Association of folate intake with cardiovascular-disease mortality and all-cause mortality among people at high risk of cardiovascular-disease (2023)

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Article preview Clinical Nutrition Summary Background & aims Methods Results Conclusions Introduction Section snippets Study population Baseline characteristics of studying variables Discussion Conclusion Author contributions Conflict of interest Acknowledgments References (47) Clin Immunol Cytokine Growth Factor Rev Nutr Metabol Cardiovasc Dis Int J Cardiol JClin Epidemiol Nutr Metabol Cardiovasc Dis JAm Coll Cardiol Lancet Lancet JAm Coll Cardiol JAm Coll Cardiol Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis JAm Med Assoc Aquantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes JAm Med Assoc Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis BMJ Vitamins as homocysteine-lowering agents JNutr Vitamin status and intake as primary determinants of homocysteinemia in an elderly population JAm Med Assoc Review: folic acid may reduce risk for CVD and stroke, and B-vitamin complex may reduce risk for stroke Ann Intern Med The effect of folic acid in patients with cardiovascular disease: a systematic review and meta-analysis Medicine (Baltim) Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial JAm Med Assoc Oral high-dose multivitamins and minerals after myocardial infarction: a randomized trial Ann Intern Med Folic acid supplementation and the risk of cardiovascular diseases: a meta-analysis of randomized controlled trials JAm Heart Assoc The association of dietary folate, B6, and B12 with cardiovascular mortality in Spain: an ecological analysis Am J Publ Health Dietary folate and vitamin b6 and B12 intake in relation to mortality from cardiovascular diseases: Japan collaborative cohort study Stroke Cited by (3) Associations of folate intake with all-cause and cause-specific mortality among individuals with diabetes In Vitro Toxicological Profile of Labetalol-Folic Acid/Folate Co-Administration in H9c2(2-1) and HepaRG Cells Intakes of Folate, Vitamin B6, and Vitamin B12 in Relation to All-Cause and Cause-Specific Mortality: A National Population-Based Cohort Recommended articles (6) Videos
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Clinical Nutrition

Volume 41, Issue 1,

January 2022

, Pages 246-254

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Summary

Background & aims

Due to the beneficial effect of folate on cardiovascular disease (CVD), folic acid supplementation is a more common practice among people at high-risk of CVD. However, long-term prospective investigations regarding the association of folate-intake with CVD-mortality and all-cause mortality among this specific population are still lacking. Therefore, this study aims to assess the association of folate-intake with CVD-mortality and all-cause mortality.

Methods

A total of 14,234 participants at high-risk of CVD were enrolled. Total folate equivalent (TFE), dietary folate equivalent (DFE), food folate, folic acid in fortified food, folic acid supplements, serum folate and red blood cell (RBC) folate were measured. The main outcome measures were CVD-mortality and all-cause mortality from baseline until 31 December 2015.

Results

During the 98,890 person-year follow-up, 2036 deaths including 682 deaths due to CVD were documented. After multivariate adjustment, a J shaped association was found: modest intake of TFE and DFE was associated with lower risk of CVD-mortality and all-cause mortality, whereas higher intake did not persistently reduce these risks. Compared to the participants without folic acid supplementation matched 28-covariates using propensity score, folic acid supplementation was associated with higher risk of CVD-mortality (HR:1.44, 95%CI:1.06–1.97, P=0.022) and all-cause mortality (HR:1.28,95%CI:1.09–1.51, P=0.003). The levels of serum-folate and RBC-folate in participants with folic acid supplementation were significantly greater than participants without folic acid supplementation (41.8nmol/l vs. 64.2nmol/l, P<0.001 for serum-folate; 1201nmol/l vs. 1608nmol/l, P<0.001 for RBC-folate). Compared with the lowest-quintile of serum-folate, the second-quintile was consistently associated with CVD-mortality (HR:0.72, 95%CI:0.53–0.99, P=0.048) and all-cause mortality (HR:0.78, 95%CI:0.64–0.94, P=0.013). Compared to the lowest-quintile of RBC-folate, the second-quintile was associated with lower all-cause mortality (HR:0.71,95%CI:0.56–0.90, P=0.005), whereas the highest-quintile was associated with higher CVD-mortality (HR:1.40,95%CI:1.02–1.93, P=0.030). The J shaped association of serum-folate and RBC-folate with CVD-mortality and all-cause mortality was also demonstrated, further supporting the results of TFE and propensity score analysis.

Conclusions

This study suggested the beneficial effects of modest folate-intake on the improvement of long-term survival, and emphasized the potentially deleterious effects of excess folic acid supplementation among US adults at high-risk of CVD.

Introduction

Cardiovascular disease (CVD), as a leading global cause of mortality, accounts for approximately 18 million deaths annually [1]. Hyperhomocysteinemia has been documented to be associated with higher risk of CVD and CVD-mortality [[2], [3], [4]], and it has been demonstrated that folate intake can lower plasma homocysteine levels [5,6]. Therefore, the potential beneficial effects of folate intake on the development and treatment of CVD have been extensively studied [[7], [8], [9], [10], [11], [12], [13], [14]]; however, evidence regarding the association of folate intake with CVD-mortality and all-cause mortality is still inconclusive. Although some prospective studies reported the inverse association of increasing dietary folate intake with lower CVD-mortality [15,16], no association of folic acid supplementation with CVD-mortality and all-cause mortality was documented in a recent meta-analysis of RCTs [7], and even some prospective and RCT studies have found that folic acid supplementation was associated with higher all-cause mortality [[17], [18], [19]].

In addition to the inconclusive results regarding the association between folate intake and mortality, concern about excess folate intake has been documented in previous studies, especially for people in the United States [[20], [21], [22]]. Mandatory fortification has made most of adults meet the daily recommended amount; however, it was estimated that the frequency of using folic acid supplements was still relatively high in the US [23]. Furthermore, due to the potential beneficial effect of folate on the prevention and treatment of CVD, using folic acid supplements may be a more common practice among people at high-risk of CVD. However, evidence from prospective investigations of these association among people at high risk of CVD is still lacking although such evidence may provide important knowledge for dietary guidelines and facilitate long-term survival among people at high risk of CVD. To fill this gap, this study therefore comprehensively examined the association of total folate equivalent (TFE), dietary folate equivalent (DFE), food folate, folic acid in fortified food, folic acid supplements, as well as folate in serum and blood red cells (RBCs) with CVD-mortality and all-cause mortality among populations at high risk of CVD from nationally representative samples of the US population.

Section snippets

Study population

The National Health and Nutrition Examination Survey (NHANES) is a stratified, multistage survey using a nationally representative sample of the noninstitutionalized civilian population of the United States, and detailed information has been described elsewhere [24]. Briefly, this study used data from 2003 to 2014 across six cycles and restricted the analysis to participants ≥18-years old, who had a diagnosed history of CVD and/or a diagnosed history of chronic heart disease and/or at least 3

Baseline characteristics of studying variables

The baseline characteristics of the studied variables across quintiles of TFE are presented in Table1. Age, non-Hispanic White, rate of college graduation, regular exercise, drinking rate and household income gradually increased, whereas the percentage of men, smoking rate, rate of hypertension medication, prevalence of diabetes and CVD gradually decreased across quintiles of TFE. The frequency of using folic acid supplements by nutritional status of DFE is presented in Supplemental Table1.

Discussion

To the best of our knowledge, this study is the first to comprehensively examine the association of folate intake with CVD-mortality and all-cause mortality among the US adults at high risk of CVD from the nationally representative samples. The inverse association of modest intake of TFE and DFE with CVD-mortality and all-cause mortality was demonstrated. Moreover, no association of folic acid supplementation with mortality was found in the total sample of this study; however, after propensity

Conclusion

In conclusion, this study suggested the beneficial effects of modest intake of TFE on the improvement of long-term survival among US adults at high risk of CVD. Furthermore, this study emphasized the potentially deleterious effects of additional folic acid supplementation, and the association of serum folate and RBC folate with CVD-mortality and all-cause mortality further strengthened these findings.

Author contributions

XX, WW, and HS conceived the study design. XX, WW, WJ and QS did the statistical analysis. WJ, YC, YL, YZ and XY repeated and validated the statistical analysis. XX and HS wrote the manuscript. All authors provided critical revisions of the draft and approved the submitted draft. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. HS is the guarantor.

Conflict of interest

The authors declare that they have no conflicts of interest.

Acknowledgments

We sincerely thank the participants and staff of the US National Health and Nutrition Examination Survey 2003–2014 for their valuable contributions.

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