Journal of Chiropractic Medicine
Volume 8, Issue 1 , Pages 15-24 , March 2009

High-dose folic acid supplementation effects on endothelial function and blood pressure in hypertensive patients: a meta-analysis of randomized controlled clinical trials

  • Marc P. McRae, MSc, DC, FACN, DACBN

      Affiliations

    • Corresponding Author InformationCorresponding author. Department of Physiology and Biochemistry, National University of Health Sciences, 200 East Roosevelt Rd, Lombard, IL 60148, USA. Tel.: +1 630 889 6592.

Received 2 May 2008 ,Revised 7 September 2008 ,Accepted 10 September 2008.

References 

  1. Burt VL, Whelton P, Roccella EJ, et al. Prevalence of hypertension in the US adult population. Results from the Third National Health and Nutrition Examination Survey, 1988-1991. Hypertension. 1995;25(3):305–313
  2. Robinson K, Arheart K, Refsum H, et al. Low circulating folate and vitamin B6 concentrations: risk factors for stroke, peripheral vascular disease, and coronary artery disease. European COMAC Group. Circulation. 1998;97(5):437–443
  3. Bunout D, Petermann M, Hirsch S, et al. Low serum folate but normal homocysteine levels in patients with atherosclerotic vascular disease and matched healthy controls. Nutrition. 2000;16(6):434–438
  4. Voutilainen S, Rissanen TH, Virtanen J, Lakka TA, Salonen JT. Kuopio Ischemic Heart Disease Risk Factor Study. Low dietary folate intake is associated with an excess incidence of acute coronary events: the Kuopio Ischemic Heart Disease Risk Factor Study. Circulation. 2001;103(22):2674–2680
  5. Forman JP, Rimm EB, Stampfer MJ, Curhan GC. Folate intake and the risk of incident hypertension among US women. JAMA. 2005;293(3):320–329
  6. Title LM, Cummings PM, Giddens K, Genest JJ, Nassar BA. Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease. J Am Coll Cardiol. 2000;36(3):758–765
  7. Doshi SN, McDowell IF, Moat SJ, et al. Folate improves endothelial function in coronary artery disease: an effect mediated by reduction of intracellular superoxide?. Arterioscler Thromb Vasc Biol. 2001;21(7):1196–1202
  8. Doshi SN, McDowell IF, Moat SJ, et al. Folic acid improves endothelial function in coronary artery disease via mechanisms largely independent of homocysteine lowering. Circulation. 2002;105(1):22–26
  9. Mangoni AA, Sherwood RA, Asonganyi B, Swift CG, Thomas S, Jackson SH. Short-term oral folic acid supplementation enhances endothelial function in patients with type 2 diabetes. Am J Hypertens. 2005;18(2 Pt 1):220–226
  10. Williams C, Kingwell BA, Burke K, McPherson J, Dart AM. Folic acid supplementation for 3 wk reduces pulse pressure and large artery stiffness independent of MTHFR genotype. Am J Clin Nutr. 2005;82(1):26–31
  11. Title LM, Ur E, Giddens K, McQueen MJ, Nassar BA. Folic acid improves endothelial dysfunction in type 2 diabetes—an effect independent of homocysteine-lowering. Vasc Med. 2006;11(2):101–109
  12. Moens AL, Claeys MJ, Wuyts FL, et al. Effect of folic acid on endothelial function following acute myocardial infarction. Am J Cardiol. 2007;99(4):476–481
  13. Bellamy MF, McDowell IF, Ramsey MW, Brownlee M, Newcombe RG, Lewis MJ. Oral folate enhances endothelial function in hyperhomocysteinaemic subjects. Eur J Clin Invest. 1999;29(8):659–662
  14. Verhaar MC, Wever RM, Kastelein JJ, et al. Effects of oral folic acid supplementation on endothelial function in familial hypercholesterolemia. A randomized placebo-controlled trial. Circulation. 1999;100(4):335–338
  15. Wilmink HW, Stroes ES, Erkelens WD, et al. Influence of folic acid on postprandial endothelial dysfunction. Arterioscler Thromb Vasc Biol. 2000;20(1):185–188
  16. Mangoni AA, Sherwood RA, Swift CG, Jackson SH. Folic acid enhances endothelial function and reduces blood pressure in smokers: a randomized controlled trial. J Intern Med. 2002;252(6):497–503
  17. Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR, Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation. 2000;101(9):948–954
  18. Schächinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation. 2000;101(16):1899–1906
  19. Moens AL, Goovaerts I, Claeys MJ, Vrints CJ. Flow-mediated vasodilation: a diagnostic instrument, or an experimental tool?. Chest. 2005;127(6):2254–2263
  20. Yoshida T, Kawano H, Miyamoto S, et al. Prognostic value of flow-mediated dilation of the brachial artery in patients with cardiovascular disease. Intern Med. 2006;45(9):575–579
  21. Woo KS, Chook P, Lolin YI, Sanderson JE, Metreweli C, Celermajer DS. Folic acid improves arterial endothelial function in adults with hyperhomocystinemia. J Am Coll Cardiol. 1999;34(7):2002–2006
  22. Lekakis JP, Papamichael CM, Papaioannou TG, et al. Oral folic acid enhances endothelial function in patients with hypercholesterolaemia receiving statins. Eur J Cardiovasc Prev Rehabil. 2004;11(5):416–420
  23. Thambyrajah J, Landray MJ, McGlynn FJ, Jones HJ, Wheeler DC, Townend JN. Does folic acid decrease plasma homocysteine and improve endothelial function in patients with predialysis renal failure?. Circulation. 2000;102(8):871–875
  24. Thambyrajah J, Landray MJ, Jones HJ, McGlynn FJ, Wheeler DC, Townend JN. 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. 2001;37(7):1858–1863
  25. Woodman RJ, Celermajer DE, Thompson PL, Hung J. Folic acid does not improve endothelial function in healthy hyperhomocysteinaemic subjects. Clin Sci (Lond). 2004;106(4):353–358
  26. Pullin CH, Ashfield-Watt PA, Burr ML, et al. 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. 2001;38(7):1799–1805
  27. Hirsch S, Pia D, Yanez P, et al. Hyperhomocysteinemia and endothelial function in young subjects: effects of vitamin supplementation. Clin Cardiol. 2002;25:495–501
  28. Olthof MR, Bots ML, Katan MB, Verhoef P. Effect of folic acid and betaine supplementation on flow-mediated dilation: a randomized, controlled study in healthy volunteers. PLoS Clin Trials. 2006;1(2):e10
  29. de Bree A, van Mierlo LA, Draijer R. Folic acid improves vascular reactivity in humans: a meta-analysis of randomized controlled trials. Am J Clin Nutr. 2007;86(3):610–617
  30. Follmann D, Elliott P, Suh I, Cutler J. Variance imputation for overviews of clinical trials with continuous response. J Clin Epidemiol. 1992;45(7):769–773
  31. Franklin SS, Larson MG, Khan SA, et al. Does the relation of blood pressure to coronary heart disease risk change with aging? The Framingham Heart Study. Circulation. 2001;103(9):1245–1249
  32. Bowman TS, Gaziano JM, Kase CS, Sesso HD, Kurth T. Blood pressure measures and risk of total, ischemic, and hemorrhagic stroke in men. Neurology. 2006;67(5):820–823
  33. Menotti A, Lanti M, Nedeljkovic S, et al. The relationship of age, blood pressure, serum cholesterol and smoking habits with the risk of typical and atypical coronary heart disease death in the European cohorts of the Seven Countries Study. Int J Cardiol. 2006;106(2):157–163
  34. Witte DR, Westerink J, de Koning EJ, van der Graaf Y, Grobbee DE, Bots ML. Is the association between flow-mediated dilation and cardiovascular risk limited to low-risk populations?. J Am Coll Cardiol. 2005;45(12):1987–1993
  35. Brevetti G, Silvestro A, Schiano V, Chiariello M. Endothelial dysfunction and cardiovascular risk prediction in peripheral arterial disease: additive value of flow-mediated dilation to ankle-brachial pressure index. Circulation. 2003;108(17):2093–2098
  36. Stehouwer CD, van Guldener C. Does homocysteine cause hypertension?. Clin Chem Lab Med. 2003;41(11):1408–1411
  37. Tawakol A, Migrino RQ, Aziz KS, et al. High-dose folic acid acutely improves coronary vasodilator function in patients with coronary artery disease. J Am Coll Cardiol. 2005;45(10):1580–1584
  38. Usui M, Matsuoka H, Miyazaki H, Ueda S, Okuda S, Imaizumi T. Endothelial dysfunction by acute hyperhomocyst(e)inaemia: restoration by folic acid. Clin Sci (Lond). 1999;96(3):235–239
  39. McDowell IF, Lang D. Homocysteine and endothelial dysfunction: a link with cardiovascular disease. J Nutr. 2000;130(2S Suppl):369S–372S
  40. Pruefer D, Scalia R, Lefer AM. Homocysteine provokes leukocyte-endothelium interaction by downregulation of nitric oxide. Gen Pharmacol. 1999;33(6):487–498
  41. Kahleová R, Palyzová D, Zvára K, et al. Essential hypertension in adolescents: association with insulin resistance and with metabolism of homocysteine and vitamins. Am J Hypertens. 2002;15(10 Pt 1):857–864
  42. Lim U, Cassano PA. Homocysteine and blood pressure in the Third National Health and Nutrition Examination Survey, 1988-1994. Am J Epidemiol. 2002;156(12):1105–1113
  43. van Dijk RA, Rauwerda JA, Steyn M, Twisk JW, Stehouwer CD. 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. Arterioscler Thromb Vasc Biol. 2001;21(12):2072–2079
  44. Kedziora-Kornatowska K, Czuczejko J, Pawluk H, et al. The markers of oxidative stress and activity of the antioxidant system in the blood of elderly patients with essential arterial hypertension. Cell Mol Biol Lett. 2004;9(4A):635–641
  45. Bellamy MF, McDowell IF, Ramsey MW, et al. Hyperhomocysteinemia after an oral methionine load acutely impairs endothelial function in healthy adults. Circulation. 1998;98(18):1848–1852
  46. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. 2002;288(16):2015–2022
  47. Verhaar MC, Wever RM, Kastelein JJ, van Dam T, Koomans HA, Rabelink TJ. 5-Methyltetrahydrofolate, the active form of folic acid, restores endothelial function in familial hypercholesterolemia. Circulation. 1998;97(3):237–241
  48. Stroes ES, van Faassen EE, Yo M, et al. Folic acid reverts dysfunction of endothelial nitric oxide synthase. Circ Res. 2000;86(11):1129–1134
  49. Huang A, Vita JA, Venema RC, Keaney JF. Ascorbic acid enhances endothelial nitric-oxide synthase activity by increasing intracellular tetrahydrobiopterin. J Biol Chem. 2000;275(23):17399–17406
  50. Baker TA, Milstien S, Katusic ZS. Effect of vitamin C on the availability of tetrahydrobiopterin in human endothelial cells. J Cardiovasc Pharmacol. 2001;37(3):333–338
  51. Heller R, Unbehaun A, Schellenberg B, Mayer B, Werner-Felmayer G, Werner ER. l-ascorbic acid potentiates endothelial nitric oxide synthesis via a chemical stabilization of tetrahydrobiopterin. J Biol Chem. 2001;276(1):40–47
  52. Xia Y, Tsai AL, Berka V, Zweier JL. Superoxide generation from endothelial nitric-oxide synthase. A Ca2+/calmodulin-dependent and tetrahydrobiopterin regulatory process. J Biol Chem. 1998;273(40):25804–25808
  53. Vásquez-Vivar J, Kalyanaraman B, Martásek P, et al. Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors. Proc Natl Acad Sci U S A. 1998;95(16):9220–9225
  54. Vásquez-Vivar J, Kalyanaraman B, Martásek P. The role of tetrahydrobiopterin in superoxide generation from eNOS: enzymology and physiological implications. Free Radic Res. 2003;37(2):121–127
  55. Alp NJ, Channon KM. Regulation of endothelial nitric oxide synthase by tetrahydrobiopterin in vascular disease. Arterioscler Thromb Vasc Biol. 2004;24(3):413–420
  56. Stroes E, Hijmering M, van Zandvoort M, Wever R, Rabelink TJ, van Faassen EE. Origin of superoxide production by endothelial nitric oxide synthase. FEBS Lett. 1998;438(3):161–164
  57. Dixon LJ, Morgan DR, Hughes SM, et al. Functional consequences of endothelial nitric oxide synthase uncoupling in congestive cardiac failure. Circulation. 2003;107(13):1725–1728
  58. Verhaar MC, Stroes E, Rabelink TJ. Folates and cardiovascular disease. Arterioscler Thromb Vasc Biol. 2002;22(1):6–13
  59. Moat SJ, Clarke ZL, Madhavan AK, Lewis MJ, Lang D. Folic acid reverses endothelial dysfunction induced by inhibition of tetrahydrobiopterin biosynthesis. Eur J Pharmacol. 2006;530(3):250–258
  60. Hyndman ME, Verma S, Rosenfeld RJ, Anderson TJ, Parsons HG. Interaction of 5-methyltetrahydrofolate and tetrahydrobiopterin on endothelial function. Am J Physiol Heart Circ Physiol. 2002;282(6):H2167–H2172
  61. Doshi SN, Moat SJ, Lewis MJ, McDowell IF, Giddings JC, Goodfellow J. Short-term high-dose folic acid does not alter markers of endothelial cell damage in patients with coronary heart disease. Int J Cardiol. 2004;94(2-3):203–207
  62. Bazzano LA, Reynolds K, Holder KN, He J. Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. JAMA. 2006;296(22):2720–2726
  63. Bostom AG, Carpenter MA, Kusek JW, et al. Rationale and design of the Folic Acid for Vascular Outcome Reduction In Transplantation (FAVORIT) trial. Am Heart J. 2006;152(3):448.e1–448.e7
  64. B-Vitamin Treatment Trialists' Collaboration. Homocysteine-lowering trials for prevention of cardiovascular events: a review of the design and power of the large randomized trials. Am Heart J. 2006;151(2):282–287
  65. Cole BF, Baron JA, Sandler RS, et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA. 2007;297(21):2351–2359
  66. Hultdin J, Van Guelpen B, Bergh A, Hallmans G, Stattin P. Plasma folate, vitamin B12, and homocysteine and prostate cancer risk: a prospective study. Int J Cancer. 2005;113(5):819–824
  67. Stevens VL, Rodriguez C, Pavluck AL, McCullough ML, Thun MJ, Calle EE. Folate nutrition and prostate cancer incidence in a large cohort of US men. Am J Epidemiol. 2006;163(11):989–996
  68. Kim YI. Role of folate in colon cancer development and progression. J Nutr. 2003;133(11 Suppl 1):3731S–3739S
  69. Kim YI. Will mandatory folic acid fortification prevent or promote cancer?. Am J Clin Nutr. 2004;80:1123–1128
  70. Campbell NR. How safe are folic acid supplements?. Arch Intern Med. 1996;156(15):1638–1644

PII: S1556-3707(08)00128-4

doi: 10.1016/j.jcm.2008.09.001

Journal of Chiropractic Medicine
Volume 8, Issue 1 , Pages 15-24 , March 2009