Meta-analysis of the relationship between homocysteine level and metabolic cardiovascular disease
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摘要: 目的 通过meta分析评估同型半胱氨酸(homocysteine，Hcy)水平与代谢性心血管疾病发生及死亡风险的相关性。方法 计算机检索Pubmed、中国知网(CNKI)、万方数据库和维普数据库，检索时限为建库至2023年7月24日。经过文献筛选、资料提取和质量评价，采用RevMan 5.3软件进行meta分析。结果 共纳入16篇文献，其中7篇为队列研究，9篇为随机对照试验(randomized controlled trial，RCT)。队列研究meta分析结果显示，与Hcy水平正常者相比，Hcy水平较高者全因死亡率(RR=2.38，95%CI：1.71~3.32)、代谢性心血管疾病(RR=1.91，95%CI：1.46~2.49)、卒中(RR=2.26，95%CI：1.91~2.67)和冠心病(RR=2.32，95%CI：1.40~3.83)的发生/死亡风险增加；RCT研究meta分析结果显示，叶酸联合B族维生素干预可降低人体内Hcy水平(RR=-2.85，95%CI：-3.86~-1.83)，但试验组和对照组全因死亡率、代谢性心血管疾病、心肌梗死和卒中的发生/死亡风险均无统计学意义(均P＞0.05)。结论 队列研究结果显示，体内Hcy水平升高会增加代谢性心血管疾病的发生风险和全因死亡风险。RCT结果显示，叶酸联合B族维生素干预虽然能降低体内Hcy水平，但远期内并不能观测到对代谢性心血管疾病的影响。Abstract: Objective The study was aimed to evaluate the correlation between homocysteine(Hcy) levels and the risk of metabolic cardiovascular diseases and death through meta-analysis.Methods Pubmed, CNKI, Wanfang Database, and VIP Database were searched by computer to collect literature till July 24th, 2023. After literature screening, data extraction, and quality evaluation, meta-analysis was conducted using RevMan 5.3 software.Results A total of 16 articles were included, of which 7 were cohort studies and 9 were RCTs. The meta-analysis results from cohort studies showed that comparing with those with normal Hcy levels, those with higher Hcy levels had a higher risk of all-cause mortality(RR=2.38, 95%CI1.71-3.32), metabolic cardiovascular diseases(RR=1.91, 95%CI1.46-2.49), stroke(RR=2.26, 95%CI1.91-2.67), and coronary heart diseases(RR=2.32, 95%CI1.40-3.83). The meta-analysis results from RCTs showed that folic acid combined with B vitamins intervention could reduce Hcy levels in the human body(RR=-2.85, 95%CI-3.86--1.83), but there were no significant differences in the incidence of all-cause mortality, metabolic cardiovascular diseases, myocardial infarction and stroke in the experimental and control groups(P > 0.05).Conclusion The results of cohort studies indicate that an increase in Hcy levels in the body over a period of time increases the risk of metabolic cardiovascular diseases and all-cause mortality. The results of RCTs indicate that although exogenous folic acid combined with B vitamins intervention can reduce Hcy levels in the body for a certain period of time, while the long-term impact on metabolic cardiovascular diseases cannot be observed.
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图 2 Hcy较高组与Hcy正常组全因死亡率比较的meta分析
Figure 2. Meta-analysis of the incidence of all-cause mortality between the high Hcy group and the normal Hcy group
图 3 Hcy较高组与Hcy正常组代谢性心血管疾病发生率比较的meta分析
Figure 3. Meta-analysis of the incidence of metabolic cardiovascular diseases between the high Hcy group and the normal Hcy group
图 4 Hcy较高组与Hcy正常组卒中发生率比较的meta分析
Figure 4. Meta-analysis of the incidence of stroke between the high Hcy group and the normal Hcy group
图 5 Hcy较高组与Hcy正常组冠心病发生率比较的meta分析
Figure 5. Meta-analysis of the incidence of coronary heart diseases between the high Hcy group and the normal Hcy group
图 6 叶酸+维生素B12+维生素B6干预组与对照组Hcy浓度比较的meta分析
Figure 6. Meta-analysis of Hcy concentration comparison between intervention group(folic acid, vitamin B12 and vitamin B6) and control group
图 7 叶酸+维生素B12+维生素B6干预组与对照组全因死亡率比较的meta分析
Figure 7. Meta-analysis of the incidence of all-cause mortality between intervention group(folic acid, vitamin B12 and vitamin B6) and control group
图 8 叶酸+维生素B12+维生素B6干预组与对照组代谢性心血管疾病发生率比较的meta分析
Figure 8. Meta-analysis of the incidence of metabolic cardiovascular diseases between intervention group(folic acid, vitamin B12 and vitamin B6) and control group
图 9 叶酸+维生素B12干预组与对照组代谢性心血管疾病发生率比较的meta分析
Figure 9. Meta-analysis of the incidence of metabolic cardiovascular diseases between intervention group(folic acid and vitamin B12) and control group
图 10 叶酸+维生素B12+维生素B6干预组与对照组心肌梗死发生率比较的meta分析
Figure 10. Meta-analysis of the incidence of myocardial infarction between intervention group(folic acid, vitamin B12 and vitamin B6) and control group
图 11 叶酸+维生素B12干预组与对照组心肌梗死发生率比较的meta分析
Figure 11. Meta-analysis of the incidence of myocardial infarction between intervention group(folic acid and vitamin B12) and control group
图 12 叶酸+维生素B12+维生素B6干预组与对照组卒中发生率比较的meta分析
Figure 12. Meta-analysis of the incidence of stroke between intervention group(folic acid, vitamin B12 and vitamin B6) and control group
图 13 叶酸+维生素B12干预组与对照组卒中发生率比较的meta分析
Figure 13. Meta-analysis of the incidence of stroke between intervention group(folic acid and vitamin B12) and control group
图 14 队列研究中代谢性心血管疾病发生率漏斗图
Figure 14. Funnel plot of the incidence of metabolic cardiovascular diseases in cohort studies
图 15 RCT中代谢性心血管疾病发生率的漏斗图(干预措施为叶酸+维生素B12+维生素B6)
Figure 15. Funnel plot of the incidence of metabolic cardiovascular diseases in RCTs(folic acid, vitamin B12 and vitamin B6)
表 1 纳入队列研究文献的基本特征
Table 1. Basic characteristics of included cohort studies
纳入研究 国家 研究对象特征 随访时间/年 年龄/岁 例数 结局指标 Hcy水平较高(>15 μmol/L) Hcy水平正常(≤15 μmol/L) Han 2015[12] 中国 原发性高血压患者 2.7 58.52±12.19 1505 3656 ③④⑤ Mo 2023[13] 中国 无冠心病、卒中、癌症者 5.69 62.93±8.25 6542 13284 ①②③ ④⑤ Ndrepepa 2006[6] 德国 2型糖尿病和冠状动脉疾病患者 4 59.9~77.0 255 252 ①②③ Sacco 2004[14] 美国 未患过卒中者 4 68.9±10.2 305 2634 ③④ Sun 2009[5] 中国 未患过卒中、心血管疾病和癌症者 11.95 Q1：51.1±9.1
Q2：55.8±10.3
Q3：60.0±10.7
Q4：64.2±11.4500 1509 ①③ ④⑤ Xiao 2013[15] 中国 接受冠状动脉造影的患者 3 21~87 249 754 ③ Zhang 2023[16] 中国 急性缺血性卒中和H型高血压患者 1 65.5±11.7 634 317 ③④ 注：结局指标：①全因死亡；②代谢性心血管疾病死亡；③代谢性心血管疾病发生；④卒中；⑤冠心病。 
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表 2 干预措施为叶酸+维生素B12+维生素B6的RCT研究文献的基本特征
Table 2. Basic characteristics of included RCTs(The intervention measure includes folic acid, vitamin B12 and vitamin B6)
纳入研究 国家 研究对象特征 随访时间/年 平均年龄/岁 例数 干预措施/mg 结局指标 试验组 对照组 试验组 对照组 试验组 对照组 Ebbing 2008[10] 挪威 疑似冠脉瓣狭窄而接受冠状动脉造影和(或)主动脉瓣造影者 3.2 61.7±10.3 62.0±9.9 771 779 0.8叶酸+0.4维生素B12+40维生素B6 安慰剂 ①③ ④⑤ Ebbing 2010[17] 挪威 缺血性心脏病患者 6.5 62.7±11.2 62.3±10.7 1708 1721 0.8叶酸+0.4维生素B12+40维生素B6 安慰剂 ②③ ④⑤ Hodis 2009[8] 美国 无CVD临床体征/症状者 3.1 61.7±10.1 61.1±9.6 248 242 5叶酸+0.4维生素B12+50维生素B6 安慰剂 ①③ Schnyder 2002[18] 瑞士 冠状动脉狭窄患者 1 63.4±10.6 61.8±11.0 272 281 1叶酸+0.4维生素B12+10维生素B6 安慰剂 ①② ③④ Song 2009[11] 美国 有CVD病史或危险因素大于等于3个者 7.3 63.1±8.9 62.9±8.9 2132 2120 2.5叶酸+1维生素B12+50维生素B6 安慰剂 ③ Toole 2004[19] 美国、加拿大、英国 急性缺血性卒中患者 2 66.4±10.8 66.2±10.8 1827 1853 2.5叶酸+0.4维生素B12+25维生素B6 0.02叶酸+0.006维生素B12+0.2维生素B6 ①③⑤ Tungkasereerak 2006[20] 泰国 同型半胱氨酸>10 mmol/L者 0.5 55.86± 13.44 55.17± 13.86 27 27 15叶酸+1维生素B12+50维生素B6 5叶酸 ⑥ 注：结局指标：①全因死亡；②代谢性心血管疾病死亡；③代谢性心血管疾病发生；④心肌梗死；⑤卒中；⑥颈动脉IMT变化。
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表 3 干预措施为叶酸+维生素B12的RCT研究文献的基本特征
Table 3. Basic characteristics of included RCTs(The intervention measure includes folic acid and vitamin B12)
纳入研究 国家 研究对象特征 随访时间/年 平均年龄/岁 例数 干预措施/mg 结局指标 试验组 对照组 试验组 对照组 Armitage 2010[21] 英国 有心肌梗死病史者 6.7 64.2±8.9 6033 6031 2叶酸+1维生素B12 安慰剂 ①②③ ④⑤ Dijk 2015[22] 荷兰 同型半胱氨酸12~50 μmol/L者 2 试验组72.5±5.8对照组72.5±5.3 295 274 0.4叶酸+0.5维生素B12 安慰剂 ③④⑥ Ebbing 2008[10] 挪威 疑似冠脉瓣狭窄而接受冠状动脉造影和(或)主动脉瓣造影者 3.2 试验组61.3±10.0对照组62.0±9.9 769 779 0.8叶酸+0.4维生素B12 安慰剂 ①③ ④⑤ Ebbing 2010[17] 挪威 缺血性心脏病患者 6.5 试验组62.3±10.9对照组62.3±10.7 1703 1721 0.8叶酸+0.4维生素B12 安慰剂 ②③ ④⑤ 注：结局指标：①全因死亡；②代谢性心血管疾病死亡；③代谢性心血管疾病发生；④心肌梗死；⑤卒中；⑥颈动脉内膜中层厚度变化。
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