Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Clinical nutrition

Association between serum folate and cardiovascular deaths among adults with hypertension

European Journal of Clinical Nutrition volume 74, pages 970–978 (2020)Cite this article

Subjects

Abstract

Background

A significant shift toward high folate concentrations has been taking place following the mandatory folate fortification. Yet the relationship between folate and health outcomes beyond neural tube defects remains understudied. We longitudinally examined relationships between serum folate and risk of cardiovascular death.

Methods

We analyzed data of 3116 adults aged ≥19 who participated in the Third National Health and Nutrition Examination Survey, 1991–1994 and were diagnosed with hypertension. Vital status was followed through December 31, 2010. Cox regression was used to estimate hazard ratios (HRs) of cardiovascular deaths for individuals with serum folate in the first quartile and fourth quartile compared with the patients with interquartile folate.

Results

After 33627 person years (p*ys) of follow-up, 1298 deaths were recorded with 638 cardiovascular disease (CVD) deaths (109 strokes and 529 heart diseases). A U-shaped association appeared after multivariable adjustment for heart disease, acute myocardial infarction, and overall CVD deaths. The mortality rate for heart disease in patients with low, moderate, and high folate were 12.18/1000 p*ys, 14.12/1000 p*ys, and 23.80/1000 p*ys, respectively, and the corresponding adjusted HRs were 1.79 (95% confidence interval, CI = 1.63–1.98), 1.00 (reference), and 1.31 (1.17–1.46). The HRs of acute myocardial infarction were 2.28 (1.80–2.88), 1.00 (reference), and 1.77 (1.42–2.20) for hypertensive patients with serum folate in low quartile, interquartile, and high quartile, respectively.

Conclusions

Among hypertensive adults, both low and high folate were associated with an elevated risk of dying from cardiovascular diseases compared with adults with moderate serum folate concentration.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Pfeiffer CM, Hughes JP, Lacher DA, Bailey RL, Berry RJ, Zhang M, et al. Estimation of trends in serum and RBC folate in the U.S. population from pre- to postfortification using assay-adjusted data from the NHANES 1988-2010. J Nutr. 2012;142:886–93. https://doi.org/10.3945/jn.111.156919

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Schwartz SM, Siscovick DS, Malinow MR, Rosendaal FR, Beverly RK, Hess DL, et al. Myocardial infarction in young women in relation to plasma total homocysteine, folate, and a common variant in the methylenetetrahydrofolate reductase gene. Circulation. 1997;96:412–7.

    Article  CAS  Google Scholar 

  3. Selhub J, Jacques PF, Bostom AG, D’Agostino RB, Wilson PW, Belanger AJ, et al. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med. 1995;332:286–91. https://doi.org/10.1056/NEJM199502023320502

    Article  CAS  PubMed  Google Scholar 

  4. Loria CM, Ingram DD, Feldman JJ, Wright JD, Madans JH. Serum folate and cardiovascular disease mortality among US men and women. Arch Intern Med. 2000;160:3258–62.

    Article  CAS  Google Scholar 

  5. Morrison HI, Schaubel D, Desmeules M, Wigle DT. Serum folate and risk of fatal coronary heart disease. JAMA. 1996;275:1893–6.

    Article  CAS  Google Scholar 

  6. Folsom AR, Nieto FJ, McGovern PG, Tsai MY, Malinow MR, Eckfeldt JH, et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 1998;98:204–10.

    Article  CAS  Google Scholar 

  7. Voutilainen S, Rissanen TH, Virtanen J, Lakka TA, Salonen JT. Kuopio Ischemic Heart Disease Risk Factor S. Low dietary folate intake is associated with an excess incidence of acute coronary events: the Kuopio Ischemic Heart Disease Risk Factor Study. Circulation. 2001;103:2674–80.

    Article  CAS  Google Scholar 

  8. Huang YC, Lee MS, Wahlqvist ML. Prediction of all-cause mortality by B group vitamin status in the elderly. Clin Nutr. 2012;31:191–8. https://doi.org/10.1016/j.clnu.2011.10.010

    Article  PubMed  Google Scholar 

  9. Xun P, Liu K, Loria CM, Bujnowski D, Shikany JM, Schreiner PJ, et al. Folate intake and incidence of hypertension among American young adults: a 20-y follow-up study. Am J Clin Nutr. 2012;95:1023–30. https://doi.org/10.3945/ajcn.111.027250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hung J, Beilby JP, Knuiman MW, Divitini M. Folate and vitamin B-12 and risk of fatal cardiovascular disease: cohort study from Busselton, Western Australia. Brit Med J. 2003;326:131.

    Article  CAS  Google Scholar 

  11. Dangour AD, Breeze E, Clarke R, Shetty PS, Uauy R, Fletcher AE. Plasma homocysteine, but not folate or vitamin B-12, predicts mortality in older people in the United Kingdom. J Nutr. 2008;138:1121–8.

    Article  CAS  Google Scholar 

  12. Chasan-Taber L, Selhub J, Rosenberg IH, Malinow MR, Terry P, Tishler PV, et al. A prospective study of folate and vitamin B6 and risk of myocardial infarction in US physicians. J Am Coll Nutr. 1996;15:136–43.

    Article  CAS  Google Scholar 

  13. Roswall N, Olsen A, Christensen J, Hansen L, Dragsted LO, Overvad K, et al. Micronutrient intake in relation to all-cause mortality in a prospective Danish cohort. Food Nutr. Res. 2012;56 https://doi.org/10.3402/fnr.v56i0.5466

  14. Bird JK, Ronnenberg AG, Choi SW, Du F, Mason JB, Liu Z. Obesity is associated with increased red blood cell folate despite lower dietary intakes and serum concentrations. J Nutr. 2015;145:79–86. https://doi.org/10.3945/jn.114.199117

    Article  CAS  PubMed  Google Scholar 

  15. MacKenzie KE, Wiltshire EJ, Gent R, Hirte C, Piotto L, Couper JJ. Folate and vitamin B6 rapidly normalize endothelial dysfunction in children with type 1 diabetes mellitus. Pediatrics. 2006;118:242–53. https://doi.org/10.1542/peds.2005-2143

    Article  PubMed  Google Scholar 

  16. Mierzecki A, Kloda K, Bukowska H, Chelstowski K, Makarewicz-Wujec M, Kozlowska-Wojciechowska M. Association between low-dose folic acid supplementation and blood lipids concentrations in male and female subjects with atherosclerosis risk factors. Med Sci Monit. 2013;19:733–9. https://doi.org/10.12659/MSM.889087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wu CJ, Wang L, Li X, Wang CX, Ma JP, Xia XS. Impact of adding folic acid, vitamin B(12) and probucol to standard antihypertensive medication on plasma homocysteine and asymmetric dimethylarginine levels of essential hypertension patients. Zhonghua Xin Xue Guan Bing Za Zhi. 2012;40:1003–8.

    CAS  PubMed  Google Scholar 

  18. Aghamohammadi V, Gargari BP, Aliasgharzadeh A. Effect of folic acid supplementation on homocysteine, serum total antioxidant capacity, and malondialdehyde in patients with type 2 diabetes mellitus. J Am Coll Nutr. 2011;30:210–5.

    Article  CAS  Google Scholar 

  19. Gargari BP, Aghamohammadi V, Aliasgharzadeh A. Effect of folic acid supplementation on biochemical indices in overweight and obese men with type 2 diabetes. Diabetes Res Clin Pr. 2011;94:33–8. https://doi.org/10.1016/j.diabres.2011.07.003

    Article  CAS  Google Scholar 

  20. Zhao F, Li JP, Wang SY, Guan DM, Ge JB, Hu J, et al. The effect of baseline homocysteine level on the efficacy of enalapril maleate and folic acid tablet in lowering blood pressure and plasma homocysteine. Zhonghua Yi Xue Za Zhi. 2008;88:2957–61.

    CAS  PubMed  Google Scholar 

  21. Fu J, Tang HQ, Qin XH, Mao GY, Tang GF. Efficacy of enalapril combined with folic acid in lowering blood pressure and plasma homocysteine level. Zhonghua Yi Xue Za Zhi. 2009;89:2179–83.

    PubMed  Google Scholar 

  22. Huo Y, Li J, Qin X, Huang Y, Wang X, Gottesman RF, et al. Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial. JAMA. 2015;313:1325–35. https://doi.org/10.1001/jama.2015.2274

    Article  CAS  PubMed  Google Scholar 

  23. Wang L, Li H, Zhou Y, Jin L, Liu J. Low-dose B vitamins supplementation ameliorates cardiovascular risk: a double-blind randomized controlled trial in healthy Chinese elderly. Eur J Nutr. 2015;54:455–64. https://doi.org/10.1007/s00394-014-0729-5

    Article  CAS  PubMed  Google Scholar 

  24. Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N. Engl J Med. 2006;354:1567–77. https://doi.org/10.1056/NEJMoa060900

    Article  CAS  PubMed  Google Scholar 

  25. Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T, et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med. 2006;354:1578–88. https://doi.org/10.1056/NEJMoa055227

    Article  CAS  PubMed  Google Scholar 

  26. Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA. 2004;291:565–75. https://doi.org/10.1001/jama.291.5.565

    Article  CAS  PubMed  Google Scholar 

  27. Cole BF, Baron JA, Sandler RS, Haile RW, Ahnen DJ, Bresalier RS, et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA. 2007;297:2351–9. https://doi.org/10.1001/jama.297.21.2351

    Article  CAS  PubMed  Google Scholar 

  28. Albert CM, Cook NR, Gaziano JM, Zaharris E, MacFadyen J, Danielson E, et al. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA. 2008;299:2027–36. https://doi.org/10.1001/jama.299.17.2027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lange H, Suryapranata H, De Luca G, Borner C, Dille J, Kallmayer K, et al. Folate therapy and in-stent restenosis after coronary stenting. N Engl J Med. 2004;350:2673–81. https://doi.org/10.1056/NEJMoa032845

    Article  CAS  PubMed  Google Scholar 

  30. Ebbing M, Bonaa KH, Nygard O, Arnesen E, Ueland PM, Nordrehaug JE, et al. Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA. 2009;302:2119–26. https://doi.org/10.1001/jama.2009.1622

    Article  CAS  PubMed  Google Scholar 

  31. Ford ES, Byers TE, Giles WH. Serum folate and chronic disease risk: findings from a cohort of United States adults. Int J Epidemiol. 1998;27:592–8.

    Article  CAS  Google Scholar 

  32. Peng Y, Dong B, Wang Z. Serum folate concentrations and all-cause, cardiovascular disease and cancer mortality: a cohort study based on 1999-2010 National Health and Nutrition Examination Survey (NHANES). Int J Cardiol. 2016;219:136–42. https://doi.org/10.1016/j.ijcard.2016.06.024

    Article  PubMed  Google Scholar 

  33. National Center for Health Statistics. Plan and operation of the Third National Health and Nutrition Examination Survey (NHANES III, 1988–94). Hyattsville, MD: US Department of Health and Human Service, Public Health Service, Center for Disease Control and Prevention, 1996

  34. National Center for Health Statistics, Centers for Disease Control and Prevention. National Health and Nutrition Examination Survey—About the National Health and Nutrition Examination Survey. https://www.cdc.gov/nchs/nhanes/about_nhanes.htm. Accessed 24 Nov 2019

  35. de Benoist B. Conclusions of a WHO technical consultation on folate and vitamin B12 deficiencies. Food Nutr Bull. 2008;29:S238–44. https://doi.org/10.1177/15648265080292S129

    Article  PubMed  Google Scholar 

  36. Lainscak M, Farkas J, Frantal S, Singer P, Bauer P, Hiesmayr M, et al. Self-rated health, nutritional intake and mortality in adult hospitalized patients. Eur J Clin Invest. 2014;44:813–24.

    Article  Google Scholar 

  37. National Center for Health Statistics, Office of Analysis and Epidemiology. Public-use Linked Mortality File. National Center for Health Statistics, Office of Analysis and Epidemiology: Hyattsville, Maryland; 2015.

  38. Tamai Y, Wada K, Tsuji M, Nakamura K, Sahashi Y, Watanabe K, et al. Dietary intake of vitamin B12 and folic acid is associated with lower blood pressure in Japanese preschool children. Am J Hypertens. 2011;24:1215–21. https://doi.org/10.1038/ajh.2011.133

    Article  CAS  PubMed  Google Scholar 

  39. Voutilainen S, Virtanen JK, Rissanen TH, Alfthan G, Laukkanen J, Nyyssonen K, et al. Serum folate and homocysteine and the incidence of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study. Am J Clin Nutr. 2004;80:317–23. https://doi.org/10.1093/ajcn/80.2.317

    Article  CAS  PubMed  Google Scholar 

  40. Barter PJ, Rye KA. Homocysteine and cardiovascular disease: is HDL the link? Circ Res. 2006;99:565–6. https://doi.org/10.1161/01.RES.0000243583.39694.1f

    Article  CAS  PubMed  Google Scholar 

  41. Vanderwall CM, Tangney CC, Kwasny MJ, Gustashaw KA. Examination of circulating folate levels as a reflection of folate intakes among older adult supplement users and nonusers in the National Health and Nutrition Examination Survey 2003-2004. J Acad Nutr Diet. 2012;112:285–90. https://doi.org/10.1016/j.jada.2011.10.001

    Article  CAS  PubMed  Google Scholar 

  42. Oleinik NV, Krupenko NI, Reuland SN, Krupenko SA. Leucovorin-induced resistance against FDH growth suppressor effects occurs through DHFR up-regulation. Biochem Pharm. 2006;72:256–66. https://doi.org/10.1016/j.bcp.2006.04.005

    Article  CAS  PubMed  Google Scholar 

  43. Sauer J, Mason JB, Choi SW. Too much folate: a risk factor for cancer and cardiovascular disease? Curr Opin Clin Nutr Metab Care. 2009;12:30–6. https://doi.org/10.1097/MCO.0b013e32831cec62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kim H, Eun Y, Song S. Serum folate and vitamin B12 levels are not associated with the incidence risk of atherosclerotic events over 12 years: the Korean Genome and Epidemiology Study. Nutr Res. 2019;63:34–41. https://doi.org/10.1016/j.nutres.2018.12.009

    Article  CAS  PubMed  Google Scholar 

  45. Weikert C, Dierkes J, Hoffmann K, Berger K, Drogan D, Klipstein-Grobusch K, et al. B vitamin plasma levels and the risk of ischemic stroke and transient ischemic attack in a German cohort. Stroke. 2007;38:2912–8. https://doi.org/10.1161/STROKEAHA.107.486068

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Epidemiology, Jiann-Ping Hsu College of Public Health, Georgia Southern University, Statesboro, GA, USA

    Stanley Nkemjika, Emeka Ifebi, Logan T. Cowan, Isaac Chun-Hai Fung, Felix Twum & Jian Zhang

  2. Department of Population Health Sciences, School of Public Health, Georgia State University, Atlanta, GA, USA

    Stanley Nkemjika

  3. Veterans Affairs Medical Center, Augusta, GA, USA

    Fengqi Liu

Authors
  1. Stanley Nkemjika
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emeka Ifebi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Logan T. Cowan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Isaac Chun-Hai Fung
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Felix Twum
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fengqi Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JZ and FL developed the original research question and oversaw the entire project. Part of the results were submitted by EI in partial fulfillment of the degree requirements for his Master of Public Health. SN and FT updated the data and rewrote the report. IC-HF supervised EI capstone project and edited the manuscript. TC helped in data analyses and manuscript rewriting.

Corresponding author

Correspondence to Jian Zhang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nkemjika, S., Ifebi, E., Cowan, L.T. et al. Association between serum folate and cardiovascular deaths among adults with hypertension. Eur J Clin Nutr 74, 970–978 (2020). https://doi.org/10.1038/s41430-019-0533-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41430-019-0533-7

This article is cited by

Search

Advanced search

Quick links