Meta-analysis
Homocysteine level and risk of different stroke types: A meta-analysis of prospective observational studies

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Abstract

Background and aims

Inconsistent findings have been reported regarding the association between elevated plasma homocysteine (Hcy) levels and the risk of different types of strokes. We conducted this meta-analysis to identify the association between homocysteine (Hcy) levels and different kinds of strokes or recurrences of strokes.

Methods and results

PubMed and Embase databases were searched for relevant studies published prior to April 2013. Only prospective studies that compared elevated Hcy levels with the risk of different types of strokes were selected. Results were presented as the relative risk (RR) and the corresponding 95% confidence intervals (CI) comparing the highest Hcy category group with the lowest Hcy category group. Nine studies composed of 13,284 participants were included. The pooled RR of ischemic strokes when comparing the highest Hcy category group with the lowest Hcy category group was 1.69 (95% CI: 1.29–2.20) in a fixed-effect model. The pooled RR of hemorrhagic strokes and recurrent strokes when comparing the highest Hcy category group with the lowest Hcy category group in a fixed-effect model was 1.65 (95% CI: 0.61–4.45) and 1.76 (95% CI: 1.37–2.24), respectively.

Conclusions

This meta-analysis indicated that elevated Hcy levels are associated with an increased risk for ischemic strokes and recurrent strokes but had no distinct association with hemorrhagic strokes.

Introduction

Stroke remains a leading cause of mortality and disability [1], [2]. According to its underlying pathology, strokes can be divided into ischemic and hemorrhagic strokes. Ischemic stroke is caused by a blocked arterial blood vessel, whereas hemorrhagic stroke is due to an arterial blood vessel rupture in or surrounding the brain [3]. Many risk factors, such as hypertension, diabetes, and smoking, are associated with strokes. Therefore, identification of these modifiable risk factors may lead to more effective prediction of stroke events and recurrences.

Homocysteine (Hcy) is a sulfur-containing amino acid produced by the demethylation of the essential amino acid methionine. Studies that have assessed the relationship between Hcy levels and stroke subtypes have shown different results. An elevated plasma Hcy level has been identified as a risk factor for ischemic strokes [4], [5], [6], [7] and recurrent strokes [8], [9]; however, not all reports show a positive association between elevated plasma Hcy levels and ischemic strokes [10], [11] or hemorrhagic strokes [6], [12]. In previously published clinical evidence, three well-designed meta-analyses [13], [14], [15] found that a moderate elevation of Hcy levels was associated with an increased risk of stroke; however, in each of the meta-analyses, these conclusions are mostly based on case–control studies, which makes it difficult to determine whether or not an elevated Hcy level is a precursor or a consequence of stroke. Additionally, these meta-analyses did not address the homocysteine level and different stroke types. A recently published meta-analysis [16] showed that homocysteine-lowering therapy significantly reduced the occurrence of strokes but not in divided subgroups according to ischemic vs. hemorrhagic stroke or occurrence of fatal strokes. Apart from the negative findings in subgroups from these trials are related to intervention duration or degree of Hcy lowering, there may be subgroups of individuals that could benefit from Hcy lowering in stroke prevention. Therefore, the identification of the Hcy level and the risk for different kinds of strokes or subtypes might benefit these subgroups of individuals.

The purpose of the present meta-analysis is to quantitatively assess findings from prospective studies on the plasma Hcy levels and the risk of stroke subtypes or recurrences.

Section snippets

Study selection

The study was performed in accordance with the Meta-analysis of Observational Studies in Epidemiology guidelines [17]. PubMed and Embase databases were searched for relevant studies that assess the association between Hcy and the risk of stroke published prior to April 2013. No language restrictions were applied. Potentially relevant studies were identified by the medical subject heading (MeSH) terms that contained the following keywords: hyperhomocysteinemia or homocysteine, stroke, ischemic

Literature search

After the application of search strategy, a total of 1278 potentially relevant citations were identified in our initial literature search. After screening the abstracts or titles, 1202 studies were excluded primarily because they were reviews, animal studies, or not relevant to our analysis. After reviewing the full texts, nine studies [4], [5], [6], [7], [8], [9], [10], [11], [12] were included in the meta-analysis. A flow chart showing the study selection is presented in Fig. 1. No additional

Discussion

The findings of the current meta-analysis indicate that an elevated Hcy level is associated with an increased risk of ischemic strokes and recurrent strokes. Participants with the highest Hcy levels had an increased risk of 69% for ischemic strokes and 76% for recurrent strokes, respectively; however, subjects with elevated Hcy levels showed some trend with an increased risk for hemorrhagic strokes in which this positive association was not statistically significant (RR: 1.65; 95% CI:

Conclusion

In conclusion, this meta-analysis provided evidence that elevated Hcy levels increased the risk of ischemic strokes and recurrent strokes but not hemorrhagic strokes. Additional well-designed prospective studies regarding the relationship between Hcy levels and the risk of stroke subtypes are needed to further clarify this question.

Conflict of interest

There are no conflicts of interest for any of the authors.

Acknowledgments

The authors wish to thank Shijun Wang for his assistance in proofreading.

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