Association between plasma total homocysteine (tHcy) and strokes: A meta-analysis

Hang Li; Lingfeng Shu; Qinghai Dai; Tao Wu

doi:10.1515/pteridines-2022-0044

Article Open Access

Association between plasma total homocysteine (tHcy) and strokes: A meta-analysis

Hang Li , Lingfeng Shu , Qinghai Dai and Tao Wu

Published/Copyright: November 8, 2022

Published by

Become an author with De Gruyter Brill

Author Information Explore this Subject

From the journal Pteridines Volume 33 Issue 1

Abstract

Objective

Inconsistent findings have been reported regarding the association between elevated plasma total homocysteine (tHcy) and the risk of different types of strokes. We conducted this meta-analysis to identify the association between tHcy and different kinds of strokes or recurrences of strokes, and provide evidence for preventing.

Methods

Relevant studies published before May 1, 2022 in databases such as PubMed, EMBASE, the Cochrane Library, CNKI, and Wanfang were retrieved. Two researchers independently searched and extracted the data, and used Stata 16.0 statistical software for analysis. Results were presented as the odds risk (OR) and the corresponding 95% confidence intervals (CI).

Results

In total, 24 articles were included, involving 51,426 subjects, of which 4,983 had stroke events during follow-up. Relative to lower tHcy, higher tHcy were associated with increased stroke (OR = 1.95, 95% CI: 1.59–2.37), ischemic stroke (OR = 1.71, 95% CI: 1.39–2.11), hemorrhagic stroke (OR = 1.99, 95% CI: 1.03–3.84), and recurrent stroke (OR = 1.25, 95% CI: 1.12–1.39), respectively.

Conclusions

This study shows that elevated tHcy increases the risk of stroke, including ischemic stroke and hemorrhagic stroke, and is closely related to the recurrence of stroke. It is recommended to pay attention to the detection of tHcy in the management of stroke patients in the future, and take effective measures to prevent and delay the progression of stroke.

Keywords: homocysteine; stroke; ischemic stroke; hemorrhagic stroke; recurrent strokes; meta-analysis

Stroke is an acute cerebrovascular condition in which brain tissue is damaged due to the sudden rupture or blockage of blood vessels in or around the brain. According to its underlying pathological mechanism, stroke is generally divided into ischemic stroke and hemorrhagic stroke [1]. Stroke has become one of the public health problems in China due to its high disability, mortality, and recurrence rates [2]. It is associated with a variety of risk factors, such as hypertension, diabetes, hyperlipidemia, and smoking. The early identification of these modifiable risk factors is effective in predicting the onset and recurrence of stroke.

Plasma total homocysteine (tHcy), which includes homocysteine, its dimer homocysteine, and mixed cysteine–homocysteine disulfide. According to the consensus nomenclature, this is called plasma total homocysteine and abbreviated “tHcy” [3]. Hcy is a sulfur-containing amino acid produced during methionine demethylation and has a toxic effect on vascular endothelial cells and neurons. Previous studies [4–6] showed that elevated tHcy increase the risk of ischemic stroke and recurrent stroke, but another research [7] did not find an association between these two. Therefore, the relationship between tHcy and stroke type is controversial. The present work examined the existing studies on the correlation between tHcy and stroke types to explore their correlation and provide a theoretical basis for the prevention of stroke.

1 Materials and methods

1.1 Literature retrieval strategy

Relevant studies published before May 1, 2022 were searched in PubMed, EMBASE, Cochrane Library, CNKI, and Wanfang databases. The following English terms were used for searching the combination of subject words and free words: “stroke,” “ischemic stroke,” “recurrent stroke,” “hemorrhagic stroke,” “hyperhomocysteinemia,” and “homocysteine.” All the references were searched manually to ensure that the studies were included as comprehensively as possible.

1.2 Inclusion criteria

(1) Case–control or cohort studies on the association of Hcy with stroke; (2) diagnosis of stroke is based on strict neurological examination and confirmed by CT or MRI and meets the diagnostic criteria of the World Health Organization; (3) odds ratios (OR), relative hazard (RR), or risk ratios (HR) and their 95% confidence intervals (95% CI) are reported in the literature. Studies, conference abstracts, reviews, and cross-sectional studies whose raw data are not available were excluded.

1.3 Data extraction and quality assessment

The relevant information of the included study was independently extracted by two investigators according to the inclusion and exclusion criteria, and third-party arbitration gave a decision in the event of a dispute. The following data were extracted: first author, year of publication, country, age, study design type, median follow-up time, sample size, tHcy in exposure and control groups, number of outcomes, stroke outcome type, outcome effect of OR, RR, or HR, and 95% CI. If the study calculated single-factor and multivariate effect values, then the multivariate results with plenty of information were extracted. The quality of included studies was assessed using the Newcastle–Ottawa Scale (NOS), which can evaluate the quality of case–control and cohort studies [8]. This table contains nine items with a full score of nine points, and six points and above means that the study can be included in the analysis with high quality.

1.4 Statistical analysis

The results were analyzed using Stata 16.0 software. OR, RR, or HR can be considered similar when their effect sizes are small [9]. Therefore, this study used OR and 95% CI to assess the association of tHcy with stroke. The heterogeneity of the included studies was evaluated by I ² test and P-value. If P ≤ 0.1 or I ² ≥ 50%, then heterogeneity existed, and a random-effects model was used. Otherwise, a fixed-effects model was employed. Subgroup analysis and sensitivity analysis were used to explore heterogeneity sources and outcome stability. Publication bias was evaluated using a funnel chart. If the number of included studies for an outcome event is less than or equal to 3, then the event will be no longer evaluated as biased. Unless otherwise specified, the bilateral P-value <0.05 was considered to be statistically significant.

2 Results

2.1 Literature retrieval results

In total, 8,401 Chinese and English studies were retrieved from CNKI, Wanfang, PubMed, EMBASE, and Cochrane. A total of 1,613 duplicate studies were excluded. After the titles and abstracts were read, 6,512 articles that did not meet the inclusion criteria were eliminated, and the remaining 276 articles were included. After the full text was read, 252 irrelevant or incomplete studies were excluded. Finally, 24 studies were included in this work. The specific retrieval process is shown in Figure 1.

Figure 1

Publication electronic searching flow chart demonstrate that 24 studies were finally included for meta-analysis.

2.2 Basic characteristics and quality evaluation of the included studies

In total, 51,426 people were involved in the 24 included articles, of which 4,983 suffered from strokes during the follow-up period of 1–17 years. Fifteen studies [10–24] reported an association between tHcy and first-time stroke, 13 studies [10–20,24,25] reported an association between tHcy and ischemic stroke, four studies [13,16–18] reported an association between tHcy and hemorrhagic stroke, and ten studies [7,20,25–32] reported an association between tHcy and recurrent stroke. Fourteen of these studies were from China, and the rest were from other countries, such as the United States, Japan, and the United Kingdom. According to the NOS criteria, 24 studies scored 5–9 points and thus were considered of moderate quality and above and were included in the analysis (Table 1).

Table 1

Characteristics of included studies

Author	Public year	Nation	Age median Mean (SD)	Design	Follow-up (year)	N	No. of events	Event	Effect	Hcy-case (μmol/L)	Hcy-control (μmol/L)	NOS
Verhoef et al. [10]	1994	America	40–84	Case–control	5	536	109	Ischemic	OR	>12.7	≤12.7	7
Bostom et al. [11]	1999	America	70 ± 7	Cohort	9.9	1,947	165/153	Stroke/ischemic	HR	≥14.24	<9.25	9
Fallon et al. [12]	2001	Britain	50–64	Cohort	10.2	2,254	107	Ischemic	HR	>19.0	<8.2	8
Iso et al. [13]	2004	Japan	65.3	Case–control	10	600	98/52	Ischemic/hemorrhagic	OR	≥11.0	<7.0	7
Sacco et al. [14]	2004	America	68.9 ± 10.2	Cohort	5	2,939	125	Ischemic	HR	≥15	<10	8
Bos et al. [26]	2005	Netherlands	18–45	Cohort	2.5	161	14	Recurrent	HR	≥13.7	≤10.7	6
Virtanen et al. [15]	2005	Finland	46–64	Cohort	9.6	1,015	34	Ischemic	RR	≥11.4	<9.6	9
Cui et al. [16]	2008	Japan	40–79	Case–control	10	610	101/131	Ischemic/hemorrhagic	OR	≥15.3	<10.5	9
Sun et al. [17]	2009	China	—	Cohort	11.95	2,009	92/22	Ischemic/hemorrhagic	HR	≥11.67	<6.53	8
Zhang et al. [27]	2009	China	35–74	Cohort	4.5	1,823	347	Recurrent	RR	≥19.8	<11.5	8
Hultdin et al. [18]	2011	Sweden	25–74	Case–control	4.2	778	321/60	Ischemic/hemorrhagic	RR	Highest quartile	Lowest quartile	7
Han et al. [19]	2015	China	—	Cohort	2.7	5,488	197	Ischemic	HR	≥30	<15	6
Ji et al. [28]	2015	China	—	Cohort	1	351	116	Recurrent	RR	≥22.75	<12.45	6
Shi et al. [20]	2015	China	54–71	Cohort	4	3,799	95/425	Ischemic/recurrent	HR	>18.6	≤10.0	5
Ma et al. [21]	2015	China	58 ± 12	Cohort	2.7	5,161	197	Stroke	HR	≥15	<15	7
Kumral et al. [7]	2016	Turkey	65 ± 14	Cohort	5	8,784	307	Recurrent	HR	>14.50	≤14.49	8
Yue et al. [29]	2016	China	62.7 ± 8.3	Cohort	3	3,799	702	Recurrent	HR	≥15	<15	6
Gao [30]	2017	China	62.82 ± 8.46	Cohort	3	1,366	253	Recurrent	HR	≥15	<15	6
Shi et al. [25]	2018	China	58.95 ± 10.25	Cohort	1.5	2,800	220	Recurrent ischemic	HR	>15.5	≤9.65	6
Lv et al. [31]	2019	China	70.9 ± 10.4	Cohort	2	142	25	Recurrent	OR	>15	≤15	8
Anniwaer et al. [32]	2019	China	69.92 ± 8.6	Cohort	3	231	72	Recurrent	HR	>15	≤15	9
Feng et al. [22]	2020	China	70.2 ± 9.8	Cohort	17	1,226	237	Stroke	HR	>15	<10	7
Li et al. [24]	2021	China	49.45 ± 10.65	Cohort	7.15	2,350	93	Ischemic	HR	>18.2	<11.6	8
Zhang et al. [23]	2021	China	69.13 ± 8.04	Cohort	4.84	1,257	113	Stroke	HR	≥15	<15	7

2.3 Meta-analysis results

2.3.1 Association of tHcy with first-time stroke

As shown in Figure 2, 15 studies [10–24] reported an association between tHcy and first-time stroke. Iso et al., Cui et al., Sun et al., and Hultdin et al. reported the outcome of ischemic stroke and hemorrhagic stroke. Feng et al. and Zhang et al. analyzed hypertensive and non-hypertensive populations, respectively. All the aforementioned studies were categorized as independent. Owing to the heterogeneity between the studies (I ² = 55.7%, P = 0.001), a random-effects model was used to compare the risk of first stroke between the highest and lowest tHcy groups. The results showed that high tHcy increased the risk of first-time stroke (OR = 1.95, 95% CI: 1.59–2.37). Subgroup analysis based on follow-up length showed that high tHcy were associated with an increased risk of first-time stroke regardless of follow-up length (follow-up >5 years: OR = 2.10, 95% CI: 1.54–2.87; follow-up ≤5 years: OR = 1.82, 95% CI: 1.37–2.42).

Figure 2

Forest plots showing the effect of elevated Hcy levels on strokes. High Hcy levels increased the risk of first-time stroke (OR = 1.95). Subgroup analysis showed that high Hcy levels were associated with an increased risk of first-time stroke regardless of follow-up length.

2.3.2 Association of tHcy with ischemic stroke

As shown in Figure 3, 13 studies [10–20,24,25] reported an association between tHcy and ischemic stroke. Owing to the heterogeneity between the studies (I ² = 45.2%, P = 0.039), a random-effects model was used to compare the risk of ischemic stroke between the highest and lowest tHcy groups, and the pooled adjusted OR was 1.71 (95% CI: 1.39–2.11). Subgroup analysis based on follow-up length showed that high tHcy were associated with an increased risk of ischemic stroke regardless of follow-up length (follow-up >5 years: OR = 1.81, 95% CI: 1.37–2.40; follow-up ≤5 years, OR = 1.60, 95% CI: 1.12–2.28).

Figure 3

Forest plots showing the effect of elevated Hcy levels on ischemic strokes. High Hcy levels increased the risk of ischemic strokes with adjusted OR of 1.71. Subgroup analysis based on follow-up length showed that high Hcy levels were associated with an increased risk of ischemic stroke regardless of follow-up length.

2.3.3 Association of tHcy with hemorrhagic stroke

As shown in Figure 4, four studies [13,16–18] reported an association between tHcy and hemorrhagic stroke. The risk of hemorrhagic stroke was compared between the highest and lowest Hcy-level groups using a fixed-effects model, and the pooled adjusted OR was 1.99 (95% CI: 1.03–3.84. I ² = 4.45%, P = 0.217).

Figure 4

Forest plots showing the effect of elevated Hcy levels on hemorrhagic strokes. The risk of hemorrhagic stroke was compared between the highest and lowest Hcy-level groups using a fixed-effects model, and the pooled adjusted OR was 1.99.

2.3.4 Association of tHcy with recurrent stroke

As shown in Figure 5, ten studies [7,20,25–32] reported an association between tHcy and recurrent stroke. Owing to the heterogeneity between the studies (I ² = 87.8%, P < 0.001), a random-effects model was used to compare the risk of stroke recurrence between the highest and lowest tHcy groups. The results showed that high tHcy increased the risk of recurrent stroke (OR = 1.25, 95% CI: 1.12–1.39).

Figure 5

Forest plots showing the effect of elevated Hcy levels on recurrent strokes. The high Hcy levels increased the risk of recurrent stroke (OR = 1.25).

2.4 Publication bias and sensitivity analysis

According to the sensitivity analysis of each type of stroke in Figure 6, the deletion of any of the included studies had no significant effect on the combination of the remaining OR, confirming the stability of the final results of the current research. Funnel plots were used to assess the publication bias in the included studies. No significant publication bias was noted (Figure 7).

Figure 6

Sensitivity analysis of the relationship between Hcy levels and strokes. The deletion of any of the included studies had no significant effect on the combination of the remaining works and OR, confirming the stability of the final results of the current research: (a) strokes; (b) ischemic strokes, (c) hemorrhagic strokes, and (d) recurrent strokes.

Figure 7

Funnel plots analysis to detect the publication bias for Hcy levels and strokes and no significant publication bias was noted: (a) strokes; (b) ischemic strokes, and (c) recurrent strokes.

3 Discussion

This study showed that elevated tHcy are associated with an increased risk of first-time stroke, ischemic stroke, hemorrhagic stroke, and recurrent stroke. The risk of first-time stroke, ischemic stroke, hemorrhagic stroke, and recurrent stroke in the high-level tHcy population is 1.95, 1.71, 1.99, and 1.25 times higher than that in the low-level tHcy population, respectively. A previous meta-analysis [4] involving 15 studies showed an increased risk of ischemic stroke (RR = 1.71) and hemorrhagic stroke (RR = 1.24) in the high tHcy populations. Zhou et al. [33] showed that the level of tHcy in patients with cerebral hemorrhage was higher than that in the control group, and this result is consistent with the current findings. Mao and Han [34] found that the tHcy were higher in patients with ischemic stroke than in healthy controls and were also positively correlated with the risk of developing atherosclerotic subtype and arteriolar occlusion subtype. Another report [32] suggested that elevated tHcy in the acute phase of stroke can increase the likelihood of stroke recurrence. Shi et al. [25] found that among patients with aortic cerebral infarction, the risk of recurrent stroke in the high tHcy group was 1.76 times higher than that in the low tHcy group, which was consistent with the present results. tHcy are closely related to the scores of neural deficit-related scale at different stages of stroke and have predictive significance for adverse stroke outcomes. In addition, the tHcy assay is simple and easy to implement. Therefore, measuring tHcy concentrations is important for understanding the severity and prognosis of stroke.

The association between tHcy and stroke is not fully understood. Different types of strokes have different pathophysiological mechanisms. Serum tHcy may be responsible for ischemic stroke because elevated tHcy destroy endothelial cells, inhibit nitric oxide synthesis, and enhance the adhesion of platelets to endothelial cells, thus interfering with coagulation and leading to atherosclerotic plaque formation [35]. Experiments confirmed that Hcy [36] is closely related to carotid plaques, especially unstable plaques. In addition to damaging vascular endothelial cells and promoting vascular smooth muscle cell proliferation, platelet aggregation and adhesion, and prethrombotic factor expression, Hcy can indirectly affect angiogenesis in ischemic areas by damaging vascular regeneration and collateral circulation after cerebral infarction [37], resulting in stroke recurrence. At present, the mechanism of the effect of serum tHcy level on hemorrhagic stroke has not been fully elucidated. This action of tHcy may be related to reducing vascular elasticity by stimulating smooth muscle cell proliferation, endothelial dysfunction, and vasospasm [38]. However, as known that tHcy is a clotting factor, so an increase in hemorrhagic stroke seems unlikely. We analyzed the data for hemorrhagic stroke in the present meta-analysis and found that three of the included studies had no association between tHcy and hemorrhagic stroke. Only one study identified the correlation. Therefore, whether, higher tHcy were associated with increased stroke should be further discussed. Furthermore, high tHcy is associated with higher blood pressure and the high blood pressure is correlated with the increased risk of hemorrhagic stroke. Previously, studies have demonstrated that reducing tHcy can decrease the risk of stroke. Benefit of B vitamins was obscured in the early trials by harm from cyanocobalamin among participants with renal failure. B vitamins do reduce the risk of stroke, as proven in the China Stroke Primary Prevention Trial [39–41]. Therefore, large randomized controlled trials and institutional studies are still needed to confirm the relationship between tHcy and stroke types or recurrent stroke.

Most of the studies included in this work had adjusted for confounding factors to reduce their influence on the results and ensure the reliability of the results to some extent. Nevertheless, some limitations must be addressed. First, except for hemorrhagic stroke, heterogeneity was observed in the combined analysis of other types of stroke and may be caused by different etiological mechanisms. Second, elevated tHcy are influenced by a variety of factors, such as malnutrition, genetic factors, drug-induced (folic acid, vitamin B12, and vitamin B6 supplementation), disease (diabetes and kidney disease), and lifestyle factors (smoking and lack of physical activity). Third, the adjusted confounding factors varied for different studies. Finally, the studies on recurrent stroke all had a follow-up of <5 years; hence, the long-term effect of tHcy on recurrent stroke could not be analyzed.

Furthermore, several previously published meta-analysis about this topic had been published in the literature. We summarized the previously relevant meta-analysis and demonstrated them by a table (Table 2).

Table 2

Previously published studies relevant to plasma homocysteine levels and strokes

Study	Year	Studies included	Patients	Outcomes	Conclusion
Present manuscript	2022	24	Ischemic stroke, hemorrhagic stroke, and recurrent stroke	Hcy level and stroke correlation	Hcy level increases the risk of stroke, risk is closely related to the recurrence of stroke
Huang et al. [42]	2021	17	Acute ischemic stroke patients	Survival outcomes	Hcy level may serve as an independent predictor for unfavorable survival outcomes in AIS patients
Holmen et al. [43]	2021	5	Ischemic stroke	Correlation between Hcy level and ischemic stroke	A dose–response association between Hcy levels and ischemic stroke
Zhang et al. [44]	2020	13	Ischemic stroke subtypes only in Chinese	Ischemic stroke group had significantly higher levels of homocysteine than controls (SMD = 1.15, 95% CI = 0.85–1.45, P < 0.05)	Ischemic stroke patients and the TOAST of ischemic stroke patients in Chinese had significantly higher homocysteine levels than the controls
Wu et al. [45]	2020	10	Stroke and ischemic stroke	Hcy level was associated with increased risk of stroke (RR = 1.58, 95% CI 1.25–2.00, I ² = 39.5%) and IS (RR = 1.54, 95% CI 1.21–1.97, I ² = 36.4%) for the highest versus the lowest categories	Elevated Hcy level was associated with increased risk of stroke and IS
He et al. [6]	2014	9	Ischemic strokes, hemorrhagic stroke, and recurrent strokes	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). 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	Elevated Hcy levels are associated with an increased risk for ischemic strokes and recurrent strokes but had no distinct association with hemorrhagic strokes
Homocysteine Studies Collaboration [46]	2002	30	Heart disease and stroke (most in heart)	A 25% lower usual (corrected for regression dilution bias) homocysteine level (about 3 μmol/L [0.41 mg/L]) was associated with an 11% (OR, 0.89; 95% confidence interval [CI], 0.83–0.96) lower IHD risk and 19% (OR, 0.81; 95% CI, 0.69–0.95) lower stroke risk	Elevated homocysteine is at most a modest independent predictor of IHD and stroke risk in healthy populations

In conclusion, this study suggested that elevated tHcy increase the risk of stroke, including ischemic and hemorrhagic, and are closely associated with the recurrence of stroke. tHcy detection is recommended for the management of patients with stroke, effective measures must be taken to prevent and delay the progression of stroke.

Conflict of interest: Authors state no conflict of interest.
Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

[1] Tsao CW, Aday AW, Almarzooq ZI, Alonso A, Beaton AZ, Bittencourt MS, et al. Heart disease and stroke statistics-2022 update: a report from the American heart association. Circulation. 2022;145(8):e153–639.10.1161/CIR.0000000000001052Search in Google Scholar PubMed

[2] Wu YZ, Chen WW. Prevalence of stroke in China. Prev Treat Cardio-Cerebral-Vasc Dis. 2016;16(6):410–4.Search in Google Scholar

[3] Mudd SH, Finkelstein JD, Refsum H, Ueland PM, Malinow MR, Lentz SR, et al. Homocysteine and its disulfide derivatives: a suggested consensus terminology. Arterioscler Thromb Vasc Biol. 2000;20:1704–6.10.1161/01.ATV.20.7.1704Search in Google Scholar

[4] Wang L, Shen J, Chen CX, Chen ZB, Shen XJ, Song YJ, et al. Meta analysis of the correlation between blood homocysteine level and different subtypes of stroke. Chin J Gerontol. 2018;38(9):2052–5.Search in Google Scholar

[5] Liao Q, Gao J, Zhu L, Chen S, Zhong YZ, Jiang XL, et al. Relationship between hyperhomocysteinemia and the risk of stroke recurrence: a meta-analysis. Chin Nurs Res. 2020;34(20):3561–71.Search in Google Scholar

[6] He Y, Li Y, Chen Y, Feng L, Nie Z. Homocysteine level and risk of different stroke types: a meta-analysis of prospective observational studies. Nutr Metab Cardiovasc Dis. 2014;24(11):1158–65.10.1016/j.numecd.2014.05.011Search in Google Scholar PubMed

[7] Kumral E, Saruhan G, Aktert D, Orman M. Association of hyperhomocysteinemia with stroke recurrence after initial stroke. J Stroke Cerebrovasc Dis. 2016;25(8):2047–54.10.1016/j.jstrokecerebrovasdis.2016.05.008Search in Google Scholar PubMed

[8] Stang A. Critical evaluation of the Newcastle–Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25(9):603–5.10.1007/s10654-010-9491-zSearch in Google Scholar PubMed

[9] Davies HT, Crombie IK, Tavakoli M. When can odds ratios mislead? BMJ. 1998;316(7136):989–91.10.1136/bmj.316.7136.989Search in Google Scholar PubMed PubMed Central

[10] Verhoef P, Hennekens CH, Malinow MR, Kok FJ, Willett WC, Stampfer MJ. A prospective study of plasma homocyst(e)ine and risk of ischemic stroke. Stroke. 1994;25(10):1924–30.10.1161/01.STR.25.10.1924Search in Google Scholar

[11] Bostom AG, Rosenberg IH, Silbershatz H, Jacques PF, Selhub J, D'Agostino RB, et al. Nonfasting plasma total homocysteine levels and stroke incidence in elderly persons: the Framingham study. Ann Intern Med. 1999;131(5):352–5.10.7326/0003-4819-131-5-199909070-00006Search in Google Scholar PubMed

[12] Fallon UB, Elwood P, Ben-Shlomo Y, Ubbink JB, Greenwood R, Smith GD. Homocysteine and ischaemic stroke in men: the Caerphilly study. J Epidemiol Commun Health. 2001;55(2):91–6.10.1136/jech.55.2.91Search in Google Scholar PubMed PubMed Central

[13] Iso H, Moriyama Y, Sato S, Kitamura A, Tanigawa T, Yamagishi K, et al. Serum total homocysteine concentrations and risk of stroke and its subtypes in Japanese. Circulation. 2004;109(22):2766–72.10.1161/01.CIR.0000131942.77635.2DSearch in Google Scholar PubMed

[14] Sacco RL, Anand K, Lee HS, Boden-Albala B, Stabler S, Allen R, et al. Homocysteine and the risk of ischemic stroke in a triethnic cohort: the Northern Manhattan study. Stroke. 2004;35(10):2263–9.10.1161/01.STR.0000142374.33919.92Search in Google Scholar PubMed

[15] Virtanen JK, Voutilainen S, Happonen P, Alfthan G, Kaikkonen J, Mursu J, et al. Serum homocysteine, folate and risk of stroke: Kuopio ischaemic heart disease risk factor (KIHD) study. Eur J Cardiovasc Prev Rehabil. 2005;12(4):369–75.10.1097/01.hjr.0000160834.75466.b0Search in Google Scholar PubMed

[16] Cui R, Moriyama Y, Koike KA, Date C, Kikuchi S, Tamakoshi A, et al. Serum total homocysteine concentrations and risk of mortality from stroke and coronary heart disease in Japanese: the JACC study. Atherosclerosis. 2008;198(2):412–8.10.1016/j.atherosclerosis.2007.09.029Search in Google Scholar PubMed

[17] Sun Y, Chien KL, Hsu HC, Su TC, Chen MF, Lee YT. Use of serum homocysteine to predict stroke, coronary heart disease and death in ethnic Chinese. 12-year prospective cohort study. Circ J. 2009;73(8):1423–30.10.1253/circj.CJ-08-1077Search in Google Scholar

[18] Hultdin J, Van Guelpen B, Winkvist A, Hallmans G, Weinehall L, Stegmayr B, et al. Prospective study of first stroke in relation to plasma homocysteine and MTHFR 677C > T and 1298A > C genotypes and haplotypes – evidence for an association with hemorrhagic stroke. Clin Chem Lab Med. 2011;49(9):1555–62.10.1515/CCLM.2011.234Search in Google Scholar PubMed

[19] Han L, Wu Q, Wang C, Hao Y, Zhao J, Zhang L, et al. Homocysteine, ischemic stroke, and coronary heart disease in hypertensive patients: a population-based, prospective cohort study. Stroke. 2015;46(7):1777–86.10.1161/STROKEAHA.115.009111Search in Google Scholar PubMed

[20] Shi Z, Guan Y, Huo YR, Liu S, Zhang M, Lu H, et al. Elevated total homocysteine levels in acute ischemic stroke are associated with long-term mortality. Stroke. 2015;46(9):2419–25.10.1161/STROKEAHA.115.009136Search in Google Scholar PubMed PubMed Central

[21] Ma J, Chen Z, Chen S, Peng X, Liu S, Zhao D, et al. A prospective study on the association of plasma homocysteine level with stroke in hypertensive patients. Chin J Intern Med. 2015;54(4):296–301.Search in Google Scholar

[22] Feng Y, Kang K, Xue Q, Chen Y, Wang W, Cao J. Value of plasma homocysteine to predict stroke, cardiovascular diseases, and new-onset hypertension: a retrospective cohort study. Medicine (Baltimore). 2020;99(34):e21541.10.1097/MD.0000000000021541Search in Google Scholar PubMed PubMed Central

[23] Zhang ZY, Gu X, Tang Z, Guan SC, Liu HJ, Wu XG, et al. Homocysteine, hypertension, and risks of cardiovascular events and all-cause death in the Chinese elderly population: a prospective study. J Geriatr Cardiol. 2021;18(10):796–808.Search in Google Scholar

[24] Li N, Cai X, Zhu Q, Yao X, Lin M, Gan L, et al. Association between plasma homocysteine concentrations and the first ischemic stroke in hypertensive patients with obstructive sleep apnea: a 7-year retrospective cohort study from China. Dis Markers. 2021;2021:9953858.10.1155/2021/9953858Search in Google Scholar PubMed PubMed Central

[25] Shi Z, Liu S, Guan Y, Zhang M, Lu H, Yue W, et al. Changes in total homocysteine levels after acute stroke and recurrence of stroke. Sci Rep. 2018;8(1):6993.10.1038/s41598-018-25398-5Search in Google Scholar PubMed PubMed Central

[26] Bos MJ, van Goor ML, Koudstaal PJ, Dippel DW. Plasma homocysteine is a risk factor for recurrent vascular events in young patients with an ischaemic stroke or TIA. J Neurol. 2005;252(3):332–7.10.1007/s00415-005-0647-9Search in Google Scholar PubMed

[27] Zhang W, Sun K, Chen J, Liao Y, Qin Q, Ma A, et al. High plasma homocysteine levels contribute to the risk of stroke recurrence and all-cause mortality in a large prospective stroke population. Clin Sci (Lond). 2009;118(3):187–94.10.1042/CS20090142Search in Google Scholar PubMed

[28] Ji Y, Song B, Xu Y, Fang H, Wu J, Sun S, et al. Prognostic significance of homocysteine levels in acute ischemic stroke: a prospective cohort study. Curr Neurovasc Res. 2015;12(4):334–40.10.2174/1567202612666150807112205Search in Google Scholar PubMed

[29] Yue W, Wu H, Shi ZH, Zhang YJ, Wang H, Li X, et al. Relationships between plasma homocysteine level and both recurrence and mortality in patients with acute ischemic stroke. Chin J Neuromed. 2016;15(7):654–9.Search in Google Scholar

[30] Gao SX. Research on the relationship between homocysteine and death and disease recurrence in patients with acute ischemic stroke. Chin J Practical Med. 2017;44(20):77–80.Search in Google Scholar

[31] Lv KN, Zhao XM, Wang L, Hu ZW. Study on the relationship between hyperhomocysteinemia and risk of re-current cerebral infarction. J North Sichuan Med Coll. 2019;34(2):259–61.Search in Google Scholar

[32] Anniwaer J, Liu MZ, Xue KD, Maimaiti A, Xiamixiding A. Homocysteine might increase the risk of recurrence in patients presenting with primary cerebral infarction. Int J Neurosci. 2019;129(7):654–9.10.1080/00207454.2018.1517762Search in Google Scholar PubMed

[33] Zhou Z, Liang Y, Qu H, Zhao M, Guo F, Zhao C, et al. Plasma homocysteine concentrations and risk of intracerebral hemorrhage: a systematic review and meta-analysis. Sci Rep. 2018;8(1):2568.10.1038/s41598-018-21019-3Search in Google Scholar PubMed PubMed Central

[34] Mao X, Han L. The relationship of methylenetetrahydrofolate reductase gene C677T polymorphism and ischemic stroke in Chinese Han population. Ann Clin Lab Sci. 2018;48(2):242–7.Search in Google Scholar

[35] Djuric D, Jakovljevic V, Zivkovic V, Srejovic I. Homocysteine and homocysteine-related compounds: an overview of the roles in the pathology of the cardiovascular and nervous systems. Can J Physiol Pharmacol. 2018;96(10):991–1003.10.1139/cjpp-2018-0112Search in Google Scholar PubMed

[36] Shang J, Wang W, Feng J, Luo GG, Dang Y, Sun J, et al. Carotid plaque stiffness measured with supersonic shear imaging and its correlation with serum homocysteine level in ischemic stroke patients. Korean J Radiol. 2018;19(1):15–22.10.3348/kjr.2018.19.1.15Search in Google Scholar PubMed PubMed Central

[37] Duan J, Murohara T, Ikeda H, Sasaki K, Shintani S, Akita T, et al. Hyperhomocysteinemia impairs angiogenesis in response to hindlimb ischemia. Arterioscler Thromb Vasc Biol. 2000;20(12):2579–85.10.1161/01.ATV.20.12.2579Search in Google Scholar

[38] Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekowitz MD, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(7):2160–236.10.1161/STR.0000000000000024Search in Google Scholar PubMed

[39] Huo Y, Li J, Qin X, Huang Y, Wang X, Gottesman RF, et al. Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial. JAMA. 2015;313(13):1325–35.10.1001/jama.2015.2274Search in Google Scholar PubMed

[40] Qin X, Li J, Spence JD, Zhang Y, Li Y, Wang X, et al. Folic acid therapy reduces the first stroke risk associated with hypercholesterolemia among hypertensive patients. Stroke. 2016;47(11):2805–12.10.1161/STROKEAHA.116.014578Search in Google Scholar PubMed

[41] Qin X, Spence JD, Li J, Zhang Y, Li Y, Sun N, et al. Interaction of serum vitamin B12 and folate with MTHFR genotypes on risk of ischemic stroke. Neurology. 2020;94(11):e1126–36.10.1212/WNL.0000000000008932Search in Google Scholar PubMed PubMed Central

[42] Huang S, Cai J, Tian Y. The prognostic value of homocysteine in acute ischemic stroke patients: a systematic review and meta-analysis. Front Syst Neurosci. 2020;14:600582.10.3389/fnsys.2020.600582Search in Google Scholar PubMed PubMed Central

[43] Holmen M, Hvas AM, Arendt J. Hyperhomocysteinemia and ischemic stroke: a potential dose–response association – a systematic review and meta-analysis. TH Open. 2021;5(3):e420–37.10.1055/s-0041-1735978Search in Google Scholar PubMed PubMed Central

[44] Zhang T, Jiang Y, Zhang S, Tie T, Cheng Y, Su X, et al. The association between homocysteine and ischemic stroke subtypes in Chinese: a meta-analysis. Medicine (Baltimore). 2020;99(12):e19467.10.1097/MD.0000000000019467Search in Google Scholar PubMed PubMed Central

[45] Wu X, Zhou Q, Chen Q, Li Q, Guo C, Tian G, et al. Association of homocysteine level with risk of stroke: a dose–response meta-analysis of prospective cohort studies. Nutr Metab Cardiovasc Dis. 2020;30(11):1861–9.10.1016/j.numecd.2020.07.026Search in Google Scholar PubMed

[46] Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. 2002;288(16):2015–22.10.1001/jama.288.16.2015Search in Google Scholar PubMed

Received: 2022-08-06

Revised: 2022-10-14

Accepted: 2022-10-17

Published Online: 2022-11-08

This work is licensed under the Creative Commons Attribution 4.0 International License.

Articles in the same Issue

https://doi.org/10.1515/pteridines-2022-0044

Keywords for this article

homocysteine; stroke; ischemic stroke; hemorrhagic stroke; recurrent strokes; meta-analysis

Creative Commons

BY 4.0