Objective To systematically review the effectiveness and safety of the combined treatment of antihypertensive drugs and folic acid for hypertension complicated with hyperhomocysteinemia (HHcy).

Methods The system retrieved relevant randomized treatment of antihypertensive drugs and folic acid for hypertension complicated with HHcy controlled trials from CNKI, VIP Database, WanFang Data, PubMed, Web of Science, Embase, The Cochrane Library, with the search period ranging from the inception to April 2025. The Cochrane risk of bias assessment tool was used to evaluate the quality of the included literature. Meanwhile, RevMan 5.4 and Stata 18.0 software were employed to conduct statistical analysis of the extracted data.

Results A total of 41 studies were included, involving 6,674 patients. The results of the Meta-analysis showed that combined treatment significantly reduced homocysteine levels [SMD = -2.08, 95% CI (-2.46, -1.70), P < 0.001], systolic blood pressure[SMD=-1.23, 95% CI (-1.57, -0.89), P < 0.001], and diastolic blood pressure[SMD=-1.18, 95% CI (-1.51, -0.86), P < 0.001] compared to monotherapy with antihypertensive drugs. In the summary of 20 adverse event analyses, supplementation with folic acid significantly reduced the occurrence of adverse events [RR=0.47, 95% CI (0.38, 0.59), P < 0.05]; the risk of adverse events was the lowest when the folic acid dose was >0.4 - ≤0.8 mg and the intervention duration was > 6 months.

Conclusion In patients with HHcy combined with hypertension, treatment with an antihypertensive regimen based on enalapril in combination with folic acid can significantly reduce homocysteine levels and blood pressure, and has good safety.

1. 陈学英, 郑淑云. 高同型半胱氨酸血症与心血管疾病关系及治疗研究进展[J]. 河北中医, 2012, 34(8): 1257-1259.ChenXY, ZhengSY. Research progress on the relationship between hyperhomocysteinemia and cardiovascular disease and its treatment[J]. Hebei Journal of Traditional Chinese Medicine, 2012, 34(8): 1257-1259. DOI: 10.3969/j.issn.1002-2619.2012.08.083.

2. ReddyVS, TrinathJ, ReddyGB. Implication of homocysteine in protein quality control processes[J]. Biochimie, 2019, 165: 19-31. DOI: 10.1016/j.biochi.2019.06.019.

3. WyseATS, BoberminLD, SantosTMD, et al. Homocysteine and gliotoxicity[J]. Neurotox Res, 2021, 39(3): 966-974. DOI: 10.1007/s12640-021-00359-5.

4. AlamSF, KumarS, GangulyP. Measurement of homocysteine: a historical perspective[J]. J Clin Biochem Nutr, 2019, 65(3): 171-177. DOI: 10.3164/jcbn.19-32.

5. 李东晓, 张尧, 张宏武, 等. 高同型半胱氨酸血症的诊断、治疗与预防专家共识[J]. 罕少疾病杂志, 2022, 29(6): 1-4.LiDX, ZhangY, ZhangHW, et al. The expert consensus on the diagnosis, treatment and prevention of hyperhomocysteinemia[J]. Journal of Rare and Uncommon Diseases, 2022, 29(6): 1-4. DOI: 10.3969/j.issn.1009-3257.2022.06.001.

6. WuDF, YinRX, DengJL. Homocysteine, hyperhomocysteinemia, and H-type hypertension[J]. Eur J Prev Cardiol, 2024, 31(9): 1092-1103. DOI: 10.1093/eurjpc/zwae052.

7. HanH, WangF, ChenJ, et al. Changes in biothiol levels are closely associated with Alzheimer's disease[J]. J Alzheimers Dis, 2021, 82(2): 527-540. DOI: 10.3233/JAD-210092.

8. TsukamotoM, HishidaA, TamuraT, et al. GWAS of folate metabolism with gene-environment interaction analysis revealed the possible role of lifestyles in the control of blood folate metabolites in Japanese: the J-MICC study[J]. J Epidemiol, 2024, 34(5): 228-237. DOI: 10.2188/jea.JE20220250.

9. ZaricBL, ObradovicM, BajicV, et al. Homocysteine and hyperhomocysteinaemia[J]. Curr Med Chem, 2019, 26(16): 2948-2961. DOI: 10.2174/0929867325666180508110948.

10. JiC, YiH, HuangJ, et al. Propofol alleviates inflammation and apoptosis in HCY‑induced HUVECs by inhibiting endoplasmic reticulum stress[J]. Mol Med Rep, 2021, 23(5):333. DOI: 10.3892/mmr.2021.11988.

11. LiJ, GeP, ZhangQ, et al. Hyperhomocysteinemia is a risk factor for postoperative ischemia in adult patients with moyamoya disease[J]. Neurosurg Rev, 2021, 44(5): 2913-2921. DOI: 10.1007/s10143-021-01512-8.

12. WaldDS, LawM, MorrisJK. Homocysteine and cardiovascular disease: evidence on causality from a Meta-analysis[J]. BMJ, 2002, 325(7374): 1202. DOI: 10.1136/bmj.325.7374.1202.

13. MenezoY, ElderK, ClementA, et al. Folic acid, folinic acid, 5 methyl tetrahydrofolate supplementation for mutations that affect epigenesis through the folate and one-carbon cycles[J]. Biomolecules, 2022, 12(2): 197. DOI: 10.3390/biom12020197.

14. YuanS, MasonAM, CarterP, et al. Homocysteine, B vitamins, and cardiovascular disease: a Mendelian randomization study[J]. BMC Med, 2021, 19(1): 97. DOI: 10.1186/s12916-021-01977-w.

15. AngeliniA, CappuccilliML, MagnoniG, et al. The link between homocysteine, folic acid and vitamin B₁₂ in chronic kidney disease[J]. G Ital Nefrol, 2021, 38(4): 2021-vol4. https://pubmed.ncbi.nlm.nih.gov/34469084/.

16. 宋霞, 路孝琴. 叶酸对社区慢性病伴高同型半胱氨酸血症患者血清HCY水平的影响[J]. 继续医学教育, 2023, 37(9): 177-180.SongX, LuXQ. Effect of folic acid on serum HCY levels in community patients with chronic diseases complicated with hyperhomocysteinemia[J]. Continuing Medical Education, 2023, 37(9): 177-180. DOI: 10.3969/j.issn.1004-6763.2023.09.045.

17. 隋小芳, 王娜, 庞诗琴, 等. 叶酸在H型高血压治疗中的研究进展[J]. 中国现代医生, 2023, 61(22): 130-133.SuiXF, WangN, PangSQ, et al. Research progress of folic acid in the treatment of H-type hypertension[J]. China Modern Doctor, 2023, 61(22): 130-133. DOI: 10.3969/j.issn.1673-9701.2023.22.031.

18. 庄婵娟. 叶酸联合降压药治疗高同型半胱氨酸血症合并高血压的临床效果分析[J]. 中国社区医师, 2024, 40(11): 6-8.ZhuangCJ. Clinical effect analysis of folic acid combined with antihypertensive drugs in the treatment of hyperhomocysteinemia complicated with hypertension[J]. Chinese Community Doctors, 2024, 40(11): 6-8. DOI: 10.3969/j.issn.1006-6659.2024.11.002.

19. 王艳芳. 不同剂量叶酸联合维生素B₁₂治疗老年高血压合并高同型半胱氨酸血症的临床效果[J]. 中外医药研究, 2024, 3(10): 64-66.WangYF. Clinical effect of different doses of folic acid combined with vitamin B₁₂ in the treatment of elderly hypertension complicated with hyperhomocysteinemia[J]. Chinese and Foreign Medical Research, 2024, 3(10): 64-66. DOI: 10.3969/j.issn.2096-6229.2024.10.022.

20. 任炳楠. BHMT和CBS基因多态性与叶酸治疗HHcy效果的关联性研究[D]. 郑州: 郑州大学, 2019. http://cdmd.cnki.com.cn/article/cdmd-10459-1019142893.htm.

21. Amir-BehghadamiM, JanatiA. Population, intervention, comparison, outcomes and study (PICOS) design as a framework to formulate eligibility criteria in systematic reviews[J]. Emerg Med J, 2020, 37(6): 387. DOI: 10.1136/emermed-2020-209567.

22. HigginsJP, AltmanDG, GøtzschePC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials[J]. BMJ, 2011, 343: d5928. DOI: 10.1136/bmj.d5928.

23. 赵锋, 李建平, 王淑玉, 等. 高血压人群基线同型半胱氨酸水平对依那普利叶酸片降压及降同型半胱氨酸疗效的分析[J]. 中华医学杂志, 2008, 88(42): 2957-2961.ZhaoF, LiJP, WangSY, et al. Effect of baseline homocysteine level on the antihypertensive and homocysteine-lowering efficacy of enalapril-folic acid tablet in hypertensive population[J]. National Medical Journal of China, 2008, 88(42): 2957-2961. DOI: 10.3321/j.issn:0376-2491.2008.42.003.

24. 刘慧, 李海剑, 李玉东, 等. 叶酸对伴有高同型半胱氨酸血症的高血压患者内生肌酐清除率的影响[J]. 临床荟萃, 2010, 25(2): 156-157. [LiuH, LiHJ, LiYD, et al. Effect of folic acid on endogenous creatinine clearance rate in hypertensive patients with hyperhomocysteinemia[J]. Clinical Focus, 2010, 25(2): 156-157.https://d.wanfangdata.com.cn/periodical/CihQZXJpb2RpY2FsQ0hJU29scjkyMDI2MDYxMDIwMjYwNjEwMTYxMjM4Eg1sY2hjMjAxMDAyMDIzGgh3eXhlMXlheQ%3D%3D.

25. 郑大炜, 刘志远. 叶酸对H型高血压患者内生肌酐清除率的影响[J]. 医药论坛杂志, 2011, 32(6): 67-68.ZhengDW, LiuZY. Effect of folic acid on endogenous creatinine clearance rate in patients with H-type hypertension[J]. Journal of Medical Forum, 2011, 32(6): 67-68. DOI:CNKI:SUN:HYYX.0.2011-06-030.

26. 李志玲, 徐新伟, 刘玉梅, 等. 缬沙坦联合叶酸对老年高血压肾病患者降压及降同型半胱氨酸的临床研究[J]. 中国实用医药, 2012, 7(22): 1-4.LiZL, XuXW, LiuYM, et al. Clinical study of valsartan combined with folic acid on blood pressure and homocysteine reduction in elderly hypertensive patients with nephropathy[J]. China Practical Medicine, 2012, 7(22): 1-4. DOI: 10.3969/j.issn.1673-7555.2012.22.001.

27. 王瑗. 马来酸依那普利叶酸片复合制剂治疗伴有血浆同型半胱氨酸升高的原发性高血压病患者的疗效观察[J]. 中国医药指南, 2012, 10(10): 522-523.WangY. Efficacy observation of enalapril maleate folic acid compound tablet in the treatment of essential hypertension patients with elevated plasma homocysteine[J]. Guide of China Medicine, 2012, 10(10): 522-523. DOI: 10.3969/j.issn.1671-8194.2012.10.389.

28. 吴桂玲, 王利民. 依那普利叶酸片与依那普利片在H型高血压病患者中降压及降低同型半胱氨酸的疗效比较[J]. 中国实用医刊, 2012, 39(21): 51-53.WuGL, WangLM. Comparison of efficacy between enalapril-folic acid tablet and enalapril tablet in reducing blood pressure and homocysteine in patients with H-type hypertension[J]. Chinese Journal of Practical Medicine, 2012, 39(21): 51-53. DOI: 10.3760/cma.j.issn.1674-4756.2012.21.021.

29. 冯智敏, 雷露雯, 刘家欣. 叶酸对伴有高同型半胱氨酸血症高血压患者的脑梗死发病率的影响研究[J]. 中国药房, 2013, 24(26): 2447-2449.FengZM, LeiLW, LiuJX. Effect of folic acid on the incidence of cerebral infarction in hypertensive patients with hyperhomocysteinemia[J]. China Pharmacy, 2013, 24(26): 2447-2449. DOI: 10.6039/j.issn.1001-0408.2013.08.16.

30. 马刚, 何灿辉. 马来酸依那普利叶酸片的降压作用及对血清同型半胱氨酸、炎性因子的影响[J]. 海南医学院学报, 2014, 20(12): 1630-1632,1635.MaG, HeCH. Antihypertensive effect of enalapril maleate folic acid tablet and its influence on serum homocysteine and inflammatory factors[J]. Journal of Hainan Medical University, 2014, 20(12): 1630-1632,1635. DOI: 10.13210/j.cnki.jhmu.20141030.004.

31. 王齐芳, 黄文生, 田克瑶, 等. 叶酸对伴有高同型半胱氨酸血症的农村高血压患者内生肌酐清除率的影响[J]. 社区医学杂志, 2014, 12(14): 41-42. [WangQF, HuangWS, TianKY, et al. Effect of folic acid on endogenous creatinine clearance rate in rural hypertensive patients with hyperhomocysteinemia[J]. Journal of Community Medicine, 2014, 12(14): 41-42.MjYwNjEwMTYxMjM4Eg9zcXl4enoyMDE0MTQwMTcaCDY2MjFnbG9m.https://d.wanfangdata.com.cn/periodical/CihQZXJpb2RpY2FsQ0hJU29scjkyMDI2MDYxMDIw

32. 严志芳. 高龄H型高血压患者脑梗死的复发相关因素及药物治疗分析[J]. 中国药业, 2014, 23(23): 117-118. [YanZF. Analysis of recurrence factors and drug treatment of cerebral infarction in elderly patients with H-type hypertension[J]. China Pharmaceuticals, 2014, 23(23): 117-118.https://d.wanfangdata.com.cn/periodical/zgyy201423065.

33. 袁俊. 马来酸依那普利叶酸片对伴H型高血压急性脑梗死患者的影响[J]. 井冈山大学学报(自然科学版), 2014, 35(3): 86-88.YuanJ. Effect of enalapril maleate folic acid tablet on acute cerebral infarction patients with H-type hypertension[J]. Journal of Jinggangshan University (Natural Science Edition), 2014, 35(3): 86-88. DOI: 10.3969/j.issn.1674-8085.2014.03.020.

34. 方根强. 叶酸干预治疗对H型老年高血压患者Hcy水平和心血管事件的影响[J]. 湖南师范大学学报(医学版), 2015, 12(5): 32-35.FangGQ. Effect of folic acid intervention on Hcy level and cardiovascular events in elderly patients with H-type hypertension[J]. Journal of Hunan Normal University (Medical Science), 2015, 12(5): 32-35. DOI: CNKI:SUN:HNYG.0.2015-05-012.

35. 李志明, 申健, 刘锦光, 等. 叶酸联合降压药对高同型半胱氨酸血症高血压患者临床疗效的研究[J]. 现代医院, 2015, 15(10): 25-28.LiZM, ShenJ, LiuJG, et al. Clinical efficacy of folic acid combined with antihypertensive drugs in patients with hyperhomocysteinemia and hypertension[J]. Modern Hospital, 2015, 15(10): 25-28. DOI: 10.3969/j.issn.1671-332X.2015.10.008.

36. 权青云, 张愉, 孙鹃, 等. 依那普利叶酸片对H型高血压病人颈动脉粥样硬化斑块的影响[C]. 北京: 第十六届全军神经内科学专业学术会议论文集, 2015: 174.

37. 赵静岩. 依那普利联合叶酸治疗老年性高血压预防再次脑卒中临床效果分析[J]. 世界最新医学信息文摘(连续型电子期刊), 2015, 15(A2): 194,197.ZhaoJY. Clinical effect analysis of enalapril combined with folic acid in the treatment of senile hypertension to prevent recurrent stroke[J]. World Latest Medicine Information (Electronic Version), 2015, 15(A2): 194,197. DOI: CNKI:SUN:WMIA.0.2015-A2-146.

38. 毕立雄. 依那普利叶酸片在H型高血压病防治中的临床应用效果观察[J]. 云南医药, 2016, 37(6): 692-694.BiLX. Clinical application effect observation of enalapril-folic acid tablet in the prevention and treatment of H-type hypertension[J]. Medicine and Pharmacy of Yunnan, 2016, 37(6): 692-694. DOI:CNKI:SUN:YNYY.0.2016-06-045.

39. 高鹏. 叶酸片治疗高同型半胱氨酸血症合并原发性高血压的临床疗效[J]. 临床合理用药杂志, 2016, 9(6): 1-2, 5.GaoP. Clinical efficacy of folic acid tablet in the treatment of hyperhomocysteinemia complicated with essential hypertension[J]. Chinese Journal of Clinical Rational Drug Use, 2016, 9(6): 1-2, 5. DOI:10.15887/j.cnki.13-1389/r.2016.06.001.

40. 康聚贤, 张培. 早期联合治疗H型高血压急性脑梗死临床效果观察[J]. 现代医药卫生, 2016, 32(17): 2641-2643.KangJX, ZhangP. Clinical effect observation of early combined treatment for acute cerebral infarction with H-type hypertension[J]. Modern Medicine and Health, 2016, 32(17): 2641-2643. DOI: 10.3969/j.issn.1009-5519.2016.17.007.

41. 赵玉红, 孙红凤, 林秀恩, 等. 早期干预及综合管理高同型半胱氨酸血症人群对高血压并发症防治及血糖的影响研究[J]. 中国社区医师, 2016, 32(16): 170-171,173.ZhaoYH, SunHF, LinXE, et al. Effect of early intervention and comprehensive management of hyperhomocysteinemia population on prevention of hypertension complications and blood glucose[J]. Chinese Community Doctors, 2016, 32(16): 170-171,173. DOI: 10.3969/j.issn.1007-614x.2016.16.108.

42. 康聚贤, 张培, 马赟英, 等. 尼莫地平联合叶酸治疗伴H型高血压急性脑梗死的临床研究[J]. 中西医结合心脑血管病杂志, 2017, 15(9): 1115-1118.KangJX, ZhangP, MaYY, et al. Clinical study of nimodipine combined with folic acid in the treatment of acute cerebral infarction with H-type hypertension[J]. Chinese Journal of Integrative Medicine on Cardio-Cerebrovascular Disease, 2017, 15(9): 1115-1118. DOI:10.3969/j.issn.1672-1349.2017.09.034.

43. 任春艳, 刘文忠. 叶酸联合依那普利治疗高同型半胱氨酸血症高血压的疗效分析[J]. 临床合理用药杂志, 2017, 10(22):13-14.RenCY, LiuWZ. Efficacy analysis of folic acid combined with enalapril in the treatment of hyperhomocysteinemia and hypertension[J]. Chinese Journal of Clinical Rational Drug Use, 2017, 10(22):13-14. DOI: 10.15887/j.cnki.13-1389/r.2017.22.008.

44. 王玉娟, 张弘, 刘坤, 等. 马来酸依那普利叶酸片复合制剂治疗H型高血压病疗效观察[J]. 当代医学, 2017, 23(10): 8-10.WangYJ, ZhangH, LiuK, et al. Efficacy observation of enalapril maleate folic acid compound tablet in the treatment of H-type hypertension[J]. Contemporary Medicine, 2017, 23(10): 8-10. DOI:10.3969/j.issn.1009-4393.2017.10.003.

45. 周骏, 朱海, 秦忠. 叶酸联合贝那普利治疗高血压合并高同型半胱氨酸血症的临床研究[J]. 现代药物与临床, 2017, 32(7): 1273-1276.ZhouJ, ZhuH, QinZ. Clinical study of folic acid combined with benazepril in the treatment of hypertension complicated with hyperhomocysteinemia[J]. Drugs & Clinic, 2017, 32(7): 1273-1276. DOI: 10.7501/j.issn.1674-5515.2017.07.025.

46. 段波. 依那普利对伴高同型半胱氨酸血症高血压患者血压、心功能及HCY水平的影响[J]. 首都食品与医药, 2018, 25(12): 41. [DuanB. Effect of enalapril on blood pressure, cardiac function and HCY level in hypertensive patients with hyperhomocysteinemia[J]. Capital Food Medicine, 2018, 25(12): 41.https://wap.cnki.net/touch/web/Journal/Article/YYSD201812036.html.

47. 龚海荣, 梅光艳. 依那普利叶酸片治疗H型高血压的疗效和安全性评价[J]. 中国继续医学教育, 2018, 10(4): 128-130.GongHR, MeiGY. Efficacy and safety evaluation of enalapril-folic acid tablet in the treatment of H-type hypertension[J]. China Continuing Medical Education, 2018, 10(4): 128-130. DOI: 10.3969/j.issn.1674-9308.2018.04.070.

48. 聂鹏. 马来酸依那普利叶酸片治疗H型高血压的疗效观察[J]. 中国社区医师, 2018, 34(1): 24,26.NieP. Efficacy observation of enalapril maleate folic acid tablet in the treatment of H-type hypertension[J]. Chinese Community Doctors, 2018, 34(1): 24,26. DOI: 10.3969/j.issn.1007-614x.2018.1.12.

49. 武建芳. 叶酸联合贝那普利治疗高血压合并高同型半胱氨酸血症的临床效果观察[J]. 医药前沿, 2018, 8(34): 135-136.WuJF. Clinical effect observation of folic acid combined with benazepril in the treatment of hypertension complicated with hyperhomocysteinemia[J]. Medical Frontier, 2018, 8(34): 135-136. DOI: 10.3969/j.issn.2095-1752.2018.34.118.

50. 徐辉, 郑淑萍, 黄芬, 等. 叶酸联合缬沙坦治疗伴有高同型半胱氨酸血症的原发性高血压疗效分析[J]. 慢性病学杂志, 2018, 19(S1): 7-10.XuH, ZhengSP, HuangF, et al. Efficacy analysis of folic acid combined with valsartan in the treatment of essential hypertension with hyperhomocysteinemia[J]. Journal of Chronic Diseases, 2018, 19(S1): 7-10. DOI: 10.16440/j.cnki.1674-8166.2018.s1.004.

51. 许海华, 徐明星, 王砚青, 等. 马来酸依那普利叶酸片对高血压伴高同型半胱氨酸血症患者颈动脉粥样硬化的影响及相关机制研究[J]. 世界临床药物, 2018, 39(8): 549-554.XuHH, XuMX, WangYQ, et al. Effect of enalapril maleate folic acid tablet on carotid atherosclerosis in patients with hypertension and hyperhomocysteinemia and related mechanism study[J]. World Clinical Drugs, 2018, 39(8): 549-554. DOI: 10.16766/j.cnki.issn.1674-4152.001305.

52. 张涛, 陈劢. 依那普利联合叶酸片对42例H型高血压患者血管内皮功能、血清生化指标的影响[J]. 武警后勤学院学报(医学版), 2018, 27(8): 682-685.ZhangT, ChenM. Effect of enalapril combined with folic acid tablet on vascular endothelial function and serum biochemical indexes in 42 patients with H-type hypertension[J]. Journal of Logistics University of PAP (Medical Edition), 2018, 27(8): 682-685. DOI: CNKI:SUN:WUXB.0.2018-08-012.

53. 陈敏, 王剑波, 朱惠仙, 等. 社区综合干预治疗H型高血压的效果评估[J]. 上海医药, 2019, 40(18): 35-38.ChenM, WangJB, ZhuHX, et al. Effect evaluation of community comprehensive intervention in the treatment of H-type hypertension[J]. Shanghai Medical & Pharmaceutical Journal, 2019, 40(18): 35-38. DOI: 10.3969/j.issn.1006-1533.2019.18.011.

54. 李刚. 降同型半胱氨酸治疗对高血压动脉硬化性脑梗死合并高同型半胱氨酸血症患者的效果分析[J]. 中国实用医药, 2019, 14(36): 85-87.LiG. Effect analysis of homocysteine-lowering therapy on patients with hypertensive arteriosclerotic cerebral infarction complicated with hyperhomocysteinemia[J]. China Practical Medicine, 2019, 14(36): 85-87. DOI: 10.14163/j.cnki.11-5547/r.2019.36.046.

55. 蔡嵩, 郑成, 宫海滨, 等. 依那普利叶酸片治疗伴有高同型半胱氨酸血症原发性高血压卒中患者临床疗效[J]. 慢性病学杂志, 2020, 21(1): 24-27.CaiS, ZhengC, GongHB, et al. Clinical efficacy of enalapril-folic acid tablet in the treatment of stroke patients with essential hypertension and hyperhomocysteinemia[J]. Journal of Chronic Diseases, 2020, 21(1): 24-27. DOI: 10.13555/j.cnki.c.j.2025.12.001.

56. 陈伟君, 黄国飞, 叶金汉, 等. 叶酸辅助治疗对伴高同型半胱氨酸血症高血压患者颈动脉硬化的影响[J]. 广州医科大学学报, 2020, 48(1): 31-34.ChenWJ, HuangGF, YeJH, et al. Effect of folic acid adjuvant therapy on carotid atherosclerosis in hypertensive patients with hyperhomocysteinemia[J]. Journal of Guangzhou Medical University, 2020, 48(1): 31-34. DOI: 10.3969/j.issn.2095-9664.2020.01.08.

57. 吕红娟. 马来酸依那普利叶酸片对高血压伴高同型半胱氨酸血症患者颈动脉粥样硬化的影响及相关机制研究[J]. 中西医结合心血管病电子杂志, 2020, 8(31): 72-73.LyuHJ. Effect of enalapril maleate folic acid tablet on carotid atherosclerosis in patients with hypertension and hyperhomocysteinemia and related mechanism study[J]. Cardiovascular Disease Journal of Integrated Traditional Chinese and Western Medicine (Electronic), 2020, 8(31): 72-73. DOI: 10.16282/j.cnki.cn11-9336/r.2020.31.051.

58. 裴焱, 袁先仙. 叶酸补充干预对原发性高血压伴同型半胱氨酸血症患者Hcy水平影响研究[J]. 标记免疫分析与临床, 2020, 27(8): 1386-1389.PeiY, YuanXX. Effect of folic acid supplementation intervention on Hcy level in patients with essential hypertension and homocysteinemia[J]. Labeled Immunoassays and Clinical Medicine, 2020, 27(8): 1386-1389. DOI: 10.11748/bjmy.issn.1006-1703.2020.08.025.

59. 任玥. 马来酸依那普利叶酸治疗中青年H型高血压的观察[J]. 中国药物与临床, 2020, 20(22): 3764-3765.RenY. Observation of enalapril maleate folic acid in the treatment of young and middle-aged H-type hypertension[J]. Chinese Remedies & Clinics, 2020, 20(22): 3764-3765. DOI: 10.11655/zgywylc2020.22.021.

60. ZhangS, WangT, WangH, et al. Effects of individualized administration of folic acid on prothrombotic state and vascular endothelial function with H-type hypertension: a double-blinded, randomized clinical cohort study[J]. Medicine, 2022, 101(3): e28628. DOI: 10.1097/MD.0000000000028628.

61. 王华玲. 马来酸依那普利叶酸片治疗H型高血压的临床分析[J]. 中文科技期刊数据库(引文版)医药卫生, 2023(5): 54-57. [WangHL. Clinical analysis of enalapril maleate folic acid tablet in the treatment of H-type hypertension[J]. Chinese Science and Technology Journal Database (Citation Edition) Medicine and Health, 2023(5): 54-57.&resourceId=1000003693719&type=1.https://www.cqvip.com/doc/journal/1000003693719?sign=173049ca3749dc9284d571ab4d270645b4ee27efa6da424449d7f03130a8dcfc&expireTime=1798361689151

62. 张田玲, 孙晓琳, 孙彩丽. 沙库巴曲缬沙坦钠片联合叶酸治疗对H型高血压患者血压、sdLDL-C水平及血浆Hcy的影响[J]. 分子诊断与治疗杂志, 2024, 16(2): 383-386.ZhangTL, SunXL, SunCL. Effect of sacubitril/valsartan sodium tablet combined with folic acid on blood pressure, sdLDL-C level and plasma Hcy in patients with H-type hypertension[J]. Journal of Molecular Diagnostics and Therapy, 2024, 16(2): 383-386. DOI: 10.3969/j.issn.1674-6929.2024.02.043.

63. 那一凡, 谭玲. 叶酸在治疗高同型半胱氨酸血症相关疾病中的合理应用[J]. 中国医院用药评价与分析, 2021, 21(4): 508-512.NaYF, TanL. Rational application of folic acid in the treatment of hyperhomocysteinemia-related diseases[J]. Evaluation and Analysis of Drug-Use in Hospitals of China, 2021, 21(4): 508-512. DOI: 10.14009/j.issn.1672-2124.2021.04.030.

64. 中国医药教育协会临床合理用药专业委员会, 中国医疗保健国际交流促进会高血压分会, 中国妇幼保健协会围产营养与代谢专业委员会, 等.中国临床合理补充叶酸多学科专家共识[J]. 医药导报, 2021, 40(1): 1-19. DOI: 10.3870/j.issn.1004-0781.2021.01.001.

65. WangWW, WangXS, ZhangZR, et al. A Meta-analysis of folic acid in combination with anti-hypertension drugs in patients with hypertension and hyperhomocysteinemia[J]. Front Pharmacol, 2017, 8: 585. DOI: 10.3389/fphar.2017.00585.

66. YangHT, LeeM, HongKS, et al. Efficacy of folic acid supplementation in cardiovascular disease prevention: an updated Meta-analysis of randomized controlled trials[J]. Eur J Intern Med, 2012, 23(8): 745-754. DOI: 10.1016/j.ejim.2012.07.004.

67. VukadinovićD, VukadinovićAN, LavallD, et al. Rate of cough during treatment with angiotensin-converting enzyme inhibitors: a Meta-analysis of randomized placebo-controlled trials[J]. Clin Pharmacol Ther, 2019, 105(3): 652-660. DOI: 10.1002/cpt.1241.

68. 韦小未, 张俊峰. 心血管事件残余风险研究进展[J]. 医学综述, 2015, 21(19): 3516-3519.WeiXW, ZhangJF. Research progress on residual risk of cardiovascular events[J]. Medical Recapitulate, 2015, 21(19): 3516-3519. DOI: 10.3969/j.issn.1006-2084.2015.19.022.

69. WangY, JinY, WangY, et al. The effect of folic acid in patients with cardiovascular disease: a systematic review and Meta-analysis[J]. Medicine (Baltimore), 2019, 98(37): e17095. DOI: 10.1097/MD.0000000000017095.

70. HouH, ZhaoH. Epigenetic factors in atherosclerosis: DNA methylation, folic acid metabolism, and intestinal microbiota[J]. Clin Chim Acta, 2021, 512: 7-11. DOI: 10.1016/j.cca.2020.10.032.

71. WangX, QinX, DemirtasH, et al. Efficacy of folic acid supplementation in stroke prevention: a Meta-analysis[J]. Lancet, 2007, 369(9576): 1876-1882. DOI: 10.1016/S0140-6736(07)60854-X.

72. ChenP, TangL, SongY, et al. Association of folic acid dosage with circulating unmetabolized folic acid in Chinese adults with H-type hypertension: a multicenter, double-blind, randomized controlled trial[J]. Front Nutr, 2023, 10: 1191610. DOI: 10.3389/fnut.2023.1191610.

73. RaghubeerS, MatshaTE. Methylenetetrahydrofolate (MTHFR), the one-carbon cycle, and cardiovascular risks[J]. Nutrients, 2021, 13(12):4562. DOI: 10.3390/nu13124562.

74. KumarA, PalfreyHA, PathakR, et al. The metabolism and significance of homocysteine in nutrition and health[J]. Nutr Metab (Lond), 2017, 14: 78. DOI: 10.1186/s12986-017-0233-z.

75. KayeAD, JehaGM, PhamAD, et al. Folic Acid Supplementation in patients with elevated homocysteine levels[J]. Adv Ther, 2020, 37(10): 4149-4164. DOI: 10.1007/s12325-020-01474-z.