(Circulation. 1999;100:219-221.)
© 1999 American Heart Association, Inc.
Brief Rapid Communications |
Plasma 
-Tocopherol and Coronary Endothelium-Dependent Vasodilator Function
From the Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass, and Linus Pauling Institute, Oregon State University, Corvallis (B.F., J.H.S.).
Correspondence to Scott Kinlay, MBBS, PhD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. E-mail skinlay{at}massmed.org
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background—In the presence of atherosclerosis, the coronary endothelial vasomotor response to acetylcholine is frequently abnormal but is variable between patients. We tested the hypothesis that the plasma concentration of
-tocopherol
is associated with the preservation of nitric oxide–mediated
endothelium-dependent vasomotion.
Methods and Results—We studied 15 men and 6 women (mean age
61±10 years) at coronary angiography who were not taking
vitamin supplements. Coronary
endothelium-dependent and -independent vasomotion was
assessed by intracoronary infusions of acetylcholine and
nitroglycerin. The vasomotor responses were compared
with the plasma concentration of -tocopherol and the
plasma -tocopherol concentration relative to total lipid
(total cholesterol plus triglycerides). The
mean plasma -tocopherol was 25.6±6.1 µmol/L,
total cholesterol 193±27 mg/dL, triglycerides
115±66 mg/dL, and -tocopherol to total lipid
4.2±0.9 µmol · L-1 ·
(mmol/L)-1. The mean vasomotor response to acetylcholine
was -1% (range -33% to 28%) and to nitroglycerin
22% (range 0% to 54%). Plasma -tocopherol was
significantly correlated with the acetylcholine response
(r=0.49, P<0.05) but not the
nitroglycerin response (r=0.13,
P>0.05). The acetylcholine response remained
significant after adjustment for other potential sources of oxidant
stress (total cholesterol, diabetes mellitus, smoking,
angina class) (P<0.01). The relative concentration of
-tocopherol to total lipid was not related to
endothelial function (r=0.24,
P=0.3, n=20).
Conclusions—-Tocopherol may preserve
endothelial vasomotor function in patients with
coronary atherosclerosis. This effect may be
related primarily to the action of -tocopherol in the
vascular wall. Further studies that assess the impact of
-tocopherol supplementation as therapy of
endothelial dysfunction are justified.
Key Words: endothelium • antioxidants • atherosclerosis
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Nitric oxide plays an essential role in the regulation of arterial tone.1 Nitric oxide also inhibits local inflammation, coagulation, and cell proliferation.1 Loss of nitric oxide impairs these protective mechanisms throughout the development of atherosclerosis.
Evidence is accumulating that oxidant stress contributes to endothelial dysfunction in coronary atherosclerosis by enhancing the degradation and inhibiting the synthesis of nitric oxide.1 2 Antioxidants can restore endothelium-mediated vasodilator function in patients with atherosclerosis or with coronary risk factors.3 4 5 6
In the presence of coronary atherosclerosis or its risk factors, coronary endothelial vasomotor function is abnormal on average but is variable from patient to patient when assessed with acetylcholine or other stimuli.7 8 Endogenous mechanisms may preserve the availability of nitric oxide in some patients.
-Tocopherol is a potent lipid-soluble antioxidant and
the most abundant isomer of vitamin E found in humans.9 It
circulates in plasma within LDL particles and is also taken up by
arterial wall cells. We tested the hypothesis that plasma
concentrations of -tocopherol account for some of the
variability in the coronary
endothelium-dependent vasomotor function in patients
with coronary atherosclerosis.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Study Subjects
We studied 21 patients referred for coronary angiography for evaluation of chest pain. Eligibility criteria included age 18 to 80 years, total cholesterol <280 mg/dL, and a diameter stenosis in
1 coronary artery >30%. Subjects were
excluded because of rest angina within 24 hours of
catheterization; consumption of any vitamin
supplements; inability to safely withhold vasoactive medications,
including nitrates, ACE inhibitors, or calcium-channel
antagonists for 18 hours before
catheterization; or if angiography revealed extensive
3-vessel or left main coronary artery disease (diameter
stenoses >50%). The study was approved by the Human Research Committee of the Brigham and Women's Hospital. Written informed consent was obtained from each patient.
Assessment of Coronary Vasoreactivity
Coronary endothelium-dependent responses
were assessed according to a protocol established in our
laboratory7 by graded infusions of acetylcholine
(Miochol-E, OMJ Pharmaceuticals) into the left anterior descending
or circumflex arteries over a period of 2 minutes, with estimated final
concentrations of 10-8,
10-7, and 10-6 mol/L.
Endothelium-independent vasodilation was assessed by an
infusion of nitroglycerin at 25 µg/min over a period
of 2 minutes.
Quantitative angiography was used to assess the diameters of 2 coronary segments in response to the drug infusions according to a previously established protocol,3 and the measurements were averaged.
Vitamin E Assay
Blood was drawn at the time of coronary angiography
after an overnight fast into tubes with heparin anticoagulation. Plasma
was stored at -80°C and shipped on dry ice for the measurement of
-tocopherol by high-performance liquid
chromatography with electrochemical
detection.10 Total, HDL, and LDL cholesterol
and triglycerides were measured at the time of
coronary angiography. Because the protection of lipoprotein
lipids from oxidation depends on the relative concentration of
-tocopherol to total lipid, plasma
-tocopherol levels were expressed both in absolute
µmol/L concentration and as the ratio of -tocopherol
(µmol/L)/(total cholesterol+triglycerides)
(mmol/L), as described.11
Definitions of Clinical Variables
Diabetes was defined by a medical history of treatment with
diet, oral hypoglycemic agents, or insulin; hypertension by the use of
antihypertensive therapy; and current smoking as 1 cigarette per day
in the previous 30 days. Anginal classes were defined according to
Braunwald criteria12 as stable angina, unstable angina
without rest pain, and unstable angina with rest pain from 24 hours to
1 month before the study.
Of the 21 patients, 7 (33%) had stable angina, 10 (48%) unstable angina without rest pain, and 4 (19%) unstable angina with rest pain from 24 hours to 1 month before catheterization. Six patients (29%) had diabetes mellitus, 6 (29%) hypertension, and 3 (14%) were current smokers. Medications included ACE inhibitors in 3 patients, statins in 7, and conjugated estrogens in 1. Ten (46%) had 2-vessel disease, 9 (43%) had single-vessel disease, and 2 (10%) had a mild stenosis (30% to 50%) in 1 coronary artery.
Statistical Analysis
Plasma -tocopherol and vasomotor function were
described by mean±SD and related by Pearson correlation coefficient
and 95% CI. Linear regression was used to adjust this relationship for
other potential sources of oxidant stress (total
cholesterol level, anginal class, diabetes, and smoking
status).
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We studied 21 patients, 15 men and 6 women (age 61±10 years, mean±SD). The mean plasma
-tocopherol concentration was
25.6±6.1 µmol/L (SD), the mean cholesterol 193±27
mg/dL, and the mean triglycerides 115±66 mg/dL.
Responses to the maximal concentration of acetylcholine ranged from
-33% to 28% diameter change, mean -1±16% (negative numbers
indicate vasoconstriction). Responses to nitroglycerin
ranged from 0% to 54% dilation, mean 22±13%. The
Figure
depicts the relationships between
plasma -tocopherol concentrations and the
coronary vasomotor responses to acetylcholine and
nitroglycerin. -Tocopherol
concentrations were positively correlated with the maximal response to
acetylcholine (r=0.49, 95% CI=0.07, 0.99;
P<0.05). In contrast, the responses to the
endothelium-independent vasodilator
nitroglycerin were not associated with plasma
-tocopherol concentrations (r=0.13, 95%
CI=-0.33, 0.59; P=0.6).
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Other potential sources of oxidant stress or
endothelial vasodilator dysfunction (including
medications) did not diminish the strength of the relationship between
plasma -tocopherol concentrations and the response to
acetylcholine. After adjustment for serum cholesterol,
diabetes mellitus, smoking, and anginal class, for every 10-µmol/L
increase in -tocopherol there was an 18% increase in
the vasodilator response to acetylcholine (95% CI=7%, 30%;
P<0.01).
The mean plasma -tocopherol concentration adjusted for
total lipid was 4.2±0.9 µmol ·
L-1 · (mmol/L)-1.
There was no significant relationship between
endothelium-dependent vasomotion and lipid-adjusted
plasma -tocopherol levels (r=0.24, 95%
CI=-0.23, 0.62; P=0.3, n=20).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In patients with coronary atherosclerosis, we found a positive relationship between plasma concentration of the antioxidant
-tocopherol and
endothelium-dependent vasodilator function. Low
concentrations of -tocopherol were associated with a
loss of endothelium-dependent vasodilation, whereas
high concentrations of -tocopherol were associated with
preserved endothelial function. Thus, the concentration
of -tocopherol may contribute to the variability in this
endothelium-dependent response. Endothelium-dependent vasodilation is impaired in the presence of atherosclerosis or risk factors for atherosclerosis. However, endothelial dysfunction is mutable. For example, administration of lipid-lowering therapy,1 ACE inhibitors,13 estrogen replacement,14 L-arginine,15 16 or antioxidant therapy3 4 5 6 can restore endothelium-dependent vasomotor responses to acetylcholine or to shear stress.
Oxidant stress is an important mechanism of endothelial vasodilator dysfunction by inactivating nitric oxide and reducing its synthesis.1 2 Several pathways have been implicated in generating oxygen-derived free radicals in atherosclerosis, including NADH/NADPH oxidases, xanthine oxidase, lipoxygenases, and nitric oxide synthase.2 17 18 Natural antioxidant defense mechanisms are in place to combat oxidant stress; these include intracellular and extracellular forms of superoxide dismutase, glutathione and glutathione peroxidases, catalase, and the antioxidant vitamins E and C.2 18
-Tocopherol, an isomer of vitamin E, is the most
abundant lipid-soluble antioxidant in humans and concentrates in LDL
particles as well as in the arterial wall. Supplementation
with vitamin E has been shown to augment the bioavailability of
endothelium-derived nitric oxide in experimental
atherosclerosis.19 Treatment with vitamin
E reversed the impairment of endothelium-dependent
vasodilation in the brachial artery of patients with coronary
vasospastic angina.5
Low vitamin E concentrations may be a cause or a consequence of
endothelial dysfunction and elevated oxidant stress. In
the present study, a low concentration of vitamin E may have been a
causal factor in endothelial dysfunction because it
permitted oxidative damage to occur. The presence of a relationship
between endothelial vasomotor function and the absolute
concentration of -tocopherol, and the absence of a
relationship between endothelial vasomotor function and
-tocopherol adjusted for total lipid (an index of
lipoprotein protection by -tocopherol) suggest that
-tocopherol acts primarily in the arterial
wall.19 -Tocopherol accounted for 
25%
of the variance in the acetylcholine response
(r2=0.24), with the remainder
explained by other factors.
Our study enrolled patients who derived vitamin E from their diet only
and excluded patients consuming vitamin supplements. Further studies
that assess the impact of vitamin E supplementation on coronary
endothelial function are necessary to assess the role
of vitamin E as potentially useful therapy. The present study
supports the hypothesis that plasma -tocopherol
concentration favorably affects coronary
endothelial function in patients with coronary
atherosclerosis, thus lowering the risk of clinical
events.9
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Acknowledgments |
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This study was supported by NIH grants PO1-HL-48743 and 1P50-HL-56985.
Received April 7, 1999; revision received May 21, 1999; accepted May 26, 1999.
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