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(Circulation. 1997;95:1119-1121.)
© 1997 American Heart Association, Inc.

Articles

Hyperhomocyst(e)inemia Is Associated With Impaired Endothelium-Dependent Vasodilation in Humans

Ahmed Tawakol, MD; Torbjørn Omland, MD, PhD; Marie Gerhard, MD; James T. Wu, PhD; Mark A. Creager, MD

the Vascular Medicine and Atherosclerosis Unit (A.T., T.O., M.G., M.A.C.), Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass, and Associated Regional and University Pathologists, Inc Laboratories (J.T.W.), Salt Lake City, Utah.

Correspondence to Mark A. Creager, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115.

	Abstract

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Background Hyperhomocyst(e)inemia is a risk factor for atherosclerosis and is prevalent in the elderly. The objective of this study was to determine whether hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans.

Methods and Results High-resolution vascular ultrasonography was used to study endothelium-dependent and -independent vasodilation in a nonatherosclerotic peripheral conduit artery of 26 elderly hyperhomocyst(e)inemic subjects and 15 age- and sex-matched subjects with normal homocysteine levels. Flow-mediated, endothelium-dependent (nitric oxide–mediated) vasodilation was assessed by measuring the percent change in brachial artery diameter during reactive hyperemia. Endothelium-independent vasodilation was assessed after the administration of 0.4 mg sublingual nitroglycerin. Endothelium-dependent vasodilation was significantly impaired in the hyperhomocyst(e)inemic subjects compared with control subjects (3.7±0.6% versus 8.1±1.2%; P=.004), whereas endothelium-independent vasodilation was not different between the two groups (10.1±1.6% versus 9.3±1.5%; P=NS). In a linear regression analysis with serum homocysteine concentration, folic acid, age, sex, cholesterol (serum total, LDL, or HDL cholesterol), mean arterial blood pressure, use of antihypertensive medication, and baseline brachial artery diameter included as covariates, serum homocysteine concentration emerged as the only significant predictor of flow-mediated vasodilation.

Conclusions These data indicate that hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans and suggest that the bioavailability of nitric oxide is decreased in hyperhomocyst(e)inemic humans. (. 1997;95:1119-1121.)

Key Words: endothelium • endothelium-derived factors • homocysteine • vasodilation

	Introduction

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Homocysteine is a sulfur-containing amino acid that is formed during methionine metabolism. Serum homocysteine concentrations are frequently elevated in the elderly; in individuals deficient in folic acid, cyanocobalamin (vitamin B₁₂) or pyridoxal phosphate (vitamin B₆); and in the presence of various enzyme abnormalities including deficiencies in cystathionine ß-synthase and thermolability of 5,10-methylenetetrahydrofolate reductase.^{1 2 3} It is now well established that mild to moderate elevations in serum homocysteine are associated with an increased incidence of vascular disease.^{4 5 6} Cellular and animal studies^{7 8} indicate that homocysteine reduces the bioavailability of endothelium-derived nitric oxide. We hypothesized that mild to moderate elevations in the serum homocysteine concentration are associated with decreased nitric oxide bioavailability in humans, manifested by impaired endothelium-dependent vasodilation. Accordingly, we used high-resolution ultrasonography to measure endothelium-dependent and endothelium-independent vasodilation in a nonatherosclerotic peripheral conduit artery, the brachial artery, of elderly subjects with and without hyperhomocyst(e)inemia.

	Methods

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Patient Population and Homocysteine Measurements
One hundred sixty subjects, aged 60 to 80 years, were recruited through the Harvard Cooperative Program on Aging. Serum was obtained after an overnight fast; it was promptly spun, separated, and frozen and was then sent to the Associated Regional and University Pathologists, Inc (Salt Lake City, Utah) for measurement of free plus bound homocysteine by the use of previously described methods.⁹ Hyperhomocyst(e)inemia was prospectively defined as a fasting serum homocysteine concentration 16 µmol/L on the basis of a study⁴ of serum homocysteine concentrations and risk of myocardial infarction, which found that the relative risk of myocardial infarction was significantly increased in subjects with serum homocysteine concentrations >15.8 µmol/L. This serum homocysteine concentration corresponded to the upper quartile of fasting homocysteine concentrations in our population. Thus, subjects with homocysteine levels in the upper and lower quartiles (16 µmol/L and <11 µmol/L) were subsequently invited for further evaluation, which included a history and physical examination as well as measurement of serum fasting total, LDL, and HDL cholesterol and folic acid, cyanocobalamin, and pyridoxal phosphate concentrations. Exclusion criteria included the following: smoking; systolic blood pressure >160 mm Hg or diastolic blood pressure >90 mm Hg despite treatment; serum cholesterol level above the 75th percentile for age and sex; history of vascular disease; diabetes; family history of premature coronary artery disease; or any clinical manifestation of atherosclerosis, such as coronary artery disease, peripheral artery disease, or carotid artery disease. Twenty-six hyperhomocyst(e)inemic individuals and 15 eligible age- and sex-matched individuals with serum homocysteine concentrations 11 µmol/L were asked and agreed to participate in vascular function studies. The study protocol was approved by the Human Research Committee of the Brigham and Women's Hospital, and informed consent was obtained from each subject.

Vascular Measurements
Endothelium-dependent and -independent vasodilation was assessed by high-resolution ultrasonography, a technique that has been described previously and validated.^{10 11} Longitudinal images of the brachial artery were obtained 10 to 80 mm proximal to the antecubital fossa by use of a Toshiba model SSA-140A scanner (Tochigi-ken) equipped with a 7.5-MHz high-resolution linear-array transducer. Endothelium-dependent vasodilation was assessed by measuring the percent change from baseline of brachial artery diameter during reactive hyperemia. To create this stimulus, a pneumatic cuff was placed on the upper arm and inflated to suprasystolic pressures for 5 minutes. The brachial artery was then imaged for 2 minutes after cuff deflation, during reactive hyperemia. Peak brachial artery blood flow velocity was measured by use of Doppler ultrasonography to assess the blood flow stimulus during reactive hyperemia. After 7 minutes were allowed to pass, a repeat baseline scan of the brachial artery was obtained. Thereafter, 0.4 mg sublingual nitroglycerin was administered to 10 hyperhomocyst(e)inemic and 11 control subjects to assess endothelium-independent vasodilation. The artery was scanned for an additional 4 minutes. Blood pressure and heart rate were monitored during this procedure.

All images were recorded on super VHS videotape for subsequent analysis. Images corresponding to the resting state, 60 seconds after cuff deflation, and 3 minutes after nitroglycerin administration were selected and digitized. Two investigators blinded to the subjects' homocysteine concentrations subsequently analyzed the images.

Statistical Analysis
Continuous data are expressed as mean±SE. Student's t tests and ² tests with Yates' correction were used to compare differences between groups for continuous and categorical data, respectively. Univariate and multivariate linear regression analysis was used to assess the association between potential predictor variables and the change in brachial artery diameter after reactive hyperemia. A value of P<.05 was considered significant.

	Results

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Baseline Characteristics
The clinical characteristics of the study population are provided in the Table. The mean fasting serum homocysteine concentrations were 19.2±0.8 µmol/L in the hyperhomocyst(e)inemic group and 8.2±0.4 µmol/L in the control group (P<.001).There were no significant between-group differences for age, sex, cholesterol (serum total, LDL, or HDL cholesterol), blood pressure, use of antihypertensive medication, or baseline brachial artery diameter. Serum folic acid concentration was lower in the hyperhomocyst(e)inemic subjects than in the control subjects. There were no significant differences between hyperhomocyst(e)inemic and control subjects for concentrations of pyridoxal phosphate or cyanocobalamin.

View this table: [in this window] [in a new window]   Table 1. Clinical Characteristics of Study Population

Vascular Function
The time-averaged flow velocity during peak reactive hyperemia, a measure of the stimulus for flow-mediated vasodilation, was the same for both groups (110±10 versus 100±10 cm/s; P=NS). Flow-mediated, endothelium-dependent vasodilation was significantly decreased in the hyperhomocyst(e)inemic subjects compared with control subjects (3.7±0.6% versus 8.1±1.2%; P=.004), whereas endothelium-independent vasodilation to sublingual nitroglycerin was not different between the two groups (10.1±1.6% versus 9.3±1.5%; P=NS) (Figure). By univariate analysis, homocysteine concentration correlated inversely with flow-mediated vasodilation (r=.44, P=.004). Furthermore, in a linear regression analysis, with serum homocysteine concentration, folic acid, age, sex, cholesterol (serum total, LDL, or HDL cholesterol), mean arterial blood pressure, use of antihypertensive medication, and baseline brachial artery diameter included as covariates, serum homocysteine concentration emerged as the only significant predictor of flow-mediated vasodilation (P=.008).

View larger version (13K): [in this window] [in a new window]   Figure 1. The effect of hyperhomocyst(e)inemia on flow-mediated, endothelium-dependent vasodilation and on trinitroglycerin (TNG)-induced, endothelium-independent vasodilation.

	Discussion

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The important new finding in this study is that mild to moderate elevation in serum homocysteine concentrations in elderly humans is associated with impaired endothelium-dependent vasodilation. Because impaired endothelial function is believed to be an early step in the pathogenesis and pathophysiology of atherosclerosis, this observation illuminates a potentially important mechanism by which homocysteine may predispose a person to vascular diseases.

Our findings extend those made recently in monkeys with diet-induced moderate hyperhomocyst(e)inemia by Lentz et al,⁸ who reported that endothelium-dependent vasodilation is impaired in carotid artery rings in vitro and hindlimb resistance vessels in vivo. Celermajer et al,¹² using a technique similar to the one used in the present study, detected abnormal endothelium-dependent vasodilation in children with severe elevations in serum homocysteine concentrations due to homozygous homocystinuria, a rare genetic disease. In that study, however, their parents, obligate heterozygotes for cystathionine ß-synthase deficiency, had neither abnormal endothelial function nor elevations in their homocysteine levels.

Although the precise mechanisms are not known, homocysteine may decrease the bioavailability of nitric oxide by reducing its synthesis or by increasing its degradation via the generation of oxygen-derived free radicals such as superoxide anion and hydrogen peroxide.^{13 14 15} In addition, homocysteine increases lipid peroxidation, which then may impair expression of nitric oxide synthase and directly degrade nitric oxide.^{16 17 18}

Therapeutic measures to lower homocysteine levels are inexpensive, safe, and effective. Therapy with folic acid, vitamin B₆, and vitamin B₁₂ can reduce homocysteine levels in most cases within 3 months.^{19 20} It follows, then, that studies should be undertaken to determine whether lowering homocysteine concentrations with B-vitamin therapy can improve endothelium-dependent vasodilation and ultimately reduce the incidence of vascular events.

	Acknowledgments

 
This research was supported by a National Institutes of Health program project grant in vascular biology and medicine (HL-48743). Dr Creager is a recipient of a National Heart, Lung, and Blood Institute academic award in systemic and pulmonary vascular medicine (HL-02663). Dr Gerhard is a recipient of a Harvard/MIT Health Sciences and Technology–Beth Israel fellowship. Dr Omland is a recipient of a J. William Fulbright award. We gratefully acknowledge the Claude D. Pepper Older Americans Independence Center (AG08812) for its assistance in recruiting participants for this study and Dr Joseph Polak for developing the software used in the image analysis.

Received August 2, 1996; revision received January 6, 1997; accepted January 7, 1997.

	References

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K. Sydow, E. Schwedhelm, N. Arakawa, S. M. Bode-Boger, D. Tsikas, B. Hornig, J. C. Frolich, and R. H. Boger ADMA and oxidative stress are responsible for endothelial dysfunction in hyperhomocyst(e)inemia: effects of L-arginine and B vitamins Cardiovasc Res, January 1, 2003; 57(1): 244 - 252. [Abstract]