ray absorptiometry (DXA, Lunar DPX-L, with system software 1.2).
Statistical Analysis
Results are shown as the mean±SEM. MAP is expressed in
millimeters of mercury, and LBF is expressed in liters per minute.
Changes in blood flow are expressed as percent change (%
) to adjust
for differences at baseline. LVR was calculated as MAP divided by LBF
and is presented in arbitrary units. Total
cholesterol levels of <25th percentile (NHANES
III15 ) were used to define the group with low normal range
cholesterol (n=20), and total cholesterol
levels of >25th but <75th percentile (NHANES III15 ) were
used to define the group with high normal range cholesterol
(n=13). Therefore, both groups were made up of subjects exhibiting
serum cholesterol levels <75th percentile according to
criteria established by NHANES III. Therefore, the terms "low
cholesterol" and "high cholesterol" group
refer to stratification according to total cholesterol
levels. To analyze the effect of normal range LDL
cholesterol levels on endothelium-dependent
vasodilation, NHANES III percentiles15 for LDL
cholesterol were applied in exactly the same fashion to
define groups with LDL cholesterol levels in the low
(<25th percentile) and high (>25th but <75th percentile) normal
ranges. Two-way ANOVA was used to compare the changes in LBF in
response to the graded drug infusions between the groups with low and
high normal range cholesterol levels. When significant
differences between groups were found by ANOVA, this was followed by
post hoc testing with Fisher's protected least significant
difference.
Simple linear regression analysis was performed to assess the relationship between the maximal increase in LBF in response to the intrafemoral artery infusions of MCh or SNP and serum total cholesterol, HDL cholesterol, LDL cholesterol, and triglyceride and free fatty acid levels.
Statistical significance was accepted at a level of P<.05. Statistics were performed on a Power Macintosh computer with StatView IV (Abacus Concepts, Inc).
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Results |
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MCh Study
Lipids
Whole group. Mean total cholesterol levels were 165.2±5.7 mg/dL, and LDL and HDL cholesterol levels were 101.1±5.1 and 42.4±2.5 mg/dL, respectively. Triglyceride levels averaged 97.9±8.0 mg/dL and were in the normal range.
High and low cholesterol groups. Grouping the
subjects according to their percentiles of total
cholesterol levels of <25th percentile (low) or >25th
percentile (high) resulted as expected in two groups with significantly
different total and LDL cholesterol levels. HDL
cholesterol levels were similar in both groups.
Triglyceride levels were slightly higher in the high
cholesterol group but were still in the normal range. Table 2 shows the lipid levels of the low and
high cholesterol groups. Table 2 also reveals the subject
characteristics of the two groups that were comparable throughout.
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25th (Low) or >25th (High) Percentile
Hemodynamic Measurements
Whole group. Basal MAP was 89.6±1.5 mm Hg, and
basal LBF was 0.234±0.020 L/min. In response to the graded
intrafemoral artery infusions of MCh, LBF increased in a dose-dependent
fashion (P<.0001) with no changes in MAP.
High and low cholesterol groups. Both groups had
comparable basal rates of LBF and levels of MAP (Table 2
). However, the
LBF response to the graded intrafemoral artery infusions of MCh was
much more pronounced (P<.0001) in the low compared with the
high cholesterol group. This difference in LBF response
between the groups was clearly evident when comparing the rates of
absolute LBF, as seen in Fig 1A, or the
percent increase above baseline, as shown in Fig 1B. The differences in
LBF response to Mch were equally impressive when the LBF response was
assessed in the groups according LDL cholesterol levels of
lesser or greater than the 25th percentile, as seen in Fig 2A and 2B. Furthermore, percent maximal
endothelium-dependent vasodilation in the high
cholesterol group (146±13%) was nearly half that
(268±34%) observed in the low cholesterol group
(P<.01, high versus low). Changes in LVR in response to
graded intrafemoral artery infusions of Mch mirrored the changes in
LBF. Basal LVR was 448±53 and 494±43 units in the low and high
cholesterol groups, respectively (P=NS). LVR
decreased in a dose-dependent fashion in both groups, but the decrease
in LVR was more pronounced in the low cholesterol group. In
response to the graded intrafemoral artery infusion of Mch, LVR
declined to 324±35, 227±27, 195±23, 175±23, and 145±19 units in
the low cholesterol group and to 381±35, 313±40, 266±23,
231±16, and 212±16 units in the high cholesterol
(P<.0005 low versus high). The data indicate that both LDL
and total cholesterol levels in the upper normal range are
associated with decreased endothelium-dependent
vasodilation.
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) and
high (
) normal cholesterol groups
(P<.0001, ANOVA, low vs high). B, Percent increments
(%
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Nitroprusside Study
Lipids
Whole group. Mean total cholesterol levels
were 167.1±5.4 mg/dL, and LDL and HDL cholesterol
levels were 107.1±4.9 and 36.4±2.5 mg/dL, respectively.
Triglyceride levels were 126.9±10.0 mg/dL and also
in the normal range.
High and low cholesterol groups. Grouping the
subjects into low and high cholesterol groups resulted as
expected in two groups with significantly different total and LDL
cholesterol levels. HDL cholesterol levels were
similar in both groups. Triglyceride levels were higher in
the high cholesterol group but were still in the normal
range. Table 2 gives the lipid levels of the low and high
cholesterol. Table 2 also reveals that the subject
characteristics of the two groups were comparable throughout.
Hemodynamic Measurements
Whole group. Basal MAP was 89.8±1.6 mm Hg, and
basal LBF was 0.243±0.028 L/min. In response to the graded
intrafemoral artery infusions of SNP, LBF increased in a dose-dependent
fashion (P<.0001) with no changes in MAP.
High and low cholesterol groups. Both the high
and low cholesterol groups had comparable basal rates of
LBF and levels of MAP (Table 2). LBF in response to the graded
intrafemoral artery infusions of SNP was somewhat higher in the low
compared with the high cholesterol group (P<.05
by ANOVA; Fig 3A). However, this
difference in LBF response between the groups completely disappeared
when comparing the percent increase above baseline (Fig 3B). Assessing
the LBF response to SNP in the groups according LDL
cholesterol levels of lesser or greater than the 25th
percentile (NHANES III)15 yielded the same result as for
total cholesterol. Changes in LVR in response to graded
intrafemoral artery infusions of SNP mirrored the changes in LBF. Basal
LVR was 405±52 and 510±26 units in the low and the high
cholesterol groups, respectively (P=NS). LVR
decreased in a dose-dependent fashion in both groups. In response to
the graded intrafemoral artery infusion of SNP, LVR declined to
297±54, 253±47, and 212±42 units in the low cholesterol
group and to 465±51, 391±45, and 239±24 units in the high
cholesterol group (P=NS). These results
demonstrate that both total and LDL cholesterol in the
normal range have no effect on modulating
endothelium-independent vasodilation.
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Correlational Analyses
Simple linear regression analyses examining the
relationship between maximum increment in LBF in response to MCh or SNP
and lipid parameters are shown in Table 3. Total cholesterol levels
correlated inversely and significantly with maximal
endothelial-dependent vasodilation as determined by the
response to the intrafemoral artery infusions of Mch (Fig 4A) but had no impact on
endothelium-independent vasodilation achieved by
intrafemoral infusion of SNP. LDL cholesterol levels were
also inversely and significantly correlated (Fig 4B) with maximal
endothelium-dependent vasodilation. However, LDL
cholesterol levels had no effect on
endothelium-independent vasodilation. In contrast to
the inverse relationship between total and LDL cholesterol
and maximal endothelium-dependent vasodilation, HDL
cholesterol, triglycerides, and free fatty
acids did not have any relation to the maximal
endothelium-dependent or -independent vasodilation.
Thus, these results suggest that endothelium-dependent
vasodilation is inversely and continuously related to prevailing total
and LDL cholesterol levels.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In this study, we tested the hypothesis that cholesterol levels in the normal range may be associated with impaired endothelium-dependent vasodilation. The results of our study demonstrate that (1) total cholesterol and LDL cholesterol levels at the upper end of the normal range are associated with significant decreases in endothelium-dependent vasodilation, (2) a significant inverse continuous relationship exists between maximum endothelium-mediated vasodilation and both total and LDL cholesterol levels, and (3) there is no effect of total or LDL cholesterol on endothelium-independent vasodilation. These findings suggest that cholesterol even at levels within the normal range may cause endothelial dysfunction.
Cholesterol is now recognized as a major cause of
macrovascular disease.1 2 3 The mechanism by which serum
cholesterol elevations cause cardiovascular
disease is not completely understood. Impaired
endothelium-dependent vasodilation associated with
elevated cholesterol levels could represent one
such mechanism. Endothelium-dependent vasodilation,
which depends at least in part on the production/release of
nitric oxide,20 has been demonstrated to be impaired in
subjects with moderately elevated cholesterol levels
(260 mg/dL).4 5 6 7 Because the relationship between
cholesterol levels and cardiovascular
disease is linear and apparently without a threshold,1 2
it is reasonable to ask whether cholesterol levels even in
the normal range might be associated with impaired
endothelium-dependent vasodilation. It is important to
note that the levels of total cholesterol, LDL
cholesterol, HDL cholesterol, and
triglycerides in our subjects were nearly identical to
those reported in the control subjects of the studies that found
decreased endothelium-dependent vasodilation in
hypercholesterolemic subjects.4 5 6 7 Although
our study group had cholesterol levels that were within the
normal range, there were impressive differences in the LBF response to
the endothelium-dependent vasodilator MCh between
subjects on the upper versus the lower range of normal
cholesterol levels. The subjects in the upper range
exhibited only half the LBF increase in response to MCh. Although this
difference could have been artificially generated by the selection of
the percentiles for the definition of high versus low normal
cholesterol groups, this is not likely because nearly
identical differences were found when we compared
endothelium-dependent vasodilation between groups with
<50th and >50th but <75th percentile total cholesterol
levels (NHANES III15 ). Moreover, regression
analysis showed a significant albeit modest continuous linear
inverse relationship between cholesterol levels and maximum
achieved endothelium-dependent increases in LBF. It
should be noted that the relationship between total
cholesterol or LDL cholesterol levels and
maximum endothelium-dependent vasodilation was quite
variable. However, this variability is not unexpected given the
number of factors that modulate endothelium-dependent
vasodilation, eg, blood pressure,21 22 age,23
insulin sensitivity,24 25 and body fat
content.25 Therefore, it is clear that
cholesterol levels alone cannot serve as a predictor of
endothelial function. Nevertheless, it is important to
realize that cholesterol levels even in the normal range
may explain 20% of the variance in
endothelium-dependent vasodilation.
The blunted response to MCh associated with cholesterol levels in the high normal range are likely the result of alterations in endothelial release of vasoactive substances, altered metabolism of these substances, or impaired action of these substances at the level of the vascular smooth muscle cell. MCh causes vasodilation via the production/release of EDNO9 but also through the release of other vasoactive factors like endothelium-dependent hyperpolarizing factor26 27 28 and prostaglandins.29 30 In subjects with high normal cholesterol levels, production/release of EDNO or endothelium-dependent hyperpolarizing factor could be reduced in response to MCh, leading to lower increases in LBF. Currently, no in vivo data are available regarding rates of nitric oxide production in response to MCh or regarding the contribution of endothelium-dependent hyperpolarizing factor to the vasodilatory response to MCh in subjects with normal or elevated cholesterol levels. However, hypercholesterolemic animals have been shown to exhibit increased basal rates of EDNO production.31 Furthermore, basal EDNO-dependent blood flow and blood flow responses to bradykinin that are largely EDNO dependent have been reported to be normal in frankly hypercholesterolemic humans,5 7 suggesting that production/release of EDNO in hypercholesterolemic subjects is normal. It is therefore possible that higher cholesterol levels may cause rapid degradation of NO perhaps via formation of oxygen radicals as suggested by others.32 33 Alternatively, cholesterol elevations could either increase the release of vasoconstrictor prostaglandins like thromboxane or reduce the release of vasodilator prostaglandins like prostacyclin. Changes in production of prostaglandins, which have been shown to be released in response to acetylcholine, could thus theoretically explain the blunted response to MCh in subjects with higher cholesterol levels. However, this seems unlikely because inhibition of prostaglandin production in humans does not appear to change the blood flow response to acetylcholine.34 Unfortunately, no studies have assessed the effect of hypercholesterolemia on prostaglandin production/release. If endothelial function and EDNO production/release are not impaired by higher cholesterol levels, it follows that the response to EDNO at the level of the vascular smooth muscle cell must be diminished. This explanation does not appear likely because the response to SNP that gauges nitric oxide action at the level of the vascular smooth muscle cell was comparable between groups with low and high normal cholesterol levels. Furthermore, the absence of any correlation between the maximum LBF response to SNP and cholesterol or other lipid levels indicates no effect of lipids on endothelium-independent vasodilation. Clearly, more research is needed to elucidate the mechanism(s) underlying the diminished endothelium-dependent vasodilation in the subjects with high cholesterol levels.
Before one can conclude that the large difference in blood flow response to MCh was due mainly to cholesterol, one has to exclude other possible factors that have been associated with impaired endothelium-dependent vasodilation. Besides the difference in cholesterol levels, triglyceride levels were significantly higher in the high normal group. Although we cannot completely rule out the possibility that elevated triglyceride levels are associated with impaired endothelium-dependent vasodilation, this seems to be unlikely. Indeed, there was no relationship between triglyceride levels and maximum endothelium-dependent vasodilation. Furthermore, increases in triglyceride concentrations in humans have not been reported to blunt endothelium-dependent vasodilation. On the other hand, obesity/insulin resistance, diabetes mellitus, hypertension, age, and smoking have been shown to be associated with decreased responses to endothelium-dependent vasodilators. Our groups were well matched for body weight, body fat content, fasting glucose and insulin levels, blood pressure, age, sex, and smoking history, suggesting that these factors are not likely to explain the differences in endothelium-dependent vasodilation between the low and high normal cholesterol groups. We did not determine insulin sensitivity in our subjects and thus cannot dismiss the possibility that differences in insulin resistance could explain part of the decreased response to Mch.25 This possibility is unlikely because the major determinants of insulin sensitivity, namely body fat content and blood pressure, were comparable between the groups. Furthermore, one would expect higher fasting insulin levels in insulin-resistant subjects, but fasting insulin levels were comparable between groups. Finally, hypercholesterolemia per se is not associated with increased insulin resistance.35 36
Our finding that cholesterol levels even in the normal range may be inversely related to endothelium-dependent vasodilation has important clinical implications. It suggests that lowering cholesterol levels even within in the normal range may improve the production/release of EDNO. This idea is supported by recent reports that lowering cholesterol levels enhances endothelium-dependent vasodilation not only in subjects with massively elevated cholesterol levels37 but also in subjects with normal cholesterol levels.38 It is important to note that lowering of average cholesterol levels in patients with documented CAD39 leads to decreased rates of myocardial infarction. Improvement of endothelium-dependent vasodilation in the coronary vasculature was also achieved in hypercholesterolemic patients with documented CAD by lowering cholesterol levels,40 which demonstrates a qualitatively comparable effect of cholesterol to modulate endothelium-dependent vasodilation at the level of the heart and skeletal muscle. Finally, our findings provide a physiological rationale for the decision of the National Cholesterol Education Program and the American Heart Association41 to abandon normal cholesterol levels and to recommend "desirable" lower cholesterol levels in the population that, if achieved, would be expected to result in greatly reduced rates of CAD and cardiovascular mortality.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by grants DK42469, MO1-RR750-19, and DK20452 from the NIH, a Veterans Affairs Merit Review Award, and Grant-in-Aid A3392 from the American Heart Association. We wish to thank Joyce Ballard for her expert and invaluable help in preparing the manuscript and Dr Naomi Fineberg from the Division of Biostatistics at the Indiana University Medical Center for her expertise and support in performing the statistical analysis.
Received May 27, 1997; revision received July 10, 1997; accepted July 21, 1997.
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