CLINICAL STUDIES
Folic acid improves arterial endothelial function in adults with hyperhomocystinemia
Kam S. Woo, MD, FRACP, FACC*,
Ping Chook, MD*,
Yvette I. Lolin, PhD ,
John E. Sanderson, MD, FACC*,
Con Metreweli, MD, FRCR and
David S. Celermajer, PhD, FRACP
* Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
Department of Clinical Chemistry, Kent and Sussex Hospital, Kent, UK
Department of Diagnostic Radiology and Organ Imaging, The Chinese University of Hong Kong, Hong Kong
Department of Medicine, University of Sydney, Sydney, Australia
Manuscript received April 13, 1998;
revised manuscript received June 17, 1999,
accepted September 1, 1999.
Reprint requests and correspondence: Prof. K. S. Woo, c/o Department of Medicine and Therapeutics, Prince of Wales Hospital, Shatin N.T., Hong Kong
b208732{at}mailserv.cuhk.edu.hk
 |
Abstract
|
|---|
OBJECTIVES
To evaluate whether oral folic acid supplementation might improve endothelial function in the arteries of asymptomatic adults with hyperhomocystinemia.
BACKGROUND
Hyperhomocystinemia is an independent risk factor for endothelial dysfunction and occlusive vascular disease. Folic acid supplementation can lower homocystine levels in subjects with hyperhomocystinemia; however, the effect of this on arterial physiology is not known.
METHODS
Adults subjects were recruited from a community-based atherosclerosis study on healthy volunteers aged 40 to 70 years who had no history of hypertension, diabetes mellitus, hyperlipidemia, ischemic heart disease or family history of premature atherosclerosis (n = 89). Seventeen subjects (aged 54 ± 10 years, 15 male) with fasting total homocystine levels above 75th percentile (mean, 9.8 ± 2.8 µmol/liter) consented to participate in a double-blind, randomized, placebo-controlled and crossover trial; each subject received oral folic acid (10 mg/day) and placebo for 8 weeks, each separated by a washout period of four weeks. Flow-mediated endothelium-dependent dilation (percent increase in diameter) of the brachial artery was assessed by high resolution ultrasound, before and after folic acid or placebo supplementation.
RESULTS
Compared with placebo, folic acid supplementation resulted in higher serum folate levels (66.2 ± 7.0 vs. 29.7 ± 14.8 nmol/liter; p < 0.001), lower total plasma homocystine levels (8.1 ± 3.1 vs. 9.5 ± 2.5 µmol/liter, p = 0.03) and significant improvement in endothelium-dependent dilation (8.2 ± 1.6% vs. 6 ± 1.3%, p < 0.001). Endothelium-independent responses to nitroglycerin were unchanged. No adverse events were observed.
CONCLUSION
Folic acid supplementation improves arterial endothelial function in adults with relative hyperhomocystinemia, with potentially beneficial effects on the atherosclerotic process.
|
Abbreviations and Acronyms
| | EDD | = endothelium-dependent dilation | | GTN | = glyceryltrinitrate (nitroglycerin) | | Hcy | = homocystine | | HHC | = hyperhomocystinemia | | tHcy | = total plasma homocystine |
|
Recent epidemiologic studies have demonstrated a clear association between hyperhomocystinemia (HHC) and premature coronary, cerebral and peripheral vascular disease (1,2). HHC is found in approximately one in three subjects with premature coronary artery disease and is therefore considered a common as well as an independent risk factor for occlusive vascular disease (1). Homocystine (Hcy) is a highly reactive amino acid, damaging to arterial endothelial cells in both cell culture and experimental animal studies (3,4), and recently we (5) and others have demonstrated impaired arterial endothelial function in otherwise healthy adults with HHC (6) or homocystine levels at upper physiologic range (7).
Folic acid is a naturally occurring nutritional element that reduces homocystine levels by increasing the rate of recycling of homocystine to methionine (2). It is unknown, however, whether oral folic acid supplements can modify vascular disease in subjects with HHC. As arterial endothelial dysfunction is an important early event in atherogenesis (8), we assessed the effect of folic acid on endothelial physiology in adults with HHC, in a double-blind, randomized, placebo-controlled study.
|
Methods
|
|---|
Subjects.
Adult subjects were recruited from a community-based atherosclerosis study carried out in Hong Kong on healthy volunteers aged 40 to 70 years who had no history of hypertension, diabetes mellitus, hyperlipidemia, ischemic heart disease or family history of premature atherosclerosis (5). None were taking any cardiovascular medications. HHC was defined as fasting total plasma Hcy (tHcy) above the 75th percentile for the 89 subjects studied to date; of the 22 adults approached, 17 gave informed consent and participated in the folic acid trial. None had been taking multivitamin supplements in the 12 months before enrollment. This study was approved by the institutional ethics committee.
Study design.
After enrollment, each subject was randomized to receive either oral folic acid (10 mg/day) or placebo for eight weeks, in a double-blind fashion, followed by a "washout" period of four weeks, then crossed over to either placebo or folic acid for the final eight weeks. A 10-mg oral daily dose of folic acid is known to be safe and was chosen to maximize the Hcy-lowering effect within the time frame of the study. Subjects were reviewed at the end of each eight-week treatment period (but not after the washout phase). On each occasion, subjects attended after a 14-h fast (except for the study medication) for a blood test, measurement of resting supine blood pressure and an arterial ultrasound study (as described below). Ultrasound studies were analyzed by an observer "blinded" in every case to subject identity and to the stage of the experiment, as previously reported (9).
Methods.
At baseline study, venous blood from fasting subjects was assayed for total cholesterol, triglycerides, HDL-cholesterol, glucose and creatinine levels by standard techniques. At baseline and also after each of the eight-week treatment periods, vitamin B12 and folate levels in serum were measured by immunoassay (DPC dual count solid-phase no-boil kits), with the upper limit measured being 85.8 nmol/liter by serial dilution, and total homocystine levels assessed on frozen stored samples by enzymatic immunoassay (Abbott IMX Analyzer; Abbott Park, Illinois) (10). The coefficient of variation of this assay is 3.4% at plasma homocystine concentrations of 7.7 to 29.1 µmol/liter. On repeated measurement, we have been unable to reproduce the very high homocystine levels previously reported by our group, using high performance liquid chromatography (5). This may have been due to problems with sample preparation, or the analytical technique itself, where measurement of total plasma homocystine level along with all sulfated groups may have accounted for a significant and systematic overestimation of the true level. On reanalyzing all samples, by the enzymatic immunoassay method, the "high tHcy" group (top 25%) had levels of 10.5 ± 3.0 µmol/ liter and the "low tHcy" group had levels of 8.5 ± 1.1 µmol/ liter, and there remains a significant difference between groups (p < 0.05) (11). Therefore, the current study still enrolled a group of relatively HHC subjects, from our population.
Endothelial function of the brachial artery was studied at baseline using high resolution ultrasound, as described previously (5,9). In brief, the diameter of the brachial artery was measured on B-mode ultrasound images, using a (median frequency, 7.5 MHz) linear array transducer (L 10-5) and a standard Advanced Technology Laboratories 3000 system. Scans were acquired at rest, during posttourniquet reactive hyperemia (to induce endothelium-dependent dilation, EDD) and after sublingual glyceryltrinitrate (GTN, an endothelium-independent dilator). EDD is predominantly due to endothelial nitric oxide release (12), and endothelial responses of the brachial artery measured by this method correlate significantly well with both coronary endothelial function in the same subjects (13) and with the extent of coronary atherosclerosis (14). The accuracy, reproducibility and low interobserver error for this measurement of arterial physiology have been demonstrated previously (9).
Statistical analysis.
Descriptive data are expressed as mean ± SD. The primary study end point was the comparison between EDD on folic acid or on placebo; this was performed using the paired Student t test. Other outcome variables after folic acid or placebo were also compared using the Student t test, adjusted for multiple comparisons (15). Determinants of the folic acid-related improvement in EDD (calculated for each subject) were explored by standard univariate and multivariate regression analyses, with age, gender, degree of reactive hyperemia, vessel size, total cholesterol and change in serum folate and homocystine levels as the independent variables. Statistical significance was inferred at a two-tailed p value <0.05.
|
Results
|
|---|
All 17 subjects completed the crossover protocol. No adverse events were reported, and tablet counts revealed >90% compliance with all study medications in each case.
Subjects were aged 54 ± 10 (41 to 69) years; 15 were male and 2 were regular smokers. At baseline, the fasting tHcy measured was 9.8 ± 2.8 (8 to 20) µmol/liter, total cholesterol was 5.7 ± 0.8 (3.6 to 6.7) mmol/liter, mean serum folate level was 34.4 ± 10.4 nmol/liter, and glucose, creatinine and vitamin B12 levels were within normal limits in all subjects. EDD (percentage increase in brachial artery diameter) was 5.7 ± 1.2%, and GTN-induced dilation was 17.8 ± 5.0%.
Compared with placebo, folic acid supplementation resulted in a higher serum folate level (66.2 ± 7 after folate vs 29.7 ± 14.8 nmol/liter after placebo, p < 0.001), lower tHcy levels (8.1 ± 3 vs. 9.5 ± 2.5 µmol/liter, p = 0.03), but no significant changes in cholesterol or vitamin B12 levels (p > 0.10) (Table 1). There was a significant improvement (relative increase of 36.7 ± 21.8%) in EDD after folic acid (8.2 ± 1.6% vs. 6 ± 1.3% with placebo, mean absolute difference 2.2 ± 1.3%, p < 0.001) (Fig. 1). There was no significant change, however, in the GTN response (18 ± 2.4% vs. 16.6 ± 2.9%, p = 0.30). These data are consistent with improved endothelial function after folic acid supplementation.
View this table:
[in this window]
[in a new window]
|
Table 1 Biochemical Parameters and Vascular Study Results at Baseline, After Eight Weeks of Placebo and Eight Weeks of Folic Acid Supplementation, in 17 Adults With Hyperhomocystinemia
|
|
View larger version (15K):
[in this window]
[in a new window]
|
Figure 1 EDD at baseline and after eight weeks of therapy with either oral folic acid, 10 mg/day (left panel) or placebo (right panel). For each condition, the mean and SD for the group are presented.
|
|
On regression analyses, the folic acid-related improvement in EDD was not associated with subject age, gender, vessel size, degree of reactive hyperemia or serum total cholesterol, but associated marginally with changes in tHcy (r = –0.35, p = 0.17) and folate levels (r = 0.39, p = 0.12).
|
Discussion
|
|---|
A large number of epidemiologic studies have now identified HHC as a common and independent risk factor for premature vascular events (1,2). Cellular, experimental animal and human studies have recently implicated endothelial injury as a key early event in Hcy-related arterial disease (3–5). For example, we have previously documented impaired endothelial function in children with homozygous homocystinuria (16) and in adults in the highest quartile range of homocystine levels within our population (5,11). The relationship of hyperhomocystinemia and endothelial dysfunction has been reported to be concentration-dependent and present even at physiologic levels of homocystine (7). This may be due to the chemical effects of the free thiol group on Hcy, interacting with nitric oxide or reducing disulfide bonds in endothelial cell molecules (3,17), and/or due to the local generation of reactive oxygen species (18). The pathophysiologic consequences of such endothelial injury may include impaired release of nitric oxide by the vessel wall (3), with significant alterations in arterial reactivity and abnormal interactions among the vessel wall, platelets and leukocytes (19). All of these vascular changes associated with arterial endothelial dysfunction are known to be important events in atherogenesis (8).
Homocysteine, folate and arterial endothelial function.
Recent studies have demonstrated that oral folic acid in a daily dose of 1 to 10 mg consistently reduces Hcy levels by 10 to 20% (19–21). As Hcy itself has toxic effects on arterial endothelial cells, and folic acid has an excellent safety profile, this agent may therefore have therapeutic applications in lowering vascular risk in subjects with HHC. In this study, we now demonstrate that folic acid supplementation improves nitric oxide-mediated arterial endothelial function in healthy adults with relatively high levels of Hcy (for the population studied). After eight weeks of oral folic acid, average EDD improved from 6 ± 1.3% to 8.2 ± 1.6% (36.7 ± 21.8% relative improvement) (whereas average EDD in control subjects from our population with lower range tHcy levels is 10.8 ± 1.7%) (5). Folic acid supplementation for a brief period of 8 weeks was associated with 15% lowering of Hcy level, which conforms to the responses previously reported, but may be underestimating the potential achievable after more prolonged supplementation. The mechanism whereby folic acid improves arterial EDD is uncertain. It could be due to reduction of Hcy levels, elevation of folate levels or another mechanism (20–22). We have observed a trend of association between changes in Hcy levels and improvement in EDD, which was not statistically significant however, possibly due to the relatively small sample size. An alternative explanation for improved arterial endothelial function is an independent vascular effect of folic acid, as suggested by a recent report demonstrating that 5-methyltetrahydrofolate (an active form of folic acid) restored endothelial function in familial hypercholesterolemia (23). However, to our knowledge, there have been no data on folate supplementation given to hypercholesterolemic, smoking patients with low Hcy levels.
Studies of reversibility of endothelial dysfunction.
In the current study, we have investigated endothelial function in the brachial artery using high resolution vascular ultrasound, an accurate and reproducible test (9) that relates mainly to endothelial nitric oxide release in response to shear stress (12). Endothelial function in the brachial artery correlates significantly with that in the coronary vasculature (13) as well as with the extent of coronary disease assessed angiographically (14). As this method is noninvasive, we and others have reported the effects of certain interventions on serial measurements of endothelial function, both in the setting of primary prevention (for example, the use of L-arginine to improve EDD in asymptomatic hypercholesterolemic young adults) (24) and in secondary prevention (for example, vitamin C in patients with established coronary disease) (25). In the case of cholesterol lowering, there is evidence that this therapy improves both brachial and coronary endothelial function as well as cardiovascular outcomes (26–28). The recent demonstration that coronary endothelial function testing may have prognostic value (29) suggests that interventions that improve EDD may have clinical relevance, and this possibility awaits further prospective study. On the basis of our current observation that oral folic acid both lowers homocysteine levels in relatively HHC subjects and improves EDD, clinical trials of this well-tolerated therapy may be indicated.
Study limitations.
The current findings of improved arterial endothelial function after oral folic acid (10 mg/d) may be applicable only to asymptomatic subjects with higher range baseline Hcy levels, and may not necessarily be seen in patients with HHC in the setting of coronary artery disease or in subjects with low homocystine levels. It is also possible that lower doses of folic acid might result in similar benefit; however, the daily 10-mg dose of folic acid used in this trial was well tolerated by all subjects and not associated with any adverse events. Further studies will be required to assess if the improved endothelial function will be sustained for periods longer than eight weeks, or whether this arterial improvement will translate into a decrease in clinical event rates in subjects with HHC. As the beneficial effects on endothelial function were no longer present 12 weeks after treatment cessation (in those receiving folic acid then placebo, and in whom the folate levels had returned to baseline values), this suggests that it may be necessary to continue long-term supplementation to maintain the observed significant improvement in vascular physiology.
|
Conclusions
|
|---|
An emerging literature suggests an important link among HHC, arterial endothelial dysfunction and premature vascular events. Given the high prevalence of atherosclerosis in developed nations, strategies for intervention in this sequence of arterial damage may have important public health implications. By lowering homocystine levels and improving arterial endothelial function in humans, oral folic acid may have therapeutic potential as a vascular protective agent, in HHC subjects.
|
Acknowledgments
|
|---|
We wish to thank Alice S. P. Cheung and Lindy L. T. Chan, research nurses in the Department of Medicine and Therapeutics, The Chinese University of Hong Kong, for assistance with the enrollment of volunteers and conduct of the study.
|
Footnotes
|
|---|
This work was supported by the Research Grants Council of Hong Kong (CUHK 4282/99M), and by a grant from the Board of Management of Chinese Permanent Cemeteries via The Hong Kong Heart Foundation Ltd. Dr. Celermajer is supported by The Medical Foundation, University of Sydney.
|
References
|
|---|
1. Malinow MR. Hyperhomocysteinemia: a common and easily reversible risk factor for occlusive atherosclerosis. Circulation. 1990;81:2004–2006[Free Full Text]
2. Mayer EL, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. J Am Coll Cardiol. 1996;27:517–527[Abstract]
3. Stamler JS, Osborne JA, Jaraki O, Rabbani LE, Mullins M, Singel D, Loscalzo J. Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen. J Clin Invest. 1993;91:308–318[Medline]
4. Lentz SR, Sobey CG, Piegors DJ, Bhopatkar MY, Faraci FM, Malinow MR, Heistad DD. Vascular dysfunction in monkeys with diet-induced hyperhomocyst(e)inemia. J Clin Invest. 1996;98:24–29[Medline]
5. Woo KS, Chook P, Lolin YI, et al. Hyperhomocysteinemia is a risk factor for arterial endothelial dysfunction in humans. Circulation. 1997;96:2542–2544[Abstract/Free Full Text]
6. Tawakol A, Omland T, Gerhard M, Wu JT, Creager MA. Hyperhomocyst(e)inemia is associated with impaired endothelial-dependent vasodilatation in humans. Circulation. 1997;95:1119–1121[Abstract/Free Full Text]
7. Chambers JC, Obeid O, McGregor A, Powell-Tuck J, Boustead L, Kooner JS. The relationship between hyperhomocysteinaemia and endothelial dysfunction is concentration-dependent, and present even at physiological levels. Circulation. 1998;98:I192
8. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801–809[CrossRef][Medline]
9. Sorensen KE, Celermajer DS, Spiegelhalter DJ, et al. Noninvasive measurement of human endothelium-dependent arterial responses: accuracy and reproducibility. Br Heart J. 1995;74:247–253[Abstract/Free Full Text]
10. Shipchandler MT, Moore EG. Rapid, fully automated measurement of plasma homocyst(e)ine with the Abbott IMX analyzer. Clin Chem. 1995;41:991–994[Abstract/Free Full Text]
11. Woo KS, Lolin YI, Celermajer DS. Hyperhomocyst(e)inemia is a risk factor for arterial endothelial dysfunction in humans. Circulation 1999. In Press.
12. Joannides R, Haefeli WE, Linder L, Richard V, Bakkali EH, Thuillez C, Luscher TF. Nitric-oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo. Circulation. 1995;91:1314–1319[Abstract/Free Full Text]
13. Anderson TJ, Uehata A, Gerhard MD, et al. Close relationship of endothelial cell function in the human coronary and peripheral circulations. J Am Coll Cardiol. 1995;26:1235–1241[Abstract]
14. Neunteufl T, Katzenschlager R, Hassan A, et al. Systemic endothelial function is related to the extent and severity of coronary artery disease. Atherosclerosis. 1997;129:111–118[CrossRef][Medline]
15. Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika. 1988;75:800–802[Abstract/Free Full Text]
16. Celermajer DS, Sorensen K, Ryalls M, Robinson J, Thomas O, Leonard JV, Deanfield JE. Impaired endothelial function occurs in the systemic arteries of children with homozygous homocystinuria but not in their heterozygous parents. J Am Coll Cardiol. 1993;22:854–858[Abstract]
17. Lentz SR, Sadler JE. Inhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteine. J Clin Invest. 1991;88:1906–1914[Medline]
18. Starkebaum G, Harlan JM. Endothelial cell injury due to copper-catalyzed hydrogen peroxide formation from homocysteine. J Clin Invest. 1986;77:1370–1376[Medline]
19. Cooke JP, Tsao PS. Is NO an endogenous anti-atherogenic molecule? Arterioscler Thromb Vasc Biol. 1994;14:653–655[Free Full Text]
20. Malinow MR, Nieto FJ, Kruger WD, et al. The effects of folic acid supplementation on plasma total homocysteine are modulated by multivitamin use and methylenetetrahydrofolate reductase genotypes. Arterioscler Thromb Vasc Biol. 1997;17:1157–1162[Abstract/Free Full Text]
21. Landgren E, Israelsson B, Lindgren A, Hultberg B, Andersson A, Brattström L. Plasma homocysteine in acute myocardial infarction: homocysteine-lowering effect of folic acid. J Intern Med. 1995;237:381–388[Medline]
22. Ubbink JB. The role of vitamins in the pathogenesis and treatment of hyperhomocyst(e)inaemia. J Inherit Metab Dis. 1997;20:316–325[CrossRef][Medline]
23. Verhaar MC, Wever RMF, Kastelein JJP, van Dam T, Koomans HA, Rabelink TJ. 5-Methyltetrahydrofolate, the active form of folic acid, restores endothelial function in familial hypercholesterolemia. Circulation. 1998;97:237–241[Abstract/Free Full Text]
24. Clarkson P, Adams MR, Powe AJ, et al. Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults. J Clin Invest. 1996;97:1989–1994[Medline]
25. Levine GN, Frei B, Kouloukis SN, Gerhard MO, Keaney JFJ, Vita JA. Ascorbic acid reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation. 1996;93:1107–1113[Abstract/Free Full Text]
26. O’Driscoll G, Green D, Taylor RR. Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation. 1997;95:1126–1131[Abstract/Free Full Text]
27. Treasure CB, Klein JL, Weintraub WS, et al. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med. 1995;332:481–487[CrossRef][Medline]
28. Scandinavian Simvastatin Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–1389[CrossRef][Medline]
29. Murakami T, Mizuno S, Kaku B. Clinical morbidities in subjects with Doppler-evaluated endothelial dysfunction of coronary artery. (abstr)J Am Coll Cardiol. 1998;31:419A
This article has been cited by other articles:
|
|
|
|
 
Y. Zhang, S. P. Janssens, K. Wingler, H. H. H. W. Schmidt, and A. L. Moens
Modulating endothelial nitric oxide synthase: a new cardiovascular therapeutic strategy
Am J Physiol Heart Circ Physiol,
September 1, 2011;
301(3):
H634 - H646.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. J. Williams, J. N. Bulmer, B. A. Innes, and F. Broughton Pipkin
Possible Roles for Folic Acid in the Regulation of Trophoblast Invasion and Placental Development in Normal Early Human Pregnancy
Biol Reprod,
June 1, 2011;
84(6):
1148 - 1153.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. M. ABRAHAM and L. CHO
The homocysteine hypothesis: Still relevant to the prevention and treatment of cardiovascular disease?
Cleveland Clinic Journal of Medicine,
December 1, 2010;
77(12):
911 - 918.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Qipshidze, N. Tyagi, U. Sen, S. Givvimani, N. Metreveli, D. Lominadze, and S. C. Tyagi
Folic acid mitigated cardiac dysfunction by normalizing the levels of tissue inhibitor of metalloproteinase and homocysteine-metabolizing enzymes postmyocardial infarction in mice
Am J Physiol Heart Circ Physiol,
November 1, 2010;
299(5):
H1484 - H1493.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S.-C. Shen, W.-J. Ho, S.-C. Wu, K.-H. Yu, H.-C. Lin, Y.-S. Lin, P.-K. Tsay, and P.-H. Chu
Peripheral Vascular Endothelial Dysfunction in Glaucomatocyclitic Crisis: A Preliminary Study
Invest. Ophthalmol. Vis. Sci.,
January 1, 2010;
51(1):
272 - 276.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. M. Urbina, R. V. Williams, B. S. Alpert, R. T. Collins, S. R. Daniels, L. Hayman, M. Jacobson, L. Mahoney, M. Mietus-Snyder, A. Rocchini, et al.
Noninvasive Assessment of Subclinical Atherosclerosis in Children and Adolescents: Recommendations for Standard Assessment for Clinical Research: A Scientific Statement From the American Heart Association
Hypertension,
November 1, 2009;
54(5):
919 - 950.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Y. Lam, S. W. Seto, A. L. S. Au, C. C. W. Poon, R. W. S. Li, H. Y. Lam, W. S. Lau, S. W. Chan, S. M. Ngai, G. P. H. Leung, et al.
Folic Acid Supplementation Modifies {beta}-Adrenoceptor-Mediated In Vitro Lipolysis of Obese/Diabetic (+db/+db) Mice
Exp Biol Med,
September 1, 2009;
234(9):
1047 - 1055.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. G. Christen, R. J. Glynn, E. Y. Chew, C. M. Albert, and J. E. Manson
Folic Acid, Pyridoxine, and Cyanocobalamin Combination Treatment and Age-Related Macular Degeneration in Women: The Women's Antioxidant and Folic Acid Cardiovascular Study
Arch Intern Med,
February 23, 2009;
169(4):
335 - 341.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Siekmeier, T. Grammer, and W. Marz
Roles of Oxidants, Nitric Oxide, and Asymmetric Dimethylarginine in Endothelial Function
Journal of Cardiovascular Pharmacology and Therapeutics,
December 1, 2008;
13(4):
279 - 297.
[Abstract]
[PDF]
|
|
|
|
|
|
|
A. L. Moens, C. J. Vrints, M. J. Claeys, J.-P. Timmermans, H. C. Champion, and D. A. Kass
Mechanisms and potential therapeutic targets for folic acid in cardiovascular disease
Am J Physiol Heart Circ Physiol,
May 1, 2008;
294(5):
H1971 - H1977.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. de Bree, L. A van Mierlo, and R. Draijer
Folic acid improves vascular reactivity in humans: a meta-analysis of randomized controlled trials
Am J Clin Nutr,
September 1, 2007;
86(3):
610 - 617.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. M. de Lau, H. Refsum, A D. Smith, C. Johnston, and M. M. Breteler
Plasma folate concentration and cognitive performance: Rotterdam Scan Study
Am J Clin Nutr,
September 1, 2007;
86(3):
728 - 734.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. S. Pena, E. Wiltshire, R. Gent, L. Piotto, C. Hirte, and J. Couper
Folic Acid Does Not Improve Endothelial Function in Obese Children and Adolescents
Diabetes Care,
August 1, 2007;
30(8):
2122 - 2127.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Kaul, A. A. Zadeh, and P. K. Shah
Homocysteine Hypothesis for Atherothrombotic Cardiovascular Disease: Not Validated
J. Am. Coll. Cardiol.,
September 5, 2006;
48(5):
914 - 923.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. C. Schramm, T. Dinh, and A. Veves
Microvascular Changes in the Diabetic Foot
International Journal of Lower Extremity Wounds,
September 1, 2006;
5(3):
149 - 159.
[Abstract]
[PDF]
|
|
|
|
|
|
|
K. E. MacKenzie, E. J. Wiltshire, R. Gent, C. Hirte, L. Piotto, and J. J. Couper
Folate and Vitamin B6 Rapidly Normalize Endothelial Dysfunction In Children With Type 1 Diabetes Mellitus
Pediatrics,
July 1, 2006;
118(1):
242 - 253.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. M Title, E. Ur, K. Giddens, M. J McQueen, and B. A Nassar
Folic acid improves endothelial dysfunction in type 2 diabetes - an effect independent of homocysteine-lowering
Vascular Medicine,
May 1, 2006;
11(2):
101 - 109.
[Abstract]
[PDF]
|
|
|
|
|
|
|
U. Forstermann and T. Munzel
Endothelial Nitric Oxide Synthase in Vascular Disease: From Marvel to Menace
Circulation,
April 4, 2006;
113(13):
1708 - 1714.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H.-K. Kuo, F. A. Sorond, J.-H. Chen, A. Hashmi, W. P. Milberg, and L. A. Lipsitz
The Role of Homocysteine in Multisystem Age-Related Problems: A Systematic Review
J Gerontol A Biol Sci Med Sci,
September 1, 2005;
60(9):
1190 - 1201.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Williams, B. A Kingwell, K. Burke, J. McPherson, and A. M Dart
Folic acid supplementation for 3 wk reduces pulse pressure and large artery stiffness independent of MTHFR genotype
Am J Clin Nutr,
July 1, 2005;
82(1):
26 - 31.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. L. Bots, J. Westerink, T. J. Rabelink, and E. J.P. de Koning
Assessment of flow-mediated vasodilatation (FMD) of the brachial artery: effects of technical aspects of the FMD measurement on the FMD response
Eur. Heart J.,
February 2, 2005;
26(4):
363 - 368.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. P. Lekakis, C. M. Papamichael, T. G. Papaioannou, A. G. Dagre, K. S. Stamatelopoulos, D. Tryfonopoulos, A. D. Protogerou, S. F. Stamatelopoulos, and M. Mavrikakis
Oral folic acid enhances endothelial function in patients with hypercholesterolemia receiving statins
European Journal of Cardiovascular Prevention & Rehabilitation,
October 1, 2004;
11(5):
416 - 420.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. J. Hankey and J. W. Eikelboom
Folic Acid-Based Multivitamin Therapy to Prevent Stroke: The Jury Is Still Out
Stroke,
August 1, 2004;
35(8):
1995 - 1998.
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. S. Woo, P. Chook, C. W. Yu, R. Y.T. Sung, M. Qiao, S. S.F. Leung, C. W.K. Lam, C. Metreweli, and D. S. Celermajer
Effects of Diet and Exercise on Obesity-Related Vascular Dysfunction in Children
Circulation,
April 27, 2004;
109(16):
1981 - 1986.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Paradisi, F. Cucinelli, M. C. Mele, A. Barini, A. Lanzone, and A. Caruso
Endothelial function in post-menopausal women: effect of folic acid supplementation
Hum. Reprod.,
April 1, 2004;
19(4):
1031 - 1035.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Wotherspoon, D. W Laight, K. M Shaw, and M. H Cummings
Review: Homocysteine, endothelial dysfunction and oxidative stress in type 1 diabetes mellitus
The British Journal of Diabetes & Vascular Disease,
September 1, 2003;
3(5):
334 - 340.
[Abstract]
[PDF]
|
|
|
|
|
|
|
A. T. Merchant, F. B. Hu, D. Spiegelman, W. C. Willett, E. B. Rimm, and A. Ascherio
The Use of B Vitamin Supplements and Peripheral Arterial Disease Risk in Men Are Inversely Related
J. Nutr.,
September 1, 2003;
133(9):
2863 - 2867.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. B. Bailey, G. C. Rampersaud, and G. P. A. Kauwell
Folic Acid Supplements and Fortification Affect the Risk for Neural Tube Defects, Vascular Disease and Cancer: Evolving Science,
J. Nutr.,
June 1, 2003;
133(6):
1961S - 1968.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Girelli, N. Martinelli, F. Pizzolo, S. Friso, O. Olivieri, C. Stranieri, E. Trabetti, G. Faccini, E. Tinazzi, P. F. Pignatti, et al.
The Interaction between MTHFR 677 C->T Genotype and Folate Status Is a Determinant of Coronary Atherosclerosis Risk
J. Nutr.,
May 1, 2003;
133(5):
1281 - 1285.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Hernandez-Diaz, M. M. Werler, C. Louik, and A. A. Mitchell
Risk of Gestational Hypertension in Relation to Folic Acid Supplementation during Pregnancy
Am. J. Epidemiol.,
November 1, 2002;
156(9):
806 - 812.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Wang, C. W.H. Woo, F. L. Sung, Y. L. Siow, and K. O
Increased Monocyte Adhesion to Aortic Endothelium in Rats With Hyperhomocysteinemia: Role of Chemokine and Adhesion Molecules
Arterioscler Thromb Vasc Biol,
November 1, 2002;
22(11):
1777 - 1783.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Stanger, H.-J. Semmelrock, W. Wonisch, U. Bos, E. Pabst, and T. C. Wascher
Effects of Folate Treatment and Homocysteine Lowering on Resistance Vessel Reactivity in Atherosclerotic Subjects
J. Pharmacol. Exp. Ther.,
October 1, 2002;
303(1):
158 - 162.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Schnyder, M. Roffi, Y. Flammer, R. Pin, and O. M. Hess
Effect of Homocysteine-Lowering Therapy With Folic Acid, Vitamin B12, and Vitamin B6 on Clinical Outcome After Percutaneous Coronary Intervention: The Swiss Heart Study: A Randomized Controlled Trial
JAMA,
August 28, 2002;
288(8):
973 - 979.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Weiss, C. Keller, U. Hoffmann, and J. Loscalzo
Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia
Vascular Medicine,
August 1, 2002;
7(3):
227 - 239.
[Abstract]
[PDF]
|
|
|
|
|
|
|
A. Makin, S.H. Silverman, and G.Y.H. Lip
Peripheral vascular disease and Virchow's triad for thrombogenesis
QJM,
April 1, 2002;
95(4):
199 - 210.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M.C. Verhaar, E. Stroes, and T.J. Rabelink
Folates and Cardiovascular Disease
Arterioscler Thromb Vasc Biol,
January 1, 2002;
22(1):
6 - 13.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. H. Pullin, P. A. L. Ashfield-Watt, M. L. Burr, Z. E. Clark, M. J. Lewis, S. J. Moat, R. G. Newcombe, H. J. Powers, J. M. Whiting, and I. F. W. McDowell
Optimization of dietary folate or low-dose folic acid supplements lower homocysteine but do not enhance endothelial function in healthy adults, irrespective of the methylenetetrahydrofolate reductase (C677T) genotype
J. Am. Coll. Cardiol.,
December 1, 2001;
38(7):
1799 - 1805.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Loscalzo
Folate and Nitrate-Induced Endothelial Dysfunction: A Simple Treatment for a Complex Pathobiology
Circulation,
September 4, 2001;
104(10):
1086 - 1088.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. C CHAMBERS and J. S KOONER
Homocysteine: a novel risk factor for coronary heart disease in UK Indian Asians
Heart,
August 1, 2001;
86(2):
121 - 122.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. N. Doshi, I. F. W. McDowell, S. J. Moat, D. Lang, R. G. Newcombe, M. B. Kredan, M. J. Lewis, and J. Goodfellow
Folate Improves Endothelial Function in Coronary Artery Disease : An Effect Mediated by Reduction of Intracellular Superoxide?
Arterioscler Thromb Vasc Biol,
July 1, 2001;
21(7):
1196 - 1202.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Weger, O. Stanger, H. Deutschmann, M. Simon, W. Renner, O. Schmut, J. Semmelrock, and A. Haas
Hyperhomocyst(e)inaemia, but not MTHFR C677T mutation, as a risk factor for non-arteritic ischaemic optic neuropathy
Br J Ophthalmol,
July 1, 2001;
85(7):
803 - 806.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Thambyrajah, M. J. Landray, H. J. Jones, F. J. McGlynn, D. C. Wheeler, and J. N. Townend
A randomized double-blind placebo-controlled trial of the effect of homocysteine-lowering therapy with folic acid on endothelial function in patients with coronary artery disease
J. Am. Coll. Cardiol.,
June 1, 2001;
37(7):
1858 - 1863.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.C. Chambers and J.S. Kooner
Homocysteine -- an innocent bystander in vascular disease?
Eur. Heart J.,
May 1, 2001;
22(9):
717 - 719.
[PDF]
|
|
|
|
|
|
|
A. A Brown and F. B Hu
Dietary modulation of endothelial function: implications for cardiovascular disease
Am J Clin Nutr,
April 1, 2001;
73(4):
673 - 686.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. C. Chambers, L. Fusi, I. S. Malik, D. O. Haskard, M. De Swiet, and J. S. Kooner
Association of Maternal Endothelial Dysfunction With Preeclampsia
JAMA,
March 28, 2001;
285(12):
1607 - 1612.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. C. Chambers, P. M. Ueland, O. A. Obeid, J. Wrigley, H. Refsum, and J. S. Kooner
Improved Vascular Endothelial Function After Oral B Vitamins : An Effect Mediated Through Reduced Concentrations of Free Plasma Homocysteine
Circulation,
November 14, 2000;
102(20):
2479 - 2483.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. ROBINSON
Homocysteine, B vitamins, and risk of cardiovascular disease
Heart,
February 1, 2000;
83(2):
127 - 130.
[Full Text]
|
|
|
|
|
|
|
J. C. Chambers, P. M. Ueland, M. Wright, C. J. Dore, H. Refsum, and J. S. Kooner
Investigation of Relationship Between Reduced, Oxidized, and Protein-Bound Homocysteine and Vascular Endothelial Function in Healthy Human Subjects
Circ. Res.,
July 20, 2001;
89(2):
187 - 192.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Bennett-Richards, M. Kattenhorn, A. Donald, G. Oakley, Z. Varghese, L. Rees, and J.E. Deanfield
Does Oral Folic Acid Lower Total Homocysteine Levels and Improve Endothelial Function in Children With Chronic Renal Failure?
Circulation,
April 16, 2002;
105(15):
1810 - 1815.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Methods