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J Am Coll Cardiol, 2000; 36:758-765 © 2000 by the American College of Cardiology Foundation |
* Division of Cardiology at the Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada
Department of Pathology and Laboratory Medicine at the Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada
Institut de Recherches Cliniques de Montréal, Montréal, Québec, Canada
Manuscript received December 6, 1999; revised manuscript received February 22, 2000, accepted April 11, 2000.
Reprint requests and correspondence: Dr. Lawrence Title, Division of Cardiology, Queen Elizabeth II Health Sciences Centre, 6896-1796 Summer Street, Halifax, Nova Scotia, Canada B3H 3A7
ltitle{at}is.dal.ca
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Abstract |
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The purpose of this study was to determine whether lowering homocysteine levels with folic acid, with or without antioxidants, will improve endothelial dysfunction in patients with coronary artery disease (CAD).
BACKGROUND
Elevated plasma homocysteine levels are a risk factor for atherosclerosis. Homocysteine may promote atherogenesis through endothelial dysfunction and oxidative stress.
METHODS
In a double-blind, placebo-controlled, randomized trial, we used vascular ultrasound to assess the effect of folic acid alone or with antioxidants on brachial artery endothelium-dependent flow-mediated dilation (FMD). Seventy-five patients with CAD (screening homocysteine level 
9 µmol/liter) were randomized equally to one of three groups: placebo, folic acid alone or folic acid plus antioxidant vitamins C and E. Patients were treated for four months. Plasma folate, homocysteine, FMD and nitroglycerin-mediated dilation were measured before and after four months of treatment.
RESULTS
Plasma folate, homocysteine and FMD were unchanged in the placebo group. Compared with placebo, folic acid alone increased plasma folate by 475% (p < 0.001), reduced plasma homocysteine by 11% (p = 0.23) and significantly improved FMD from 3.2 ± 3.6% to 5.2 ± 3.9% (p = 0.04). The improvement in FMD correlated with the reduction in homocysteine (r = 0.5, p = 0.01). Folic acid plus antioxidants increased plasma folate by 438% (p < 0.001), reduced plasma homocysteine by 9% (p = 0.56) and insignificantly improved FMD from 2.6 ± 2.4% to 4.0 ± 3.7% (p = 0.45), as compared with placebo. Nitroglycerin-mediated dilation did not change significantly in any group.
CONCLUSIONS
Folic acid supplementation significantly improved endothelial dysfunction in patients with coronary atherosclerosis. Further clinical trials are required to determine whether folic acid supplementation may reduce cardiovascular events.
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Experimental evidence suggests that homocysteine may promote atherogenesis through its toxic effects on the vascular endothelium (11–13), which is likely mediated through oxidative stress (14). In humans, there is evidence that chronic hyperhomocysteinemia is associated with impaired endothelium-dependent flow-mediated vasodilation of the brachial artery (15–17).
Folic acid, alone or combined with other B vitamins, is safe and effective in lowering plasma homocysteine levels (18–25). Moreover, antioxidant vitamins, such as vitamins C and E, may have an adjunctive role in preventing homocysteine-mediated oxidative vascular injury (3,26–29). Observational studies suggest that B vitamins may reduce cardiovascular risk (30) and the extent of carotid atherosclerosis (9,31). However, there is no evidence, based on randomized, controlled trials, that folic acid supplementation, alone or with antioxidant vitamins, will reduce the risk of cardiovascular disease. Although large-scale, randomized trials to test this hypothesis are under way (32), smaller intervention trials using surrogate vascular end points may be of value (7,33). Accordingly, this clinical trial aimed to test the hypothesis that lowering plasma homocysteine levels with folic acid, alone or with antioxidant vitamins C and E, would improve impaired endothelium-dependent brachial artery flow-mediated dilation (FMD) in patients with established CAD and normal or mildly elevated levels of plasma homocysteine.
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Methods |
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Patients undergoing cardiac catheterization at the Queen Elizabeth II Health Sciences Centre were screened for entry into the trial. Patients between 18 and 75 years of age were eligible if they had angiographically proven CAD, defined as 50% stenosis of the lumen diameter in a major epicardial coronary vessel and a screening fasting plasma total homocysteine level 9 µmol/liter within four weeks of randomization. Patients were excluded if they had unstable angina or myocardial infarction within two months of screening, the need for coronary artery bypass graft surgery, uncontrolled hypertension, diabetes mellitus, fasting total cholesterol level >7.2 mmol/liter (278 mg/dl), requirements for folic acid supplementation or pernicious anemia. Patients on folic acid, B vitamins, multivitamins or antioxidants within four weeks of randomization were excluded. All patients gave written, informed consent. Of the 166 consecutive patients screened, 91 were excluded (80 had a screening homocysteine level <9 µmol/liter and 11 refused to participate). The remaining 75 patients were enrolled and underwent baseline endothelial function and biochemical assessment before randomization.
Noninvasive assessment of endothelial function. Long-acting vasoactive medications were withheld for 24 h before endothelial function testing, and smokers refrained from smoking on the morning of the test. Patients were studied after a 12-h overnight fast. Endothelium-dependent and endothelium-independent dilation of the brachial artery was assessed noninvasively using a high resolution ultrasound system (Hewlett-Packard SONOS 2500) with a 7.5-MHz linear-array vascular transducer, as previously described (34–36). The brachial artery was imaged longitudinally, 2 to 15 cm above the antecubital crease, ensuring optimal visualization of the anterior and posterior wall–lumen interfaces. This position was maintained throughout the test, and a similar position was used in the follow-up study. Baseline images and pulsed Doppler flow velocity measurements were taken. Next, a pneumatic tourniquet, placed proximally on the forearm, was inflated to 250 mm Hg of pressure for 5 min and rapidly deflated, resulting in reactive hyperemia. Doppler measurements were obtained immediately after deflation, and repeat brachial artery images were continuously recorded for 120 s to assess the response to reactive hyperemia. After 10 min of rest, brachial artery scans were obtained before (second baseline) and after administration of 0.3 mg of sublingual nitroglycerin to assess endothelium-independent vasodilation. All images were recorded on super VHS videotape for subsequent quantitative analysis.
At each phase (baseline, 1 min after reactive hyperemia, second baseline and 3 min after nitroglycerin), the end-diastolic frames (coincident with the peak of the R wave) from three consecutive cardiac cycles were digitized with a Media 100 qx video card and Macintosh G3 computer. Average end-diastolic brachial artery diameters were measured using the National Institutes of Health version (NIH)-Image version 1.61 public domain software by one observer who had no knowledge of the treatment assignment and the protocol stage. Unless the intima–lumen border was clearly defined, the media–lumen border for the anterior and posterior walls was manually traced over a 10- to 20-mm straight arterial segment, and the average diameter over this segment was determined (35). Measurements of the three sequential frames were averaged for each phase. Endothelium-dependent FMD was calculated as the percent change in brachial artery diameter after reactive hyperemia, as compared with the baseline value (intrasubject coefficient of variation 2.1%). Endothelium-independent nitroglycerin-mediated dilation (NMD) was calculated as the percent change in brachial artery diameter after nitroglycerin, as compared with the second baseline value. Brachial artery flow was calculated as the product of the Doppler velocity–time integral, heart rate and brachial artery cross-sectional area (
D2/4), where D = average arterial diameter at that phase. Reactive hyperemia was calculated as the percent change in arterial flow after tourniquet deflation, as compared with the baseline value.
Biochemical analyses. Venous blood was collected from the fasting subjects into vacutainers containing EDTA (plasma total homocysteine, folate, vitamin B12 and malondialdehyde [MDA]) and serum-separating gel (serum lipids and creatinine) at baseline and follow-up. Samples were collected on ice, and plasma was separated within 15 min and frozen at –70°C for subsequent analysis. Screening homocysteine levels were measured at the Queen Elizabeth II Health Sciences Centre, while baseline and follow-up homocysteine levels were measured at the Institut de Recherches Cliniques de Montréal by high performance liquid chromatography and fluorescence detection, as previously described (intra-assay coefficient of variation 2.3%; interassay coefficient of variation 2.5%) (37,38).
Plasma folate and vitamin B12 levels were measured immunochemically on an Abbott IMx system (Abbott Diagnostics, Abbott Park, Illinois). Serum lipid and creatinine levels were measured with a Beckman Synchron CX7 system (Beckman Coulter, Inc., Fullerton, California). Plasma MDA, a marker of lipid peroxidation, was measured in duplicate by HPLC and fluorescence detection, as previously described (39).
Treatment and follow-up. After assessment of endothelial function at baseline, patients were randomly assigned to one of three groups: placebo group (n = 25); folic acid only group (n = 25)—5 mg/day; folic acid plus antioxidants group (n = 25)—folic acid 5 mg/day plus vitamin C 2 g/day and vitamin E (d-alpha-tocopheryl acetate) 800 IU/day. Treatment assignments were blinded, with matching placebo capsules. The assigned treatment was continued for four months. Compliance was assessed by pill count and was defined as consumption of >80% of the vitamin capsules. Patients were instructed to avoid concomitant "open-label" vitamin or antioxidant use during the study. The study was conducted after folic acid fortification had been introduced in Canada in harmony with the U.S. levels (40). All other medications were held constant throughout the study, if possible. None of the smokers quit during the study. Patients underwent follow-up endothelial function and biochemical measurements after four months.
Statistical analysis. The baseline characteristics of the three groups were compared using one-way analysis of variance (ANOVA) for continuous variables and the chi-square test for categoric variables. The primary end point—the effect of treatment on endothelium-dependent FMD and endothelium-independent NMD over time—was assessed by two-way repeated measures ANOVA on an intention-to-treat basis. The change in the primary end point within each treatment group was compared with the corresponding change in the placebo group. Post hoc comparisons between treatment groups were carried out with a Bonferroni correction for multiple comparisons. Secondary end points—the effects of treatment on homocysteine, folate, vitamin B12, lipids and MDA over time—were also assessed by two-way repeated measures ANOVA, with Bonferroni correction where appropriate. As homocysteine, folate and vitamin B12 values were skewed, a logarithmic transformation was performed, and the results were expressed as geometric mean values. Linear regression was used to assess the relation between the change in FMD and the change in homocysteine, folate and MDA. A general linear model with backward elimination was used to assess clinical and biochemical predictors of the change in FMD. Categoric and continuous variables, including baseline homocysteine and folate levels and all the clinical characteristics in Table 1, were included in the model. Two-sided p values <0.05 were considered to indicate statistical significance. Continuous data are expressed as the mean value ± SD, unless stated otherwise.
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Results |
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Effects on plasma homocysteine, B vitamin, lipid and MDA levels. Plasma total homocysteine, folate, vitamin B12, serum lipid and plasma MDA levels at baseline and follow-up are shown in Table 2. There were no significant differences between the three groups at baseline.
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Overall, the geometric mean value of the baseline plasma folate level was 14.5 nmol/liter (6.4 µg/liter). No patient was folate deficient (<6.3 nmol/liter [2.8 µg/liter]) at baseline. The increase in plasma folate levels from baseline was significantly greater in the folic acid only group (475%, p < 0.001) and in the folic acid plus antioxidants (438%, p < 0.001) group as compared with the placebo group.
Plasma vitamin B12 and serum lipids did not change significantly in any group. In contrast, plasma MDA levels significantly fell in the folic acid plus antioxidants group, but remained unchanged in the placebo and folic acid only groups (p < 0.05 vs. placebo and folic acid only groups).
Effects on FMD and NMD. Basal heart rate, blood pressure, end-diastolic brachial artery diameters, brachial artery flow and reactive hyperemia were similar in each group at the baseline and follow-up (Table 3).
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Follow-up, side effects and compliance. During follow-up, the only cardiovascular events were unstable angina in three patients (one in each group). In general, the study medication was well tolerated. Side effects were noted in seven patients (two in the placebo group, four in the folic acid group and one in the folic acid plus antioxidants group) and were severe enough to discontinue the medication in four patients (two in the placebo group, one in the folic acid group and one in the folic acid plus antioxidants group). Side effects included abdominal cramps, diarrhea and rash. On the basis of their pill counts, seven patients (9%) were thought to be noncompliant with their study medications (three in the placebo group, two in the folic acid alone group and two in the folic acid plus antioxidants group). Although these noncompliant patients were included in our primary intention-to-treat analysis, excluding them did not change the overall results of the study.
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Discussion |
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Effect of homocysteine on endothelial function. There is experimental (11–13) and clinical (15–17,27,41,42) evidence suggesting that homocysteine causes endothelial dysfunction, which is a key step in the development and progression of atherosclerosis (43). Normally, the vascular endothelium plays an integral role in preventing atherosclerosis through the production of nitric oxide (NO) (44). Experimentally, homocysteine causes endothelial cell damage (11), impaired release of NO (12), increased inactivation of NO (26) and impaired endothelium-dependent vasomotor function (13). Endothelium-dependent FMD, which is dependent on the release of endothelium-derived NO, is impaired in children with homocysteinuria (15) and adults with mild to moderate elevations of homocysteine (16,17). In addition, experimentally raising plasma homocysteine levels with an oral methionine load leads to an acute, transient impairment of FMD in healthy subjects (27,29,41,42).
Effect of folic acid supplementation on endothelial function. Given its reproducibility, measurement of FMD is useful for studying the potential reversibility of endothelial dysfunction with various antiatherogenic treatments (35,36). Our patients had established coronary atherosclerosis and several risk factors, all associated with abnormal FMD (34–36). Regardless of the underlying cause, folic acid supplementation significantly improved endothelial dysfunction in our patients. The improvement was modest and, on average, did not restore vascular reactivity to the normal range (45). However, this degree of improvement is similar to the effects seen with statins (46) and ACE inhibitors (47) in patients with CAD. As statins and ACE inhibitors are associated with reduced cardiovascular events in large-scale trials, the degree of improvement in endothelial function seen with folic acid in our study may have clinical relevance.
In contrast to our findings, two previous studies failed to demonstrate improvement in endothelial function with folic acid supplementation in patients on dialysis (48,49). These conflicting results likely reflect differences in their study group, which had end-stage renal disease and marked hyperhomocysteinemia, without established atherosclerosis. In contrast, two recent studies have determined that short-term folic acid supplementation could improve endothelial function in patients with familial hypercholesterolemia and normal homocysteine levels (50) and in healthy subjects with hyperhomocysteinemia (51). Our results extend these vascular benefits of folic acid to patients with established CAD with normal or mildly elevated homocysteine levels.
Effect of folic acid on homocysteine lowering. In our study, folic acid alone (5 mg) produced a modest 11% reduction in homocysteine levels after four months. Previous studies have shown that folic acid in doses of 0.4 to 10 mg can lower homocysteine levels to varying degrees (18–25). Our results contradict the 23% reduction seen in the Homocysteine Lowering Trialists’ meta-analysis (23), but are in keeping with the 11% to 14% reduction seen when patients with CAD consumed fortified breakfast cereals (24). The limited homocysteine lowering seen in our study was likely related to the relatively low levels of homocysteine and relatively high folate levels at baseline (23) and to the confounding effect of folate fortification (23,33,52). When designing our study in 1996, the ideal dose of folic acid was unknown (32). We chose a daily dose of 5 mg on the basis of its efficacy in healthy subjects (18) and vascular patients (20,22), as there were concerns about the efficacy of low dose folic acid (0.4 mg) in patients with CAD (2). Further evidence suggests that the homocysteine-lowering effects of low dose folic acid (<0.5 mg) are similar to higher doses (>3 mg) (23,25,32).
Potential mechanisms underlying the improvement in endothelial function. The improvement in endothelial function seen with folic acid was likely mediated through multiple mechanisms. Given that this improvement correlated with the reduction in homocysteine levels, we hypothesize that lowering homocysteine levels prevented homocysteine-induced endothelial injury, impaired NO release or inactivation of NO, or all of these. However, folic acid likely has beneficial effects on NO availability that are independent of its homocysteine-lowering effect. For example, folic acid can reverse endothelial dysfunction in experimental hyperhomocysteinemia (42), and 5-methyltetrahydrofolate, the active form of folic acid, can restore endothelial function in familial hypercholesterolemia (53) without lowering homocysteine levels. Folic acid may increase NO formation by stimulating the recycling of tetrahydrobiopterin, an essential cofactor of endothelial NO synthase (54). Alternatively, folates can prevent the oxidative degradation of NO by reducing superoxide generation from NO synthase or xanthine oxidase (53). Thus, folic acid may restore endothelial function by modulating NO formation or degradation, or both.
Effect of folic acid with antioxidant vitamins on endothelial function. There is experimental evidence that homocysteine-induced endothelial injury is mediated through oxidative stress (11,12,14,26). In vitro studies suggest that homocysteine generates reactive oxygen species, including superoxide anion and hydroxyl radical, which may cause endothelial dysfunction through lipid peroxidation or by reducing the availability of NO, or both (11,12,14,26). Thus, it was surprising that the folic acid plus antioxidants did not significantly improve endothelial function, whereas folic acid alone did, despite the beneficial effects of combined therapy on lipid peroxidation. However, as the two responses on FMD were not significantly different from each other (p > 0.5 for folic acid plus antioxidants vs. folic acid alone; Fig. 1), we cannot conclude that the folic acid–antioxidants combination was less effective than folic acid alone. Importantly, our study was not sufficiently powered to indicate that folic acid was superior to the combination therapy. In contrast to our findings, recently it has been determined that pretreatment with vitamin C, alone (27,29) or with vitamin E (28), can prevent acute impairment in endothelial function in experimentally induced hyperhomocysteinemia. Moreover, long-term vitamin C supplementation has been shown to significantly improve FMD in patients with CAD (55). Although our discordant findings may simply reflect an insufficient sample size, the possibility of an unfavorable interaction between vitamins C and E and folic acid, or a prooxidant effect, cannot be excluded. It is also important to recognize that vitamin E has failed to have beneficial effects on endothelial function in patients with coronary atherosclerosis (56,57), and recently, two important mega-trials have failed to show a reduction in cardiovascular events with vitamin E (58,59).
Study limitations. First, many patients were smokers, taking lipid-lowering therapy or ACE inhibitors, which could affect FMD. However, further analysis suggests that these factors, including the unequal distribution of baseline ACE inhibitor use, did not influence our results. Second, our findings are limited to patients with established coronary atherosclerosis and "average" homocysteine levels. Therefore, these results cannot be extrapolated to the general population or to subjects with marked hyperhomocysteinemia. Finally, we studied peripheral artery function as a surrogate vascular end point, and thus our findings cannot be directly applied to other vascular beds and may not imply clinical benefit. However, endothelial dysfunction is often a generalized process (35), and endothelial dysfunction of the brachial artery is closely related to coronary endothelial dysfunction (35) and the extent of coronary atherosclerosis (60). Therefore, our findings may have relevance to the coronary circulation. By improving endothelial dysfunction and NO bioavailability, folic acid may potentially modify the atherogenic process and reduce cardiovascular events (61).
Conclusions and implications. We have shown that four months of folic acid supplementation can significantly improve endothelial dysfunction in patients with established coronary atherosclerosis. These results provide further support for the potential therapeutic role of folic acid in CAD. However, one must await the results of large-scale clinical trials to determine whether folic acid will reduce cardiovascular morbidity and mortality in patients with established CAD.
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Acknowledgments |
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