背景:在观察性研究中,同型半胱氨酸水平降低,冠心病和中风发病率也相应降低。叶酸、维生素B6和B12可使同型半胱氨酸水平降低。本文目的旨在研究补充剂能否降低心血管疾病患者发生死亡事件的风险及改善预后。方法:我们对前瞻性研究进行了系统回顾和荟萃分析,以阐明叶酸、维生素B补充与老年心血管疾病患者预后及死亡率之间的关系。本文将“室性心律失常”“心室颤动”“心源性猝死”等作为检索词,通过Pubmed、Cochrane library、Embase、CNKI、万方数据库进行检索,对所有检索到的随机对照试验进行质量评估,Meta分析通过ReviewManger5.3统计软件进行。结果:共纳入8项符合入选标准的随机对照试验(RCT),试验组(服用叶酸及维生素B)患者共计11840例,对照组(服用安慰剂)患者共计15913例,将心源性猝死及其他原因致死的发生率作为观察的重点事件。Meta分析结果显示,服用叶酸及维生素B的试验组与对照组比较在预防心源性猝死方面无显著性差异(OR = 1.04, 95% CI 0.94~1.16, P = 0.46);服用叶酸及维生素B的试验组在与对照组的全因死亡率无显著性差异(OR = 1.04, 95% CI 0.95~1.15, P = 0.38)。结论:虽然叶酸和维生素B6摄入与冠心病风险呈线性负相关,但在老年人群中,叶酸和维生素B的补偿并不能减少心源性猝死及其他原因致死的发生。分析结果不支持使用维生素B作为冠心病患者预防心源性猝死及其他原因致死的有效措施。
Background: In observational studies, the lower the level of homocysteine, the lower the incidence of coronary heart disease and stroke. Folate, vitamin B6 and B12 can reduce the level of homocys-teine. The purpose of this paper is to investigate whether supplements can reduce the risk of mor-tality events and improve outcomes in patients with cardiovascular diseases. Methods: A systematic review and meta-analysis of prospective studies were conducted to clarify the relationship between folic acid and vitamin B supplements and the prognosis and mortality of elderly patients with car-diovascular disease. “Ventricular arrhythmia”, “ventricular fibrillation”, “sudden cardiac death”, were used as search terms and searched through Pubmed, Cochrane library, Embase, CNKI, Wan-fang database. After the quality of the retrieved RCTs was evaluated, Meta-analysis was conducted using ReviewManger5.3 statistical software. Results: A total of 8 randomized controlled trials (RCT) meeting the inclusion criteria, 11840 patients in test group (taking folic acid and vitamin B) and 15913 patients in control group (taking placebo) were included. The end event was the incidence of sudden cardiac death and other causes. Meta analysis showed that there was no significant differ-ence between the test group and the control group in sudden cardiac death (OR = 1.04, 95% CI 0.94~1.16, P = 0.46) and all-cause mortality (OR = 1.04, 95% CI 0.95~1.15, P = 0.38). Conclusion: Although folate and vitamin B6 intake are linearly inverse associated with coronary heart disease risk, compensation of folate and vitamin B does not reduce the occurrence of sudden cardiac death and other causes in the elderly population. The results of the analysis do not support the use of vitamin B as an effective measure to prevent sudden cardiac death and other causes in patients with coronary heart disease.
心脏性猝死(SCD),心血管疾病,叶酸,维生素B6,Meta分析, Sudden Cardiac Death (SCD) Cardiovascular Disease Folic Acid Vitamin B6 Meta Analysis摘要
背景:在观察性研究中,同型半胱氨酸水平降低,冠心病和中风发病率也相应降低。叶酸、维生素B6和B12可使同型半胱氨酸水平降低。本文目的旨在研究补充剂能否降低心血管疾病患者发生死亡事件的风险及改善预后。方法:我们对前瞻性研究进行了系统回顾和荟萃分析,以阐明叶酸、维生素B补充与老年心血管疾病患者预后及死亡率之间的关系。本文将“室性心律失常”“心室颤动”“心源性猝死”等作为检索词,通过Pubmed、Cochrane library、Embase、CNKI、万方数据库进行检索,对所有检索到的随机对照试验进行质量评估,Meta分析通过ReviewManger5.3统计软件进行。结果:共纳入8项符合入选标准的随机对照试验(RCT),试验组(服用叶酸及维生素B)患者共计11840例,对照组(服用安慰剂)患者共计15913例,将心源性猝死及其他原因致死的发生率作为观察的重点事件。Meta分析结果显示,服用叶酸及维生素B的试验组与对照组比较在预防心源性猝死方面无显著性差异(OR = 1.04, 95% CI 0.94~1.16, P = 0.46);服用叶酸及维生素B的试验组在与对照组的全因死亡率无显著性差异(OR = 1.04, 95% CI 0.95~1.15, P = 0.38)。结论:虽然叶酸和维生素B6摄入与冠心病风险呈线性负相关,但在老年人群中,叶酸和维生素B的补偿并不能减少心源性猝死及其他原因致死的发生。分析结果不支持使用维生素B作为冠心病患者预防心源性猝死及其他原因致死的有效措施。
关键词
心脏性猝死(SCD),心血管疾病,叶酸,维生素B6,Meta分析
Folic Acid plus B Vitamin Supplementation on Prognosis and All-Cause Mortality in Older Patients with Cardiovascular Disease: A Meta Analysis
Chaonan Li, Song Hu, Jia Liu, Yongjun Mao*
Department of Geriatrics, The Affiliated Hospital of Qingdao University, Qingdao Shandong
Background: In observational studies, the lower the level of homocysteine, the lower the incidence of coronary heart disease and stroke. Folate, vitamin B6 and B12 can reduce the level of homocysteine. The purpose of this paper is to investigate whether supplements can reduce the risk of mortality events and improve outcomes in patients with cardiovascular diseases. Methods: A systematic review and meta-analysis of prospective studies were conducted to clarify the relationship between folic acid and vitamin B supplements and the prognosis and mortality of elderly patients with cardiovascular disease. “Ventricular arrhythmia”, “ventricular fibrillation”, “sudden cardiac death”, were used as search terms and searched through Pubmed, Cochrane library, Embase, CNKI, Wanfang database. After the quality of the retrieved RCTs was evaluated, Meta-analysis was conducted using ReviewManger5.3 statistical software. Results: A total of 8 randomized controlled trials (RCT) meeting the inclusion criteria, 11840 patients in test group (taking folic acid and vitamin B) and 15913 patients in control group (taking placebo) were included. The end event was the incidence of sudden cardiac death and other causes. Meta analysis showed that there was no significant difference between the test group and the control group in sudden cardiac death (OR = 1.04, 95% CI 0.94~1.16, P = 0.46) and all-cause mortality (OR = 1.04, 95% CI 0.95~1.15, P = 0.38). Conclusion: Although folate and vitamin B6 intake are linearly inverse associated with coronary heart disease risk, compensation of folate and vitamin B does not reduce the occurrence of sudden cardiac death and other causes in the elderly population. The results of the analysis do not support the use of vitamin B as an effective measure to prevent sudden cardiac death and other causes in patients with coronary heart disease.
Keywords:Sudden Cardiac Death (SCD), Cardiovascular Disease, Folic Acid, Vitamin B6, Meta Analysis
李超楠,胡 松,刘 佳,毛拥军. 叶酸联合维生素B补充剂与老年心血管疾病患者预后及全因死亡率相关性META分析Folic Acid plus B Vitamin Supplementation on Prognosis and All-Cause Mortality in Old-er Patients with Cardiovascular Disease: A Meta Analysis[J]. 临床医学进展, 2022, 12(11): 10273-10282. https://doi.org/10.12677/ACM.2022.12111482
参考文献ReferencesAlbert, C.M. and Ruskin, J.N. (2001) Risk Stratifiers for Sudden Cardiac Death (SCD) in the Community: Primary Pre-vention of SCD. Cardiovascular Research, 50, 186-196. <br>https://doi.org/10.1016/S0008-6363(00)00319-9Jouven, X., Desnos, M., Guerot, C., et al. (1999) Predicting Sudden Death in the Population: The Paris Prospective Study I. Circulation, 99, 1978-1983. <br>https://doi.org/10.1161/01.CIR.99.15.1978Maldonado, C., Soni, C.V., Todnem, N.D., et al. (2010) Hyper-homocysteinemia and Sudden Cardiac Death: Potential Arrhythmogenic Mechanisms. Current Vascular Pharmacology, 8, 64-74.
<br>https://doi.org/10.2174/157016110790226552Rosenberger, D., Gargoum, R., Tyagi, N., et al. (2011) Ho-mocysteine Enriched Diet Leads to Prolonged QT Interval and Reduced Left Ventricular Performance in Telemetric Mon-itored Mice. Nutrition, Metabolism and Cardiovascular Diseases, 21, 492-498. <br>https://doi.org/10.1016/j.numecd.2009.11.014Lipton, S.A., Kim, W.K., Choi, Y.B., et al. (1997) Neurotoxi-city Associated with Dual Actions of Homocysteine at the N-methyl-D-aspartate Receptor. Proceedings of the National Academy of Sciences of the United States of America, 94, 5923-5928. <br>https://doi.org/10.1073/pnas.94.11.5923Gill, S.S., Pulido, O.M., Mueller, R.W., et al. (1998) Molecular and Immunochemical Characterization of the Ionotropic Glutamate Receptors in the Rat Heart. Brain Research Bulletin, 46, 429-434.
<br>https://doi.org/10.1016/S0361-9230(98)00012-4Gill, S., Veinot, J., Kavanagh, M., et al. (2007) Human Heart Glutamate Receptors—Implications for Toxicology, Food Safety, and Drug Discovery. Toxicologic Pathology, 35, 411-417. <br>https://doi.org/10.1080/01926230701230361Mayer, M.L., Westbrook, G.L. and Guthrie, P.B. (1984) Voltage-Dependent Block by Mg2+ of NMDA Responses in Spinal Cord Neurones. Nature, 309, 261-263. <br>https://doi.org/10.1038/309261a0Harker, L.A., Harlan, J.M. and Ross, R. (1983) Effect of Sulfinpyrazone on Homocysteine-Induced Endothelial Injury and Arteriosclerosis in Baboons. Circulation Research, 53, 731-739. <br>https://doi.org/10.1161/01.RES.53.6.731Boushey, C.J., Beresford, S.A., Omenn, G.S., et al. (1995) A Quan-titative Assessment of Plasma Homocysteine as a Risk Factor for Vascular Disease. Probable Benefits of Increasing Folic Acid Intakes. JAMA, 274, 1049-1057.
<br>https://doi.org/10.1001/jama.1995.03530130055028Klerk, M., Verhoef, P., Clarke, R., et al. (2002) MTHFR 677C→T Polymorphism and Risk of Coronary Heart Disease: A Meta-Analysis. JAMA, 288, 2023-2031. <br>https://doi.org/10.1001/jama.288.16.2023(2005) Dose-Dependent Effects of Folic Acid on Blood Concentra-tions of Homocysteine: A Meta-Analysis of the Randomized Trials. The American Journal of Clinical Nutrition, 82, 806-812. <br>https://doi.org/10.1093/ajcn/82.4.806Li, Y., Huang, T., Zheng, Y., et al. (2016) Folic Acid Supple-mentation and the Risk of Cardiovascular Diseases: A Meta-Analysis of Randomized Controlled Trials. Journal of the American Heart Association, 5, e003768.
<br>https://doi.org/10.1161/JAHA.116.003768Arnesen, E., Refsum, H., Bønaa, K.H., et al. (1995) Serum Total Homocysteine and Coronary Heart Disease. International Journal of Epidemiology, 24, 704-709. <br>https://doi.org/10.1093/ije/24.4.704Nygård, O., Nordrehaug, J.E., Refsum, H., et al. (1997) Plasma Homo-cysteine Levels and Mortality in Patients with Coronary Artery Disease. The New England Journal of Medicine, 337, 230-236.
<br>https://doi.org/10.1056/NEJM199707243370403Wald, D.S., Law, M. and Morris, J.K. (2002) Homocysteine and Cardiovascular Disease: Evidence on Causality from a Meta-Analysis. BMJ, 325, 1202. <br>https://doi.org/10.1136/bmj.325.7374.1202Casas, J.P., Bautista, L.E., Smeeth, L., et al. (2005) Homocysteine and Stroke: Evidence on a Causal Link from Mendelian Randomisation. The Lancet, 365, 224-232. <br>https://doi.org/10.1016/S0140-6736(05)70152-5Robinson, K., Arheart, K., Refsum, H., et al. (1998) Low Circulating Folate and Vitamin B6 Concentrations: Risk Factors for Stroke, Peripheral Vascular Disease, and Coronary Artery Disease. Circulation, 97, 437-443.
<br>https://doi.org/10.1161/01.CIR.97.5.437Folsom, A.R., Nieto, F.J., McGovern, P.G., et al. (1998) 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, 98, 204-210. <br>https://doi.org/10.1161/01.CIR.98.3.204Voutilainen, S., Rissanen, T.H., Virtanen, J., Lakka, T.A., et al. (2001) Low Dietary Folate Intake Is Associated with an Excess Incidence of Acute Coronary Events: The Kuopio Is-chemic Heart Disease Risk Factor Study. Circulation, 103, 2674-2680. <br>https://doi.org/10.1161/01.CIR.103.22.2674Jacques, P.F., Selhub, J., Bostom, A.G., et al. (1999) The Effect of Folic Acid Fortification on Plasma Folate and Total Homocysteine Concentrations. The New England Journal of Med-icine, 340, 1449-1454.
<br>https://doi.org/10.1056/NEJM199905133401901Liu, X.D, Shi, M., Xia, F., Han, J.L., et al. (2015) The Chi-na Stroke Secondary Prevention Trial (CSSPT) Protocol: A Double-Blinded, Randomized, Controlled Trial of Combined Folic Acid and B Vitamins for Secondary Prevention of Stroke. International Journal of Stroke, 10, 264-268. <br>https://doi.org/10.1111/ijs.12017Wald, N.J. and Law, M.R. (2003) A Strategy to Reduce Cardiovascular Disease by More than 80%. BMJ, 326, 1419.
<br>https://doi.org/10.1136/bmj.326.7404.1419Toole, J.F., Malinow, M.R., Chambless, L.E., et al. (2004) Low-ering 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, 291, 565-575. <br>https://doi.org/10.1001/jama.291.5.565Jadad, A.R., Moore, R.A., Carroll, D., et al. (1996) Assessing the Quality of Reports of Randomized Clinical Trials: Is Blinding Necessary? Controlled Clinical Trials, 17, 1-12. <br>https://doi.org/10.1016/0197-2456(95)00134-4Albert, C.M., Cook, N.R., Gaziano, J.M., et al. (2008) 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, 299, 2027-2036. <br>https://doi.org/10.1001/jama.299.17.2027Bønaa, K.H., Njølstad, I., Ueland, P.M., et al. (2006) Homocysteine Lowering and Cardiovascular Events after Acute Myocardial Infarction. The New England Journal of Medicine, 354, 1578-1588.
<br>https://doi.org/10.1056/NEJMoa055227Ebbing, M., Bleie, Ø., Ueland, P.M., et al. (2008) Mortality and Car-diovascular Events in Patients Treated with Homocysteine-Lowering B Vitamins after Coronary Angiography: A Ran-domized Controlled Trial. JAMA, 300, 795-804.
<br>https://doi.org/10.1001/jama.300.7.795Armitage, J.M., Bowman, L., Clarke, R.J., et al. (2010) Effects of Homocysteine-Lowering with Folic Acid Plus Vitamin B12 vs Placebo on Mortality and Major Morbidity in Myocardial Infarction Survivors: A Randomized Trial. JAMA, 303, 2486-2494. <br>https://doi.org/10.1001/jama.2010.840Liakishev, A.A. (2006) Homocysteine Lowering with Folic Acid and B Vitamins in Vascular Disease. Kardiologiia, 46, Article No. 70.Galan, P., Kesse-Guyot, E., Czernichow, S., et al. (2010) Effects of B Vitamins and Omega 3 Fatty Acids on Cardiovascular Diseases: A Randomised Placebo Controlled Trial. BMJ, 341, c6273. <br>https://doi.org/10.1136/bmj.c6273Wang, L., Li, H., Zhou, Y., et al. (2015) Low-Dose B Vitamins Supplementation Ameliorates Cardiovascular Risk: A Double-Blind Randomized Controlled Trial in Healthy Chinese Elderly. European Journal of Nutrition, 54, 455-464.
<br>https://doi.org/10.1007/s00394-014-0729-5Homocysteine Studies Collaboration (2002) Homocysteine and Risk of Ischemic Heart Disease and Stroke: A Meta-Analysis. JAMA, 288, 2015-2022. <br>https://doi.org/10.1001/jama.288.16.2015Liem, A., Reynierse-Buitenwerf, G.H., Zwinderman, A.H., et al. (2003) Secondary Prevention with Folic Acid: Effects on Clinical Outcomes. Journal of the American College of Cardi-ology, 41, 2105-2113.
<br>https://doi.org/10.1016/S0735-1097(03)00485-6Liem, A.H., van Boven, A.J., Veeger, N.J., et al. (2004) Ef-ficacy of Folic Acid When Added to Statin Therapy in Patients with Hypercholesterolemia Following Acute Myocardial Infarction: A Randomised Pilot Trial. International Journal of Cardiology, 93, 175-179. <br>https://doi.org/10.1016/j.ijcard.2003.02.001Lonn, E., Held, C., Arnold, J.M., et al. (2006) Rationale, Design and Baseline Characteristics of a Large, Simple, Randomized Trial of Combined Folic Acid and Vitamins B6 and B12 in High-Risk Patients: The Heart Outcomes Prevention Evaluation (HOPE)-2 Trial. Canadian Journal of Cardiology, 22, 47-53.
<br>https://doi.org/10.1016/S0828-282X(06)70238-0Schnyder, G., Roffi, M., Pin, R., et al. (2001) Decreased Rate of Coronary Restenosis after Lowering of Plasma Homocysteine Levels. The New England Journal of Medicine, 345, 1593-1600. <br>https://doi.org/10.1056/NEJMoa011364Lange, H., Suryapranata, H., De Luca, G., et al. (2004) Folate Therapy and In-Stent Restenosis after Coronary Stenting. The New England Journal of Medicine, 350, 2673-2681. <br>https://doi.org/10.1056/NEJMoa032845Verhaar, M.C., Stroes, E. and Rabelink, T.J. (2002) Fo-lates and Cardiovascular Disease. Arteriosclerosis, Thrombosis, and Vascular Biology, 22, 6-13. <br>https://doi.org/10.1161/hq0102.102190van Dijk, R.A., Rauwerda, J.A., Steyn, M., et al. (2001) 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, Ran-domized, Placebo-Controlled Trial. Arteriosclerosis, Thrombosis, and Vascular Biology, 21, 2072-2079. <br>https://doi.org/10.1161/hq1201.100223Vermeulen, E.G., Stehouwer, C.D., Valk, J., et al. (2004) Effect of Homocysteine-Lowering Treatment with Folic Acid plus Vitamin B on Cerebrovascular Atherosclerosis and White Mat-ter Abnormalities as Determined by MRA and MRI: A Placebo-Controlled, Randomized Trial. European Journal of Clinical Investigation, 34, 256-261.
<br>https://doi.org/10.1111/j.1365-2362.2004.01332.xStanger, O., Semmelrock, H.J., Wonisch, W., et al. (2002) Effects of Folate Treatment and Homocysteine Lowering on Resistance Vessel Reactivity in Atherosclerotic Subjects. Journal of Pharmacology and Experimental Therapeutics, 303, 158-162. <br>https://doi.org/10.1124/jpet.102.036715Durga, J., van Tits, L.J., Schouten, E.G., et al. (2005) Effect of Low-ering of Homocysteine Levels on Inflammatory Markers: A Randomized Controlled Trial. Archives of Internal Medicine, 165, 1388-1394.
<br>https://doi.org/10.1001/archinte.165.12.1388Thambyrajah, J., Landray, M.J., Jones, H.J., et al. (2001) 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. Journal of the American College of Cardiology, 37, 1858-1863.
<br>https://doi.org/10.1016/S0735-1097(01)01235-9Doshi, S.N., Moat, S.J., McDowell, I.F., et al. (2002) Low-ering Plasma Homocysteine with Folic Acid in Cardiovascular Disease: What Will the Trials Tell Us? Atherosclerosis, 165, 1-3.
<br>https://doi.org/10.1016/S0021-9150(02)00191-0Woodman, R.J., Celermajer, D.E., Thompson, P.L., et al. (2004) Folic Acid Does Not Improve Endothelial Function in Healthy Hyperhomocysteinaemic Subjects. Clinical Science (London), 106, 353-358.
<br>https://doi.org/10.1042/CS20030296Dusitanond, P., Eikelboom, J.W., Hankey, G.J., et al. (2005) Homocys-teine-Lowering Treatment with Folic Acid, Cobalamin, and Pyridoxine Does Not Reduce Blood Markers of Inflammation, Endothelial Dysfunction, or Hypercoagulability in Patients with Previous Transient Ischemic Attack or Stroke: A Ran-domized Substudy of the VITATOPS Trial. Stroke, 36, 144-146. <br>https://doi.org/10.1161/01.STR.0000150494.91762.70Stover, P.J. (2004) Physiology of Folate and Vitamin B12 in Health and Disease. Nutrition Reviews, 62, S3-S12; Discussion S13. <br>https://doi.org/10.1301/nr.2004.jun.S3-S12Matsubara, K., Mori, M., Akagi, R., et al. (2004) Anti-Angiogenic Effect of Pyridoxal 5’-Phosphate, Pyridoxal and Pyridoxamine on Embryoid Bodies Derived from Mouse Embryonic Stem Cells. International Journal of Molecular Medicine, 14, 819-823. <br>https://doi.org/10.3892/ijmm.14.5.819