doi: 10.1161/hq1201.100223
© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Long-Term Homocysteine-Lowering Treatment With Folic Acid Plus Pyridoxine Is Associated With Decreased Blood Pressure but Not With Improved Brachial Artery Endothelium-Dependent Vasodilation or Carotid Artery Stiffness
A 2-Year, Randomized, Placebo-Controlled Trial
From the Institute for Cardiovascular Research Vrije Universiteit (R.A.J.M.v.D., J.A.R., M.S., J.W.R.T., C.D.A.S.) and Department of Internal Medicine (R.A.J.M.v.D., M.S., C.D.A.S.), University Hospital Vrije Universiteit, Department of Surgery (J.A.R.), University Hospital Vrije Universiteit, and Institute for Research in Extramural Medicine (J.W.R.T.), Vrije Universiteit, Amsterdam, Netherlands.
Reprint requests to Professor Coen D.A. Stehouwer, University Hospital Vrije Universiteit, Department of Internal Medicine, De Boelelaan 1117, 1081 HV Amsterdam, Netherlands, and PO Box 7057, 1007 MB Amsterdam, Netherlands. E-mail cda.stehouwer{at}vumc.nl
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Abstract |
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Homocysteine is associated with atherothrombotic disease, which may be mediated through associations of homocysteine levels with blood pressure, endothelial function, or arterial stiffness. In a placebo-controlled, randomized clinical trial, we measured blood pressure, brachial artery endothelium-dependent vasodilation, and common carotid artery stiffness in 158 clinically healthy siblings of patients with premature atherothrombotic disease at baseline and after 1 and 2 years of homocysteine-lowering treatment with folic acid (5 mg) plus pyridoxine (250 mg). Intention-to-treat analyses limited to participants (n=130) who underwent at least 1 measurement after the baseline visit showed that compared with placebo, treatment with folic acid plus pyridoxine was associated with a 3.7-mm Hg (95% CI -6.8 to -0.6 mm Hg) lower systolic and a 1.9-mm Hg (95% CI -3.7 to -0.02 mm Hg) lower diastolic blood pressure over the 2-year trial period. Together with the decreased occurrence of abnormal exercise electrocardiography tests reported previously, our results support the hypothesis that homocysteine-lowering treatment with folic acid plus pyridoxine has beneficial vascular effects. Because no effects could be demonstrated on brachial artery endothelium-dependent vasodilation or on common carotid artery stiffness, the present study does not support the hypothesis that the cardiovascular effects of homocysteine are mediated through these factors, at least in clinically healthy individuals.
Key Words: homocysteine • blood pressure • common carotid artery stiffness • brachial artery flow-mediated vasodilation • folic acid • pyridoxine
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Introduction |
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High plasma concentrations of homocysteine are associated with an increased risk of atherothrombotic disease.1 The adverse cardiovascular effects of hyperhomocysteinemia may be mediated in part through positive associations of homocysteine concentrations with blood pressure,1–3 endothelial dysfunction,4–6 and arterial stiffness.7,8 However, these associations have not been observed consistently,4,9 and the mechanisms by which hyperhomocysteinemia increases cardiovascular risk in humans remain controversial.
We have recently completed a 2-year, placebo-controlled, randomized clinical trial of homocysteine-lowering treatment with folic acid plus pyridoxine among 158 clinically healthy siblings of patients with premature atherothrombotic disease.10 At baseline, we found asymptomatic peripheral, coronary, or carotid artery disease in more than one third of these individuals,11 which is indicative of a high risk of developing clinical vascular disease. In addition, we observed that homocysteine-lowering treatment was associated with a significant reduction of the occurrence of abnormal exercise electrocardiography tests in this group.10 In the same trial, we assessed as secondary end points the effect of homocysteine-lowering treatment on blood pressure; on flow-mediated, endothelium-dependent vasodilation of the brachial artery; and on stiffness of the common carotid artery.
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Methods |
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Participants
In April 1993, we started a hyperhomocysteinemia screening program among consecutive patients with clinically manifest peripheral, cerebral, or coronary occlusive disease with onset before the age of 56 years or a history of obstetric complications, as described in detail elsewhere.10,11 From April 1993 to January 1995, we screened 737 patients, 167 of whom had postmethionine hyperhomocysteinemia: 96, 34, and 35 with peripheral, cerebral, and coronary arterial occlusive disease, respectively, and 2 with a history of obstetric complications. The siblings (n=652; 1 to 13 siblings per index patient; 628 of whom were alive at the time of our study) of these 167 patients were then invited for further studies; 475 (72.9%) agreed to participate. We excluded siblings who had a history of venous thrombosis, myocardial infarction, stroke, or peripheral arterial occlusive disease; those younger than 18 years or older than 65 years; pregnant women or women who were planning pregnancy; and those who had impaired renal function (serum creatinine >150 mmol/L) or liver function (abnormal serum transaminase concentrations or presence of physical signs). Thus, a total of 25 siblings (5.3%) were excluded. All other siblings (n=450; 167 families) underwent a methionine loading test. None used vitamin supplements. We subsequently invited all subjects with postmethionine hyperhomocysteinemia (n=125; 27.8%) to participate in the trial; 89 (71.2%) agreed and were available. Of those with a normal postmethionine plasma homocysteine level (n=325; 72.2%), we randomly invited 73 subjects, 50 (68.5%) of whom agreed to participate. These 139 participants were stratified according to family of origin and the presence of postmethionine hyperhomocysteinemia. Within each stratum, subjects were randomized by random computerized digit sampling (Figure). All participants were then treated orally with folic acid (5 mg daily) plus pyridoxine (vitamin B6; 250 mg daily) or placebo medication for 2 years in double-blind fashion. The hospital pharmacist prepared placebo and vitamin capsules in such a way as to give them the same appearance and taste and executed the treatment assignment. The randomization code was stored at the Department of Pharmacy, to which conductors of and participants in the study had no access. At baseline and after 1 and 2 years, we collected demographic and clinical data and measured blood pressure, brachial artery endothelium-dependent dilatation, and stiffness of the common carotid artery and conducted exercise electrocardiography tests. The methionine loading test was repeated after 20 months.
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General Demographic, Clinical, and Laboratory Data
The assessment of general demographic, clinical (including the exercise electrocardiography test according to the modified Bruce protocol12), and laboratory data (including the methionine loading test) has been described previously.10,11
Hemodynamic Measurements
Hemodynamic studies and blood sampling were performed on separate days. The systolic, mean, and diastolic blood pressures (in mm Hg) were recorded in the left upper arm at 10-minute intervals with an oscillometric blood pressure-measuring device (Colin Press-Mate BP-8800). Pulse pressure was calculated as systolic minus diastolic blood pressure (in mm Hg). The mean of 4 blood pressure measurements was used in statistical analyses.
Endothelium-dependent and -independent vasodilation of the brachial artery (flow-mediated vasodilation and nitroglycerin-induced vasodilation, respectively) were determined with ultrasonography in combination with an arterial wall-movement detection system that measures arterial diameter in time13; the exact protocol has been described elsewhere.4,14 In short, we used 4 minutes of forearm circulatory occlusion followed by a diameter recording after 45 to 60 seconds for measurement of endothelium-dependent vasodilation; for endothelium-independent vasodilation, we sublingually administered 400 µg of nitroglycerin and measured brachial artery diameter 5 minutes later. In our hands, short-term (1 week) coefficients of variations were 4.6% for baseline diameter, 5.5% for flow-mediated vasodilation, and 7.7% for nitroglycerin-induced vasodilation.15
The same ultrasound technique was used for the determination of common carotid artery diastolic diameter and the difference between systolic and diastolic diameter (ie, distension), which were then combined with brachial artery pulse pressure measurements to calculate compliance and distensibility coefficients. Compliance coefficient is defined as (
x diameter)x [distension/(266.6xpulse pressure)], in mm2/kPa, and distensibility coefficient as (2xdistension)/(diameterxpulse pressurex0.01333), in 1/Pa.4 In our hands, intrameasurement intraobserver variability (coefficients of variation) in the 3 recordings of 1 ultrasound measurement was 1.0% for diameter and 3.8% for distension. Intraobserver intersession (50 days; n=9) variability was 2.3% for diameter, 9.7% for distension, 9.7% for distensibility coefficient, and 8.3% for compliance coefficient.
Assessment of all outcome variables was done without knowledge of treatment allocation or of any clinical data. The trial was approved by the ethics committee of the University Hospital Vrije Universiteit, and written informed consent was obtained from all participants.
Statistical Analysis
Linear generalized estimating equations16,17 were used to analyze the influence of therapy with folic acid plus pyridoxine on the longitudinal development of the outcome variables. This technique is suitable for the analysis of longitudinal data because it takes into account that repeated observations within 1 subject are correlated. Generalized estimating equations are "pooled" analyses of within-patient and between-patient relationships, both of which represent important aspects of any treatment effect. The magnitude of the regression coefficient thus obtained is usually somewhat higher than the average difference in the changes in the outcome measure between the treatment and placebo group, because the latter only reflects the between-patient relationship.
Analyses were performed on an intention-to-treat basis with absolute values of continuous variables. Primary analyses used treatment (vitamin/placebo) as the key independent variable (model 1). Adjustments were made for the baseline value of the outcome variable only (model 2); as in model 2 with age and sex added, and mean arterial pressure in the case of common carotid artery properties and pulse pressure (model 3); and as in model 3 with baseline pyridoxine, folate, and homocysteine (fasting or after methionine) concentrations added (model 4). Model 5 was based on model 3 with further adjustment for LDL and HDL cholesterol and triglyceride concentrations at baseline and first and second follow-up, as well as baseline tobacco smoking habit (yes/no) and body mass index. Mean arterial pressure was entered into models with common carotid artery properties as an outcome because of the direct physical effects of blood pressure on arterial properties.18 Additional analyses were performed to investigate whether the use of antihypertensive medication or the baseline presence of hypertension was associated with any of the outcomes, first by adjustment for the presence of hypertension or the use of antihypertensive medication, and second by exclusion of all subjects with hypertension. For these analyses, hypertension was defined according to the World Health Organization/International Society of Hypertension 1989 definition, which was in use when this trial was designed, ie, with 160 and 95 mm Hg as cutoffs for systolic and diastolic blood pressure, respectively, or by the use of antihypertensive medication. We also analyzed whether adjustment for baseline serum lipoprotein(a) affected the results. Finally, analyses were done on an on-treatment basis. With respect to these analyses, compliance with vitamin treatment was defined as an increase at the first and second follow-ups of plasma folate and pyridoxine by >500% and >300%, respectively. Compliance with placebo treatment was defined as a maximal increase of folate and pyridoxine of <2 SDs above the baseline mean. To investigate the need for separate analyses of subjects with and without baseline postmethionine hyperhomocysteinemia, we also added the interaction term "treatment times presence of baseline postmethionine hyperhomocysteinemia" to the main analyses.
The study had 80% power at 
=0.05 to detect, between the placebo- and vitamin-treated groups, a 2.2-mm Hg difference in systolic blood pressure, a 1.6-mm Hg difference in diastolic blood pressure, a 2.3-mm Hg difference in pulse pressure, a 3.1% point difference in brachial artery flow-mediated vasodilation, a 0.09-mm2/kPa difference in the compliance coefficient, and a 2.3 1/Pa difference in the distensibility coefficient of the common carotid artery.
Probability values <0.05 were considered statistically significant. The Statistical Package for Interactive Data Analysis (SPIDA, version 6.05, North Ryde) was used for generalized estimating equations analyses and SPSS (SPSS 9.0 for Windows, SPSS Inc) for other analyses.
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Results |
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Of 198 individuals invited, 158 agreed to participate in the assessment of the primary end points.10 With regard to the assessment of the secondary end points reported here, 6 of these 158 individuals refused participation and 13 were excluded for logistical reasons. Of the remaining 139 participants, 20 (14.4%) did not complete the trials (Figure) for the following reasons: development of colon malignancy (3), declined further contact (3), anxiety (2), general malaise (1), prolonged hospital admittance for hip infection (1), and trial investigations too time-consuming (10). The median time from baseline to the first follow-up and from the first to the second follow-up was 13 months. None of the participants developed clinical complaints of impaired cardiac, cerebral, or peripheral circulation. Treatment was well tolerated.
We limited the subsequent analyses to participants who underwent at least 1 measurement after the baseline visit. Thus, 130, 128, and 124 participants were included in the analyses of treatment effects on blood pressure, brachial artery endothelium-dependent vasodilation, and common carotid artery stiffness, respectively. (Measurements of endothelium-dependent vasodilation and common carotid artery stiffness were technically impossible in 2 and 6 individuals.) Twenty-eight of the 158 individuals included in the trial10 were thus excluded from the present analyses. Their characteristics were similar to those of the 130 individuals included (data not shown). The vitamin group and placebo group were similar with regard to homocysteine and vitamin status and other clinical variables (Tables 1 and 2).
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Concentrations of Folate, Pyridoxine, and Homocysteine
Table 2 shows that vitamin treatment was associated with an increase in plasma folate and pyridoxine (both 7-fold versus placebo at the second follow-up). Fasting and postmethionine homocysteine concentrations decreased by 40.1% (95% CI 27.3% to 53.0%) and 29.7% (95% CI 19.2% to 40.1%) versus placebo (all P<0.001). Compliance with vitamin treatment, as defined in Methods, was 100%. Compliance with placebo medication was 94% at the first follow-up and 92.5% at the second follow-up, which suggests additional vitamin use in the placebo-treated group.
Blood Pressure
Baseline blood pressure was slightly higher in the placebo-treated group than in the vitamin-treated group (Table 3). Model 1 (Table 4) thus may overestimate the effects of vitamin treatment. Models 2 to 5, therefore, were adjusted for baseline blood pressure. Vitamin treatment, compared with placebo, was associated with decreased systolic (-3.7 mm Hg; 95% CI -6.8 to -0.6 mm Hg; P=0.02) and diastolic (-1.9 mm Hg; 95% CI -3.7 to -0.02 mm Hg; P=0.04) blood pressure (Table 3; Table 4, model 2). Additional adjustment for age, sex, and baseline pyridoxine, folate, or homocysteine concentrations gave similar results (Table 4, models 3 and 4). The point estimates of these treatment effects increased to -4.6 mm Hg for systolic and -2.4 mm Hg for diastolic blood pressure after further adjustment for LDL cholesterol, HDL cholesterol, and triglyceride concentrations; tobacco smoking; and body mass index (Table 4, model 5). Vitamin treatment was also associated with decreased pulse pressure (-2.3 mm Hg; 95% CI -4.2 to -0.4 mm Hg; P=0.02 versus placebo; Table 4, model 2), but this was not independent of mean arterial blood pressure (P=0.16 after adjustment).
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Brachial Artery Endothelium-Dependent and -Independent Vasodilation
Vitamin treatment, compared with placebo, was not associated with a significant change in brachial artery endothelium-dependent or -independent vasodilation (Tables 3 and 4). Further adjustments gave similar results. The increase in peak systolic flow velocity during reactive hyperemia at the first and second follow-ups did not differ between the placebo and vitamin-treatment groups (94.0% versus 94.3% [P=0.96] and 95.1% versus 99.6% [P=0.53], respectively).
Common Carotid Artery Stiffness
Compared with placebo, vitamin treatment was not associated with a significant change in common carotid artery compliance coefficient or distensibility coefficient or in common carotid artery diameter or distension (Tables 3 and 4). Analyses gave similar results when adjusted for lipoprotein(a), the use of antihypertensive medication, or the presence of hypertension at baseline. In addition, after exclusion of individuals with hypertension, the point estimates of the effect of vitamin-treatment compared with placebo on blood pressure in models 2 through 5 or on any of the other outcomes were not materially different. Results of the on-treatment analysis were similar to those of the intention-to-treat analysis for all outcome variables (data not shown). Analyses with the interaction term "treatment times presence of baseline postmethionine hyperhomocysteinemia" were not materially different from those without the interaction term. The interaction term was not statistically significant in any of the analyses (data not shown).
We performed an additional analysis with the occurrence of abnormal exercise electrocardiography tests as the dependent variable and systolic or diastolic blood pressure as time-dependent covariates to test whether the vitamin-treatment-associated reduction of the occurrence of abnormal exercise electrocardiography tests10 was influenced by changes in blood pressure (Table 5). Adjustment for the change in systolic blood pressure changed the estimate of the effect of vitamin treatment (odds ratio) from 0.41 to 0.53. A decrease in systolic blood pressure was itself associated with a decreased rate of abnormal exercise electrocardiography tests (odds ratio, 0.98 per 1-mm Hg systolic blood pressure decrease). Adjustment for the change in diastolic blood pressure did not affect the estimate of the effect of vitamin treatment.
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Discussion |
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In this 2-year trial conducted among clinically healthy individuals at increased risk of cardiovascular disease, treatment with folic acid plus pyridoxine was associated with a 3.7-mm Hg decrease of systolic blood pressure and a 1.9-mm Hg decrease of diastolic blood pressure compared with placebo. Vitamin treatment had no effects on brachial artery endothelium-dependent vasodilation or on common carotid artery stiffness. These findings suggest that the adverse cardiovascular effects of hyperhomocysteinemia are mediated in part through increased blood pressure. Conversely, our data argue against the hypothesis that the adverse effects of homocysteine are related to decreased endothelium-dependent vasodilation or increased arterial stiffness, at least in clinically healthy individuals.
We included subjects on the basis of whether or not they had high homocysteine concentrations after methionine loading, because at the time this trial was designed, concentrations of postmethionine homocysteine were thought to be more strongly associated with cardiovascular disease than fasting concentrations.19 The COMAC study has since demonstrated that the associations between cardiovascular disease and postmethionine and fasting homocysteine concentrations are of similar strength and are mutually independent.20
This trial was small and of short duration.10 The trial nevertheless had reasonably adequate power to detect changes in the outcome variables, which were chosen because they reflect potential mechanisms linking high homocysteine to cardiovascular disease. In addition, dropout was limited, and compliance with treatment allocation was high.
To maximize the chance of inducing biologically meaningful effects, we used the highest doses of folic acid and pyridoxine thought to be safe and well tolerated.10 A disadvantage of our study design was that it precluded assessment of the separate effects of folic acid and pyridoxine and of the effects of lower doses of these vitamins.
The decrease in systolic and diastolic blood pressure that we observed was approximately half the effect of the first step of a standardized antihypertensive treatment21 and about equal to the effects of a fruit- and vegetable-rich diet in subjects without hypertension.22 Blood pressure and cardiovascular risk are associated in a continuous way.23,24 Therefore, even a small decrease in blood pressure may lower cardiovascular risk. Thus, a 1.9-mm Hg decrease in diastolic pressure may decrease the risk of stroke by 10% to 13% and that of coronary heart disease by 7% to 8%.23 A 3.7-mm Hg decrease in systolic blood pressure may decrease the risk of stroke by 12% to 14%.24 Adjustment for potential confounding factors, if anything, increased the estimates of these treatment effects. Associations of hyperhomocysteinemia with increased systolic or diastolic blood pressure have been reported.1–3 Therefore, the blood pressure decrease we observed may be mediated through the homocysteine-lowering effects of the vitamin treatment. Alternatively, folic acid25 or pyridoxine26 may have had a blood pressure-lowering effect independent of homocysteine lowering.
Homocysteine-lowering treatment with folic acid plus pyridoxine had beneficial effects on 2 independently measured important outcome variables: blood pressure (this study) and the occurrence of abnormal exercise electrocardiography tests.10 In addition, the effect of vitamin treatment on the occurrence of abnormal exercise electrocardiography tests appeared to be mediated in part through the vitamin-associated decrease of systolic blood pressure, which suggests a common underlying factor. Regression of large artery and coronary atherosclerosis is an unlikely explanation, because the duration of this trial was short compared with the time course of atherosclerosis development. We hypothesize that vitamin treatment improves arterial (including coronary) vasoreactivity in a way not reflected by carotid artery stiffness and brachial artery flow-mediated vasodilation, which could then decrease both blood pressure and the occurrence of cardiac ischemia during exercise.
Hyperhomocysteinemia is thought to impair endothelial release of nitric oxide,4,5 possibly by increasing oxidative stress.27 However, homocysteine-lowering treatment was not associated with an increase of flow-mediated, endothelium-dependent dilatation of the brachial artery in our study population, although we stress that we cannot exclude a small (1.3% point) effect (Table 4). We also cannot exclude that homocysteine-lowering treatment may favorably affect endothelium-dependent vasodilation in other arteries or in individuals with hyperhomocysteinemia and atherosclerotic disease or that it may improve endothelial functions other than nitric oxide synthesis.
Vitamin treatment did not affect local common carotid artery stiffness indices. However, simultaneously occurring but opposing changes in arterial function and geometry may have obscured any such effect. First, homocysteine may enhance collagen synthesis, which would tend to increase stiffness.28 Second, homocysteine may increase degradation of the internal elastic lamina, causing increased stiffness as well as an increase in arterial diameter. Increased stiffness is associated with decreased compliance, whereas diameter enlargement increases arterial compliance.29 Third, however, homocysteine may cause lathyritic changes in collagen structure that result in decreased arterial stiffness.30 In addition, the absence of effects on common carotid artery stiffness does not rule out the possibility of changes in arterial stiffness elsewhere (for example, in the aortofemoral segment8). The tendency of pulse pressure, a measure of central artery stiffness,31 to decrease in the vitamin-treated group may also indicate an effect of vitamin treatment on central artery stiffness.
In conclusion, this placebo-controlled, randomized trial among first-degree relatives of patients with premature atherothrombotic disease shows that homocysteine-lowering treatment with folic acid plus pyridoxine is associated with a decrease in blood pressure. Previously, we found that this treatment was associated with a significant reduction in the occurrence of abnormal exercise electrocardiography tests.10 Because blood pressure and exercise electrocardiography tests are 2 independently measured outcomes, the combination of these results strongly supports the hypothesis that homocysteine-lowering treatment with folic acid and pyridoxine has beneficial cardiovascular effects. This study additionally suggests that part of the cardiovascular effects of homocysteine are blood pressure mediated.
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Acknowledgments |
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This trial was supported by the Dutch Praeventiefonds (Prevention Fund grant No. 282272).
Received July 24, 2001; accepted September 22, 2001.
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