Hyperhomocysteinemia and Ischemic Stroke: A Potential Dose-Response Association—A Systematic Review and Meta-analysis

Abstract

Background and Purpose Previous studies suggest an association between increased homocysteine (Hcy) and risk of ischemic stroke. Yet, it remains unknown whether a dose-response association exists between Hcy levels and risk of ischemic stroke.

Methods Systematic literature searches were performed in PubMed, Embase, Scopus, and Web of Science. Inclusion criteria were studies investigating ischemic stroke risk in an adult population with measured Hcy levels. We computed odds ratios (ORs) for a 5 µmol/L increase in Hcy levels using a random effects meta-analysis.

Results In total, 108 studies met the inclusion criteria of which 22 were rated as high-quality studies, and 20 studies included a dose-response analysis. Hcy levels were analyzed either as a continuous or categorical variable. The majority of the studies found an increased risk of ischemic stroke when comparing the highest-to-lowest Hcy strata. A graded association was observed over the Hcy strata, indicating a dose-response association, with the most apparent effect when Hcy levels exceeded approximately 15 µmol/L. No studies explored a potential nonlinear association between Hcy levels and ischemic stroke. Six studies were included in a meta-analysis, showing an OR of 1.43 (95% confidence interval [CI]: 1.28–1.61) per 5 µmol/L increase in Hcy levels.

Conclusion This review and meta-analysis indicate a dose-response association between Hcy levels and ischemic stroke. An evident increase in effect measures was observed when Hcy levels exceeded 15 µmol/L, indicating a nonlinear association between ischemic stroke and Hcy levels. This nonlinear association warrants further study.

This study is registered with clinical trial ( https://www.crd.york.ac.uk/prospero/ ; unique identifier: CRD42019130371).

Keywords

stroke/prevention - cerebrovascular disease - homocysteine - meta-analysis

Introduction

The comprehension that elevated homocysteine (Hcy) in plasma might predispose to arterial or venous thromboembolism emerged more than 40 years ago, when patients with homocysteinuria were observed to have a high risk of early vascular disease.[1] This led to extensive research regarding the role of Hcy in cardiovascular disease (CVD) and whether elevated Hcy is a modifiable risk factor.

Elevation of Hcy levels may be caused by several factors, including deficiency of vitamin B6, folate, and/or vitamin B12, due to insufficient intake or absorption, renal insufficiency, several drugs,[2] lifestyle factors, such as smoking and alcohol intake, or genetic factors.[3]

Among fasting individuals, normal Hcy levels commonly range from 5 to 15 µmol/L.[4] Animal studies have demonstrated that elevated Hcy levels leads to complex changes within the blood vessel wall, with increased oxidative stress, proinflammatory effects, and endothelial dysfunction, indicating that an association between increased Hcy and CVD is biologically plausible.[5] [6] [7] Several studies have investigated the potential association between elevated Hcy concentration and risk of CVD, including stroke, but results are inconsistent.[8] [9] [10]

The Norwegian Vitamin Trial indicated that treatment with folic acid and vitamin B combination therapy effectively lowered Hcy levels by 28%, but no effect was found on the incidence of ischemic stroke.[11] The Vitamin Intervention for Stroke Prevention trail demonstrated similar results, with no significant reduction in the risk of stroke among patients treated with B-vitamin combinations.[12] In contrast, the China Stroke Primary Prevention Trial reported a 24% risk reduction for ischemic stroke in the group that received folic acid treatment.[13] While, a Cochrane review from 2017 found a small reduction in risk of stroke in patients treated with B12, folate and B6 vitamins compared with patients receiving placebo.[14]

Systematic reviews of observational studies have reported a dose-response related association between Hcy levels and the risk of stroke, independent of other cardiovascular risk factors.[15] The most recent literature investigating the dose-response relationship between stroke and Hcy levels was performed in 2002; however, this review did not differentiate between ischemic stroke and hemorrhagic stroke.[15] Therefore, we performed a systematic review and meta-analysis to assess the dose-response association between Hcy levels and the risk of ischemic stroke.

Methods

The present systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.[16] The protocol was published in the Prospero database (ID: CRD42019130371).

Literature Search

Searches in PubMed, Embase, Scopus, and Web of Science were performed on May 8, 2020. Where possible, filters were applied to remove nonhuman studies, and non-English language publications. No limits were set with regard to publication year. Free-text and the Medical Subject Headings (MeSH) terms or Emtree-preferred terms were used. Search combinations included terms related to the following search categories: Hcy, thromboembolism, biomarker, and adult human population. The complete search combinations used in PubMed is provided hereinafter. Similar search combinations were used for searches in the remaining three databases.

PubMed

Search ((((((((“Homocysteine”[Mesh] OR “Hyperhomocysteinemia”[Mesh] OR homocyst* OR hyperhomocyst*))) AND ((“Embolism and Thrombosis”[Mesh] OR “Myocardial Infarction”[Mesh] OR “Acute Coronary Syndrome”[Mesh] OR “Brain Ischemia”[Mesh] OR “Stroke”[Mesh] OR “Deep vein thrombosis” OR “pulmonary embolism” OR “lung embolism” OR thrombosis OR embolism OR thromboembolism OR stroke OR “acute stroke” OR “brain infarction” OR “cerebral infarction” OR “brain ischemia” OR “cerebral ischemia” OR “ischemic stroke” OR “intracranial embolism” OR “intracranial thrombosis” OR apoplexy OR “cerebrovascular accident” OR “cerebral stroke” OR “myocardial infarction” OR “myocardial infarct” OR “heart infarct” OR “heart infarction” OR “acute coronary syndrome” OR “acute myocardial infarction” OR “brain embolism” OR “cardiovascular stroke” OR “heart attack” OR “acute myocardial infarct” OR “acute heart infarction”))) AND ((“Biomarkers”[Mesh] OR “Blood”[Mesh] OR blood OR serum OR plasma OR biomarker OR “biological marker” OR “blood level” OR “blood levels”))) AND ((“Humans”[Mesh] OR adult[MeSH Terms] OR adults[All Fields] OR adult[All Fields] OR patients[All Fields] OR patient[All Fields] OR humans[All Fields] OR human[All Fields]))) AND ((Danish[Language] OR Norwegian[Language] OR English[Language] OR swedish[Language])))) NOT ((comment[Publication Type] OR congress[Publication Type] OR letter[Publication Type] OR “Case Reports”[Publication Type])).

Initially, all thromboembolic events were included as outcome, as seen in our search combinations, resulting in a large number of eligible articles ([Fig. 1]). Therefore, our inclusion/exclusion criteria were revised after screening of abstracts to include only articles with ischemic stroke as outcome for this review. This choice was based on results found in the 2017 Cochrane review[14] which showed a potential association between Hcy and ischemic stroke in randomized trials of B-vitamin treatment.

Fig. 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRIMSA) flow diagram.[16]

Our inclusion criteria were studies investigating ischemic stroke events in patients with measured plasma Hcy providing original data on adult human populations. Both interventional and observational studies were included, including randomized trials, cohort, cross-sectional, and case-control studies. The accepted endpoint was acute ischemic stroke, including all subtypes. The exclusion criteria were as follows: nonoriginal literature, reviews, meta-analyses, guidelines, case studies, conference abstracts, and letters/editorials/comments without original data; missing information on Hcy concentration or studies including hyper-Hcy as a binary variable; endpoint of transient cerebral ischemia and arteriosclerotic lesions without sign of thrombosis, and silent brain infarction; and language other than English.

First, 100 abstracts were randomly selected and screened independently by the three authors for either exclusion or inclusion to full-text screening. Any disagreement was solved by consensus. Screening of the remaining abstracts was performed by MH. Similarly, 50 randomly selected articles proceeding to full text screening were read in full by all authors, and any disagreement was solved by consensus. Remaining papers were screened by MH for inclusion or exclusion, and in case of doubt, all three authors discussed the study in question.

Data Extraction and Quality Assessment

Data extraction from the included articles was performed by M.H. and verified by A.M.H. and J.F.H.A. Study quality was assessed by all three authors using the Study Quality Assessment Tools for Observational Cohort and Cross-Sectional studies and for Case-Control studies, National Heart, Lung, and Blood Institute, National Institute of Health, the United States.[17] Each study was rated good, fair or poor according to the estimated risk of bias. Disagreement between authors was solved by consensus.

Data Synthesis

We performed a meta-analysis of odds ratios (ORs) in which Hcy was included as a continuous linear variable.[18] [19] [20] [21] [22] [23] Hcy increments was standardized to 5 µmol/L. A random effects model was used to obtain a summary OR as a measure of the relative risk. Forest plots and funnel plots were used to visualize the data.

Results

In total, 108 original articles were included in the review. Of these, 22 articles rated good, 47 fair and 39 poor. Screening of abstracts and inclusion of articles are shown in [Fig. 1]. Articles rated good were grouped according to study design of which 18 were case-control studies and 4 were observational cohort studies, as presented in [Tables 1],[2],[3]. Only articles rated good are reported on and discussed in this article. Studies rated fair[24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] and poor[69] [70] [71] [72] [73] [74] [75] [76] [77] [78] [79] [80] [81] [82] [83] [84] [85] [86] [87] [88] [89] [90] [91] [92] [93] [94] [95] [96] [97] [98] [99] [100] [101] [102] [103] [104] are provided in [Table 4]. For the dose-response analysis, we included articles rated fair to supplement results in articles rated good ([Table 5]).

Table 1 Case-control studies investigating the association between ischemic stroke and homocysteine levels, n = 18

Study (year)	Study population Cases: n, mean age ± SD, %male Controls: n, mean age ± SD, %male	Hcy results (µmol/L) Timing of blood sampling[a]	Outcome and diagnostic criteria of ischemic stroke	Matched variables and adjusted covariates (Adj)
Campbell et al (2006)[110]	Cases: n = 252, mean age = 67 ± 8 years 73% male Controls: n = 544, mean age = 66 ± 8 years 73% male	Cases, median Hcy: 16.3 µmol/L (IQR: 13.3–20.0) Controls, median Hcy: 16.3 µmol/L (IQR: 13.3–19.2) Timing: at baseline; prior to outcome Mean follow-up till outcome: 3.9 years	Outcome: ischemic stroke Diagnostic criteria: CT scan within 3 weeks, autopsy	Matched: age (within 5 years), sex, treatment allocated (perindopril-based/ placebo, mono/dual therapy), region, most recent qualifying event at randomization Adj: matched variables, systolic blood pressure, total cholesterol, current smoking, diabetes mellitus, peripheral arterial disease, antihypertensive medication other than β-blockers, calcium channel blockers, diuretics
Cui et al (2008)[19]	Cases: n = 101, mean age = 68.7 years Male % = not stated Controls: n = 101, mean age = 67.7 Male % = not stated	Cases: 13.8 µmol/L Controls: 12.5 µmol/L Timing: prior to outcome (13–15 years)	Outcome: CVD, subclassified into ischemic stroke Diagnostic criteria: ICD9 codes 433–434, ICD10 code I63	Matched: sex, age, community, year of serum storage Adj: BMI, serum total and HDL-cholesterol, alcohol, smoking status, history of hypertension, diabetes
Eikelboom et al (2000)[23]	Cases: n = 219, mean age = 66.1 ± 12.4 years 64% male Controls: n = 205 60% male, mean age = 67.0 ± 11.8 years	Cases: 12.4 µmol/L (11.7–13.2) Controls: 10.5 µmol/L (10.0–11.0) Timing: within 7 days of outcome	Outcome: ischemic stroke Diagnostic criteria: CT scan within 3 weeks, autopsy	Matched: none Adj: age, sex, creatinine, red cell folate, serum folate, pyridoxine cobalamin, MTHFR genotype, smoking, hypertension, diabetes mellitus, hypercholesterolemia, previous vascular events
Fallon et al (2003)[21]	Study population: male smokers Cases: n = 212, mean age = 58.9 ± 5.2 years Controls: n = 212, mean age = 58.8 ± 5.3 years	Cases: 13.3 µmol/L (12.6–13.9) Controls: 12.6 µmol/L (12.0–13.2) Timing: prior to outcome	Outcome: ischemic stroke Diagnostic criteria: medical records, ICD9 codes 433–434 Register of causes of death	Matched: age (4-year range) Adj: all case/control pairs: systolic + diastolic blood pressures, total serum cholesterol, education, BMI, smoking: duration + cigarettes smoked daily + debut age, trial treatment group 120 case/control pairs: further adj. for serum folate, B6, alcohol
Haltmayer et al (2002)[20]	Study population: male patients with symptomatic PAD Cases: n = 50, mean age = 69.8 years (25–75th percentile, 61.7–73.8) Controls: n = 400, mean age = 66.6 years (25–75th percentile, 57.6–73.1)	Cases median Hcy: 18.6 µmol/L (25–75th percentile, 13.7–23.1) Controls: 15.1 µmol/L (25–75th percentile, 12.4–18.5) Timing: after outcome (5 months–21 years)	Outcome: ischemic stroke Diagnostic criteria: medical reports + additional CT scans	Matched: none Adj: age, BMI, hypertension, diabetes mellitus, current smoking, carotid stenosis >50%, total cholesterol, HDL-cholesterol, serum triglycerides
Hultdin et al (2011)[111]	Cases: n = 321 ischemic stroke n = 60 hemorrhagic stroke 55.8% male with ischemic stroke, mean age = 55.0 ± 8.1 years Controls: n = 788, 58.6% male, mean age = 55.0 ± 8.0 years	Cases: 12.8 µmol/L (±SD 5.6) Controls: 12.7 µmol/L (±SD 7.7) Timing: prior to outcome, average time to outcome >4 years	Outcome: first ever stroke, subclassified into ischemic and hemorrhagic stroke Diagnostic criteria: ICD-9 codes 430–438, CT, MRI scan, autopsy	Matched: age, sex Adj: BMI, hypertension
Iso et al (2004)[18]	Cases: n = 90, 61% male, mean age = 65.9 years Controls: n = 294, 61% male, mean age = 66.0 years	Cases: 9.8 µmol/L (9.1–10.4) Controls: 9.0 µmol/L (8.7–9.4) Timing: at inclusion, years prior to outcome	Outcome: Stroke (subclassification: hemorrhagic, lacunar, large-artery occlusive, embolic) Diagnostic criteria: stroke identified with CT, ICD9 diagnosis codes 430–438, self-reporting	Matched: sex, age, community, year of serum stored, fasting status Adj: hypertension status, BMI, current alcohol intake, cigarette smoking status, serum total cholesterol levels, log-transformed triglyceride levels, quartiles of CRP, serum glucose category
Kaplan et al (2008)[112]	Study population: Postmenopausal women Cases: n = 972, mean age = not stated Controls: n = 972, mean age = not stated	Cases, median Hcy: 8.5 µmol/L (IQR: 3.7) Controls, median Hcy: 8.2 µmol/L (25–75th percentile, 6.6–10.2) Timing: prior to outcome	Outcome: first ever ischemic stroke Diagnostic criteria: self-reporting, reports by family, medical records	Matched: age, race/ethnicity Adj: aspirin use, BMI, diabetes, systolic blood pressure, smoking, high cholesterol requiring medication, antihypertensive medication, fasting glucose, LDL, HDL
Khan et al (2008)[109]	Study population: Afro-American population of the United Kingdom Total group: n = 457, 56% male, mean age = 65.4 ± 12.2 years Cases (ischemic stroke group): n = 408, Male % = not stated, mean age = not stated Controls (nonischemic stroke group): n = 179, 62.0% male, mean age = 65.4 ± 7.4 years	Cases: 14.3 µmol/L (±SD 8.8) Controls: 11.8 µmol/L (±SD 5.7) Timing: after outcome	Outcome: stroke, including subclassification Diagnostic criteria: CT or MRI scan. Subtyping of stroke using TOAST criteria	Matched: age and sex Adj: age, sex, hypertension, diabetes, hypercholesterolemia, smoking, B12, folate, eGFR
Li et al (2003)[115]	Cases: n = 1,832 stroke patients; cerebral thrombosis: n = 807, lacunar infarction: n = 513, intracerebral hemorrhage: n = 503, 63.5% male, mean age = 60.3 ± 9.4 years Controls: n = 1,832, 57.4% male, mean age = 59.6 ± 8.8 years	Cases, median Hcy: cerebral thrombosis: 14.7 µmol/L (range: 207.8) Lacunar infarct: 14.8 µmol/L (range: 115.4) Controls, median Hcy: 12.8 µmol/L (range: 123.2) Timing: 6 weeks after outcome	Outcome: Stroke (subclassification: cerebral thrombosis, lacunar infarction, cerebral hemorrhage) Diagnostic criteria: CT/MRI scan, ICD 9 diagnosis codes 430–438	Matched: age (5-year range), community of residence Adj: age, sex, blood pressure, BMI, cigarette smoking, glucose, total cholesterol, triglycerides, glomerular filtration rate
Liang et al (2017)[114]	Study population: 377 patients with essential hypertension Cases: n = 114, 60% male, mean age = 66.59 ± 11.15 years Hypertensive controls: n = 263, 64.6% male, mean age = 65.0 ± 11.29 years Normotensive controls: n = 109, 66.1% male, mean age = 66.13 ± 10.62 years	Cases: 19.11 µmol/L (±SD 9.70) Hypertensive controls: 13.24 µmol/L (±SD = 5.96) Normotensive controls: 12.78 µmol/L (±SD = 8.00) Timing: at admission for outcome	Outcome: ischemic stroke Diagnosis criteria: MRI scan within 24 hours	Matched: age and sex Adj: age, sex, systolic + diastolic blood pressure, cigarette smoking
Loffredo et al (2005)[22]	Study population: 163 patients with nonvalvular atrial fibrillation Cases: n = 40, 40% male, mean age = 74.8 ± 8.8 years Controls: n = 123, 49.6% male, mean age = 69.2 ± 11.5 years	Cases: 18.1 µmol/L (±SD = 9.0) Controls: 15.4 µmol/L (±SD = 9.3) Timing: at inclusion, after outcome	Outcome: ischemic stroke, occurring >3 months prior to inclusion Diagnosis criteria: CT scan, medical records	Matched: none Adj: sex, hypertension, diabetes mellitus, dyslipidemia, smoking habits, prior coronary heart disease, left ventricular ejection fraction, left atrium diameter, oral anticoagulants, aspirin, predictors of tHcy, fibrinogen levels
Rueda-Clausen et al (2012)[113]	Cases: n = 238, 55% male, mean age = 66.5 years (IQR: 58.1–75) Controls: n = 238, 55% male, mean age = 70.8 years (IQR: 61–77)	Cases, median Hcy: 10.01 µmol/L (IQR: 7.79–13.2) Controls, median Hcy: 8.48 µmol/L (IQR: 7.28–10.91) Timing: within 96 hours of onset of stroke symptoms	Outcome: ischemic stroke Diagnostic criteria: CT scan within 96 hours	Matched: age, sex, region of residence Adj: age, sex, pack year of smoking, plasma creatinine levels, waist to hip ratio, hypertension, diabetes mellitus, use of statins, socioeconomic status
Shimizu et al (2002)[106]	Cases: n = 75, 52% male, mean age =75 years Controls: n = 248, 62% male, mean age = 71 years	Cases: 13.0 µmol/L Controls: 11.8 µmol/L Timing: 3 months–30 years (mean: 7.6 years) after outcome	Outcome: ischemic stroke (subclassification: lacunar, artherothrombotic, cardioembolic, undetermined) Diagnostic criteria: CT/MRI scan	Matched: age (2 years range), sex Adj: age, sex, hypertension, serum creatinine, total protein, folate, B12
Tan et al (2002)[108]	Study population: young adults (20–50 years) Cases: n = 109, 71.6% male, mean age = 43.8 ± 5.87 years Controls: n = 88, 71.6% male, mean age = 43.1 ± 6.60 years	Cases: 13.7 µmol/L (12.7–14.9) Controls: 10.8 µmol/L (9.9–11.8) Timing: within 5 days of outcome	Outcome: first ever ischemic stroke Diagnostic criteria: CT/MRI scan within 1 week	Matched: age, sex Adj: age, sex, diabetes mellitus, hypertension, hyperlipidemia, B12
Tanne et al (2003)[105]	Study population: 3,090 patients with preexisting chronic coronary artery disease Cases: n = 160, 95% male, mean age = 61.2 ± 6.3 years Controls: n = 160, 95% male, mean age =61.3 ± 6.4 years	Cases, median Hcy: 16.4 µmol/L (IQR: 12.7–14.3) Controls, median Hcy: 14.3 µmol/L (IQR: 12.0–17.8) Timing: prior to outcome	Outcome: Ischemic stroke, including subclassifications Diagnostic criteria: CT scan. Subtyping using TOAST criteria	Matched: age, sex, benzafibrate/placebo study medication (benzafibrate/placebo) Adj: Age, sex, BIP study medication, current smoking, diabetes mellitus, hypertension, previous myocardial infarction
Tascilar et al (2009)[107]	Cases: large-vessel atherosclerotic stroke: n = 103, 68% male, mean age = 61.19 ± 14.20 years Cardioembolic stroke: n = 37, 45.9% male, mean age = 73.35 ± 10.72 years Controls: n = 37, 37.8% male, mean age = 53 ± 7.45 years	Cases: large-vessel atherosclerotic stroke: 13.94 µmol/L (±SD = 6.56) Cardioembolic stroke: 14.96 µmol/L (±SD = 5.94) Controls: 10.98 µmol/L (±SD = 2.91) Timing: within 24 hours of outcome	Outcome: large-vessel atherosclerotic stroke + cardioembolic stroke Diagnostic criteria: CT/MRI scan	Matched: none Adj: sex, smoking, hypertension, diabetes mellitus, hyperlipidemia
Verhoef et al (1994)[9]	Patients: n = 109, mean age = 61.9 ± 9.1 years Controls: n = 427, mean age = 59.2 ± 8.9 years	Cases: 11.1 µmol/L (±SD = 4.0) Controls: 10.6 µmol/L (±SD 3.4) Timing: at inclusion, follow-up 5 years, outcome within these 5 years	Outcome: ischemic stroke Diagnostic criteria: medical reports, confirmed by CT scan, autopsy	Matched: age, smoking habits Adj: age, smoking habits, diabetes, hypertension, Queteet's index, aspirin assignment, total cholesterol-to-HDL cholesterol ratio, time since the last meal before the blood was drawn

Abbreviations: Adj, adjusted; BMI, body mass index; CRP, C-reactive protein; CT, computed tomography; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; Hcy, homocysteine; HDL, high density lipoprotein; ICD, International Classification of Diseases; IQR, interquartile range; LDL, low density lipoprotein; MRI; magnetic resonance imaging; MTHFR, methylenetetrahydrofolate reductase; PAD, peripheral arterial disease; SD, standard deviation; TOAST, Trial of Org 10172 in Acute Stroke Treatment.

Note: Hcy levels is indicated as mean (95% confidence interval) unless other otherwise specified. Age is indicated as mean ± standard deviation unless other otherwise specified.

^a Timing of blood sampling refers to time of blood sampling used to determinate Hcy concentration in subjects, indicating if blood sampling occurred prior to outcome or after outcome.

Table 2 Summary of results reported in studies analyzing dose-response relationship between ischemic stroke and homocysteine, n = 20

Study (year)	Outcome	Stratum 1 (µmol/L), effect measure (95% CI)	Stratum 2 (µmol/L), effect measure (95% CI)	Stratum 3 (µmol/L), effect measure (95% CI)	Stratum 4 (µmol/L), effect measure (95% CI)	Stratum 5 (µmol/L), effect measure (95% CI)	Increments, effect measure (95% CI)
Bostom et al (1999)[118]	Nonhemorrhagic stroke	13–9.25 Ref.	9.26–11.43 RR = 1.22 (0.73–2.01)	11.44–14.23 1.31 (0.79–2.16)	14.24–219.84 1.79 (1.11–2.89)
Bostom et al (1999)[118]	Atherothrombotic brain infarction	13–9.25 Ref.	9.26–11.43 RR = 1.30 (0.68–2.49)	11.44–14.23 1.82 (0.99–3-36)	14.24–219.84 1.90 (1.02–3.51)
Cui et al (2008)[19]	Ischemic stroke	<10.5 Ref.	10.5–12.4 OR = 1.83 (0.54–6.28)	12.5–15.2 1.85 (0.57–5.98)	≥15.3 4.35 (1.12–16.9)		Per 5 µmol/L OR = 1.49 (1.01–2.18)
Eikelboom et al (2000)[23]	Ischemic stroke						Per 5 µmol/L OR = 2.7 (1.4–5.1)
Fallon[a] et al (2003)[21]	Ischemic stroke	3.1–10.5 Ref.	10.6–12.6 OR = 1.7 (0.9–3.1)	12.7–15.4 1.9 (1.1–3.2)	15.4–86.2 2.1 (1.1–3.9)
Fallon[b] et al (2003)[21]	Ischemic stroke	3.1–10.5 Ref.	10.6–12.6 OR = 1.2 (0.6–2.4)	12.7–15.4 1.9 (1.0–3.6)	15.4–86.2 2.0 (1.0–4.0)		Per 4.7 µmol/L OR = 1.4 (1.1–1.7)
Haltmayer et al (2002)[20]	Ischemic stroke						Per 5.0 µmol/L OR = 1.37 (1.13–1.67)
Hultdin et al (2011)[111]	Ischemic stroke	Ref. Ref.	Men:10.3 Women: 9.5 OR = 0.99 (0.63–1.54)	Men: 12.6 Women: 11.7 1.08 (0.70, 1.69)	Men: 15.3 Women: 14.3 0.86 (0.54–1.37)
Iso et al (2004)[18]	Ischemic stroke	4.1–7.0 Ref.	7.0–8.7 OR = 1.36 (0.60–3.09)	8.7–11.0 1.45 (0.60–3.49)	11.0–47.3 3.89 (1.60–9.46)		Per 5 µmol/L OR = 1.52 (1.07–2.14)
Kaplan et al (2008)[112]	First ever ischemic stroke	<6.6 Ref.	– OR = 1.15 (0.86–1.52)	– 1.23 (0.93–1.64)	>10.4 1.26 (0.95–1.68)
Khan et al (2008)[109]	Ischemic stroke						Per 1 µmol/L increase in log Hcy: OR = 4.02 (2.13–7.57)
Liang et al (2017)[114]	Ischemic stroke						Per SD increase in log Hcy: OR = 1.62 (1.17–2.25)
Loffredo et al (2005)[22]	Ischemic stroke	4.6–7.5 Ref.	9.7–14.1 OR = 0.75 (0.31–1.82)	14.3–18.6 1.30 (0.55–3.07)	18.7–67.1 2.73 (1.23–6.08)		Per 1 µmol/L OR = 1.056 (1.00–1.12)
Petri et al (1996)[117]	Ischemic stroke						Per 1 unit in log Hcy: OR = 2.44 (1.04–5.75)
Rueda-Clausen et al (2012)[113]	Ischemic stroke	≤12.69 Ref.	>12.69 OR = 8.97 (4.07–19.75)
Shi et al (2018)[116]	Ischemic stroke	≤9.65 Ref.	9.65 ≤ 11.9 HR = 0.77 (0.42–1.40)	11.9 ≤ 15.5 1.52 (0.89–2.62)	>15.5 1.76 (1.11–3.08)
Shimizu et al (2002)[106]	Ischemic stroke	<10.4 Ref.	10.4–13.6 OR = 2.0 (0.9–4.4)	≥13.6 4.0 (1.8–8.9)
Tan et al (2002)[108]	First ever ischemic stroke	<9.6 Ref.	9.6–12.0 OR = 0.94	12.1–14.95 3.2	>14.95 4.3 (1.5–12.6)		Per 1 µmol/L increase in log Hcy: OR = 5.17 (1.96–13.63)
Tanne et al (2003)[105]	Ischemic stroke	<11.4 Ref.	11.4–13.2 OR = 1.48 (0.44–5.46)	13.3–17.4 2.11 (0.58–8.75),	>17.4 4.62 (1.32–18.86)		Per 1 µmol/L increase in ln Hcy: OR = 3.41 (1.08–12.30)
Tascilar et al (2009)[107]	Large-vessel atherosclerotic stroke	4.00–9.20 Ref.	9.21–12.40 OR = 0.813 (0.286–2.310)	12.70–15.80 1.285 (0.406–4.067)	15.90–42.80 2.449 (0.660–9.095)
Tascilar et al (2009)[107]	Cardio-embolic stroke	4.00–9.20 Ref.	9.21–12.40 OR = 0.805 (0.191–3.392)	12.70–15.80 1.929 (0.471–7.902)	15.90–42.80 5.745 (1.271–25.959)
Verhoef et al (1994)[9]	Ischemic stroke	≤12.7 Ref.	>12.7 OR = 1.2 (0.7 - 2.0)
Zee et al (2007)[119]	Ischemic stroke	<8.47 Ref.	8.48–9.97 HR = 1.02 (0.63–1.64)	9.98–11.55 1.24 (0.79–1.96)	11.56–14.04 1.01 (0.63–1.62)	>14.05 1.27 (0.80–2.00)

Abbreviations: CI, confidence interval; Hcy, homocysteine; HR, hazard ratio; OR, odds ratio; Ref., reference value; RR, risk ratio; SD, standard deviation.

Notes: numbers in parentheses after RR/OR/HR are 95% CI unless otherwise specified.

^a Results from model A in Fallon et al: 201 matched case-control pairs.

^b Results from model C in Fallon et al: 120 cases, 310 controls, unmatched.

Table 3 Cohort studies investigating the association between ischemic stroke and homocysteine levels, n = 4

Study (year)	Study population: n, % male, mean age Follow-up time	Hcy-results (µmol/L) Timing of blood sampling[a]	Outcome and diagnostic criteria of ischemic stroke	Adjusted covariates
Bostom et al (1999)[118]	Study population: elderly patients, n = 1947, 40.5%male, mean age = 70 ± 7 years Follow-up time: mean = 9.9 years	Mean Hcy: 12.65 ± 7.19 µmol/L Timing: at study inclusion, prior to outcome	Outcome: total stroke, no-hemorrhagic stroke, atherothrombotic brain infarctions Diagnostic criteria: CT scan	Age, sex, diabetes, cigarette smoking, systolic blood pressure, prior coronary heart disease, prior atrial fibrillation
Shi et al (2018)[116]	Study population: acute stroke patients Ischemic stroke: n = 2,587, 70.0% male, mean age = 60.7 ± 10.5 years Follow-up time: median 18 months	Hcy: within 3 days of ischemic stroke: 14.4 ± 10.3 µmol/L 3 months after ischemic stroke: 14.3 ± 10.0 µmol/L Timing: within 24 hours of outcome, and again three months after	Outcome: recurrence of ischemic stroke, including subclassification Diagnostic criteria: CT scan. Subtyping using TOAST criteria	Age, sex, smoking status, low-density lipoprotein cholesterol level, CRP level, apolipoprotein B/Apolipoprotein AI ratio, presence of hypertension, type-2 diabetes mellitus, coronary artery disease, obesity
Petri et al (1996)[117]	Study population: systemic lupus erythematosus patients Cases: n = 29, 14%male, mean age = 38.6 ± 15.2 years Controls: n = 308, 7.1% male, mean age = 34.5 ± 11.3 years Follow-up time: 1,619 person-years (mean 4.8 ± 1.7 years)	Cases: 10.26 ± 1.91 µmol/L Controls: 7.41 ± 1.88 µmol/L Timing: at inclusion, prior to outcome	Outcome: stroke, arterial or venous thrombotic events Diagnostic criteria of ischemic stroke: CT/MRI scan	Age, sex, race, obesity, hypercholesterolemia, hypertension, diabetes, renal insufficiency, lupus anticoagulant
Zee et al (2007)[119]	Study population: healthy white women: n = 24,968 Mean age stratified for MTHFR genotype (CC, CT, TT): CC = 54.7 ± 7.1 years; CT = 54.7 ± 7.1 years; TT = 54.7 ± 7.2 years Follow-up time: mean follow-up of 9.9 ± 1.3 years, 246, 852 person-years	Hcy: stratified for MTHFR genotype (CC, CT, TT): 11.1 ± 4.3 µmol/L, 11.4 ± 4.9 µmol/L, 12.5 ± 6.1 µmol/L Timing: at inclusion, prior to outcome	Outcome: ischemic stroke Diagnostic criteria: medical records, the National Death Index, autopsy reports, death certificates, reports from family	Age, smoking status, systolic blood pressure, total cholesterol, HDL cholesterol, diabetes mellitus, hormone use

Abbreviations: CRP, C-reactive protein; CT, computed tomography; CVD, cardiovascular disease; Hcy, homocysteine; HDL, high density lipoprotein; MRI; magnetic resonance imaging; MTHFR, methylenetetrahydrofolate reductase; TOAST, Trial of Org 10172 in Acute Stroke Treatment.

Note: Hcy levels are indicated as mean ± standard deviation unless other otherwise specified. Age is indicated as mean ± standard deviation unless other otherwise specified.

^a Timing of blood sampling, refers to time of blood sampling used to determinate Hcy concentration in subjects, indicating if blood sampling occurred prior to outcome or after outcome.

Table 4 Rating of individual studies that did not include a dose-response analysis rated fair or poor

Study (year) Rated fair	Study (year) Rated poor
Case-control studies	Case-control studies
Bosco et al (2006)[25]	Al-Allawi et al (2009)[71]
Kelly et al (2004)[31]	Alkali et al (2006)[131]
Kim et al (2011)[32]	Araki et al (1989)[72]
Kim et al (2011)[33]	Fekih-Mrissa et al (2013)[80]
Kristensen et al (1999)[34]	Ma et al (2017)[42]
Lee et al (2008)[36]	Sun et al (2005)[95]
Li et al (2018)[38]	Tas et al (2005)[96]
Lu et al (2018)[40]	Yi et al (2013)[101]
Luo et al (2017)[41]	Yingdong et al (2002)[102]
Ma et al (2011)[43]	Cross-sectional studies
Mao and Han (2018)[44]	Adunsky et al (2000)[69]
Meiklejohn et al (2001)[45]	Ben-Salem et al (2010)[73]
Modi et al (2005)[47]	Brattström et al (1992)[74]
Moe et al (2008)[48]	Cao et al (2019) [128]
Mojiminiyi et al (2008)[49]	Celikbilek et al (2014)[75]
Pezzini et al (2002)[52]	Cingozbay et al (2002)[76]
Rahman et al (2013)[54]	Coull et al (1990)[77]
Tantirittisak et al (2007)[55]	El Kossi and Zakhary (2000)[78]
Vayá et al (2011)[57]	Fatima et al (2012)[79]
Yang et al (2004)[62]	Karakurum Goksel et al (2007)[81]
Yang et al (2016)[63]	Han et al (2002)[82]
Zhang et al (2014)[66]	Karabulut et al (2017)[83]
Zhang et al (2019)[67]	Kokocińska et al (2005)[84]
Cohort studies	Li et al (2004)[85]
Press et al (1999)[53]	Liu et al (2005)[86]
Cross-sectional studies	Moghaddasi et al (2010)[87]
Dai et al (2020)[129]	Mykhalojko and Mykhalojko (2017)[88]
Haapaniemi et al (2007)[27]	Narang et al (2009)[89]
Kara et al (2009)[29]	Omrani et al (2011)[90]
Kucukarabaci et al (2008)[35]	Peng et al (2001)[91]
Lehmann et al (2015)[37]	Sawuła et al 2009[92]
Lindgren et al (1995)[39]	Sun et al (2009)[94]
Mejia et al (2011)[46]	Sönmezler et al (2013)[93]
Ustundag et al (2010)[56]	Unal et al (2013)[97]
Wei et al (2019)[130]	Urbańska et al (2006)[98]
Xia et al (2014)[60]	Wei et al (2018)[99]
Yao et al (2017)[64]	Wu et al (2017)[100]
Zhu et al (2013)[68]	Zhang et al (2014)[103]
	Zhou et al (2005)[104]

Table 5 Summary of results reported in studies rated fair analyzing dose-response relationship between ischemic stroke and homocysteine

Study (year)	Outcome	Stratum 1 (µmol/L), effect measure (95% CI)	Stratum 2 (µmol/L), effect measure (95% CI)	Stratum 3 (µmol/L), effect measure (95% CI)	Stratum 4 (µmol/L), effect measure (95% CI)	Increments, effect measure (95% CI)
Case-control studies
Atanassova et al (2007)[24]	Ischemic stroke	–	–	–	–	Per 1 µmol/L OR = 1.22 (1.03–1.44)
Delport et al (1997)[26]	Ischemic stroke	>10.53 Ref.	<10.53 OR = 3.7 (0.8–16.7)	–	–	–
Hassan et al (2004)[28]	Lacunar infarction	>10.3 Ref.	10.3–13.0 OR = 1.42 (0.70–2.89)	13.1–15.9 2.02 (1.37–2.99)	>15.9 2.06 (1.53–2.78)	–
Ma (2017)[a] [42]	Ischemic stroke	4.29–10.7 Additive model: OR = 0.43 (0.25–0.75) Ressicive model: OR = 0.09 (0.01–0.79) Dominant model: OR = 0.43 (0.23–0.82)	10.74–13.71 1.15 (0.69–1.92) 2.61 (0.74–9.18) 0.97 (0.51–1.84)	13.73–53.99 0.69 (0.42–1.14) 0.84 (0.21–3.29) 0.62 (0.35–1.11)	–	–
Parnetti et al (2004)[50]	Ischemic stroke	–	–	–	–	Per 1 µmol/L OR = 1.425 (1.300–1.562)
Perini et al (2005)[51]	Ischemic stroke	0–10 Ref.	10.1–13.2 OR = 2.1 (p < 0.001)	13.3–18.6 2.8 (p < 0.001)	>18.6 6.74 (3.78–12.02)	–
Perini et al (2005)[51]	Small artery stroke	0–10 Ref.	10.1–13.2 OR = 3.9 (1.6–8.2)	13.3–18.6 5.9 (2.6–14.4)	>18.6 16.4 (6.9–44.3)	–
Perini et al (2005)[51]	Large artery stroke	0–10 Ref.	10.1–13.2 OR = 1.5 (0.8–2.6)	13.3–18.6 2.7 (1.4–4.7)	>18.6 4.9 (2.4–9.8)	–
Perini et al (2005)[51]	Cardioembolic stroke	0–10 Ref.	10.1–13.2 OR = 1.6 (0.7–3.4)	13.3–18.6 3.0 (1.3–6.4)	>18.6 7.1 (3.6–22.1)	–
Wang et al (2015)[58]	Ischemic stroke	<15 Ref.	≥15 OR = 0.99 (0.64–1.51)	–	–	Per 5 µmol/L OR = 1.15 (1.01–1.28)
Yadav et al (2017)[61]	Ischemic stroke	<12 Ref.	≥12 OR = 0.37 (0.16–0.83)	–	–	–
Yoo et al (1998)[65]	Ischemic stroke	<15.5 Ref.	≥15.5 OR = 1.70 (1.48–1.95)	–	–	–
Cross-sectional studies
Kario et al (2001)[30]	Ischemic stroke	–	–	–	–	Per 1 SD increase OR = 2.16 (1.30–3.59)
Wang et al (2014)[59]	Ischemic stroke	<15 Ref.	15–30 OR = 0.80 (0.59–1.074)	>30 OR = 0.91 (0.49–1.67)	–	Per 5 µmol/L OR = 0.99 (0.92–1.06)

Abbreviations: CI, confidence interval; OR, odds ratio; SD, standard deviation.

Note: numbers in parentheses after OR are 95% confidence intervals unless other otherwise specified.

^a Ma et al divided participants in regard to their EPHX2 G860A genotype into grouping of the Additive, Ressicive and Dominant genotype model.

Case-Control Studies

Of the 18 case-control articles rated as good, seven studies subclassified ischemic stroke[18] [105] [106] [107] [108] [109]; 1 reported CVD with subanalyses for ischemic stroke[19] and 10 studies performed no subclassification of ischemic stroke.[9] [20] [21] [22] [23] [110] [111] [112] [113] [114]

The timing of blood sampling for measurement of Hcy levels varied among studies. Eight studies performed blood sampling prior to outcome[9] [18] [19] [21] [105] [110] [111] [112]; 10 studies performed blood sampling after outcome,[20] [22] [23] [106] [107] [108] [109] [113] [114] [115] of which four studies collected blood within 7 days of outcome,[23] [108] [113] [114] and 2 studies within 24 hours of outcome.[107] [116]

Studies with Effect Measures Based on Homocysteine Strata

Eleven studies stratified Hcy levels into several strata, estimating the risk of ischemic stroke in the lowest stratum compared with the higher strata ([Table 2]).[18] [19] [21] [22] [23] [105] [106] [107] [108] [111] [112] Nine out of 11 studies found an increased risk of ischemic stroke when comparing patients in the highest versus lowest Hcy level strata.[18] [19] [21] [22] [23] [105] [106] [107] [108] Two studies found no association between risk of ischemic stroke and Hcy level[111] [112] and one study reported an association for cardioembolic stroke, but not with large-vessel atherosclerotic stroke.[107] Two studies estimated effect measures using a dichotomous Hcy; one study found an association,[113] whereas one did not.[9]

Studies with Effect Measures Based Homocysteine Increments

Ten studies included Hcy as a continuous variable and presented effect measures based on various increments of Hcy ([Table 2]).[18] [19] [20] [21] [22] [23] [105] [108] [109] [114] All studies found an association between increasing Hcy levels and odds of ischemic stroke, despite variations in the Hcy level increments that were employed.

Six studies included analysis of ischemic stroke subclasses.[23] [105] [106] [107] [108] [109] Among these, four studies showed an association between small-vessel disease and/or large-vessel disease,[23] [106] [108] [109] and three studies demonstrated an association with cardioembolic stroke.[105] [107] [109]

Two studies did not include effect measures illustrating the dose-response association between ischemic stroke and Hcy levels.[110] [115]

Overall, in studies comparing Hcy strata, effect measures were clearly elevated when Hcy level reached 15 µmol/L and above ([Table 2]).

Cohort Studies

Four cohort studies were rated as good, ([Table 3]).[116] [117] [118] [119] Mean follow-up time ranged from 18 months to 9.9 years. Two studies included patients with CVD, with subanalyses for ischemic stroke.[117] [119] Zee et al did not find an association when comparing quintiles of Hcy levels in the population,[119] whereas Petri et al found increased risk of ischemic stroke with increasing Hcy levels.[117] Bostom et al included elderly patients with stroke and found an association for both nonhemorrhagic stroke and atherothrombotic brain infarction, when comparing the highest quartile of Hcy to the lowest quartile.[118] Shi et al investigated recurrence of ischemic stroke as outcome, with enrolment at admission for first ever stroke. Blood sampling was performed at 3 days and 3 months after enrollment. An association between the risk of recurrent ischemic stroke (within 12–36 months) and Hcy levels was found, when comparing the highest and lowest Hcy quartiles in blood samples performed 3 months after the enrollment.[116]

Meta-analysis of Dose-Response Association

Eleven studies included Hcy as a continuous variable of which six were included in the meta-analysis.[18] [19] [20] [21] [22] [23] We normalized ORs to increments of 5 µmol/L in Hcy.[21] [22] The remaining five studies performed log transformation of Hcy levels prior to statistical analysis and were therefore not included in the meta-analysis ([Table 2]).[106] [108] [109] [114] [117] The studies included in the meta-analysis reported similar results and included similar numbers of patients. All adjusted for age, sex, main CVD risk factors (diabetes, hypertension, hypercholesterolemia, smoking, and body mass index [BMI]), with an exception of Eikelboom et al that did not adjust for BMI. Eikelboom et al was the only study that adjusted for renal insufficiency ([Tables 1] and [3]).[23] We performed a random effect analysis, resulting in an OR of 1.43 (95% confidence interval [CI]: 1.28–1.61; I ² = 0.0%, p = 0.492; [Fig. 2]). A funnel plot for the meta-analysis is provided in [Fig. 3], as the resulting funnel plot was severely asymmetric.

Fig. 2 Forest plot of risk of ischemic stroke per 5 µmol/L increase in plasma homocysteine. CI, confidence interval; OR, odds ratio.

Fig. 3 Funnel plot of studies included in meta-analysis investigating the risk of ischemic stroke per 5 µmol/L increase in homocysteine.

Results reported in studies rated fair and further supported the observations reported in studies rated good ([Table 5]).

Discussion

The present study indicates a dose-response association between Hcy levels and the risk of ischemic stroke. It was apparent that risk estimates reported in studies were notably higher when reaching Hcy levels above 15 µmol/L, indicating a possible nonlinear association between Hcy and ischemic stroke. Both studies rated good and fair supported this observation.

Studies have shown that Hcy levels increase in patients within 1-week poststroke.[27] [39] [45] This could explain some of the differences observed between cases and controls in the case-control studies where blood sampling was performed in cases during hospitalization for stroke.[27] [74] Moreover, Hcy levels have been shown to increase in critically ill patients.[120] In this review, no difference in means was observed when comparing Hcy levels in blood samples obtained during the acute phases[23] [107] [108] [114] [116] and convalescence phases of ischemic stroke[20] [22] [106] [109]; but based on the aforementioned previous studies, timing of blood sampling should be considered when evaluating Hcy as an exposure.

Five studies showed an association between small- and large-vessel diseases when subclassifying stroke using the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria ([Tables 1] and [3]).[23] [106] [108] [109] [116] This finding indicates that the effect of Hcy could depend on the underlying etiologically of ischemic stroke. Large randomized controlled trails investigating the effect of Hcy-lowering B-vitamin treatment have not demonstrated an effect on vascular outcomes or stroke.[11] [12] [121] Notably, reevaluation of data suggests that the effect of Hcy-lowering treatment could vary between outcomes, with a more beneficial effect on stroke than other CVD outcomes.[14] [122] Subclassifying stroke further could help clarifying which etiologies of stroke are affected by Hcy, and which patients could potentially benefit from Hcy-lowering treatment. As such, the clinical relevance of assessing Hcy in stroke patients or screening for hyperhomocysteinemia to prevent stroke remains undetermined. Taken together with the conflicting results on the effect of Hcy-lowering vitamin treatment, this may also explain why measuring plasma Hcy is not recommended in most clinical guidelines on ischemic stroke.[11] [12] [13] [14]

The most recent review of the literature found a 59% increased risk of stroke when Hcy increased 5 µmol/L.[15] We report a similar increased risk of 43% (95% CI: 1.28–1.61) when standardizing reported ORs and using the same Hcy increments of 5 µmol/L.[18] [19] [20] [21] [22] [23]

The studies included in the present review assumed a linear association between Hcy levels and ischemic stroke; however, without describing this further or commenting on the hidden assumption of a linear association. As we observed a clear elevation in risk when surpassing 15 µmol/L, our results question this assumption of a linear association. Additionally, several studies performed a logarithmic transformation of Hcy levels prior to statistical analysis, indicating that they initially observed a nonlinear association with ischemic stroke risk, but without exploring this further.

To assess publication bias, we performed a funnel plot of our meta-analysis ([Fig. 3]). Generally, at least 10 studies with varying sample sizes should be included for the test to have the power to distinguish chance from true asymmetry. Even though only six studies were included in the meta-analysis, we included the funnel plot as it was severely asymmetric. This could indicate publication bias, but it may also result from an overestimation of the effect of Hcy because of small study populations.[123]

Several large randomized controlled trials of Hcy-lowering treatment report mainly no effect on risk of CVD.[12] [13] [14] [124] These studies were excluded in the inclusion process of this review, as Hcy levels were not reported in the studies.

Strengths and Limitations

One of the strengths of the present systematic review was the strict requirement of outcome definition required for inclusion. Numerous studies investigating the relationship between Hcy and stroke do not differentiate between hemorrhagic or ischemic stroke in their outcome variable which could lead to a reduction of estimates toward the null.[10] [125] [126] Second, this review only included multivariable adjusted risk estimates.

Some limitations have to be considered as well. First, statistical analyses were not standardized across studies and a meta-analysis of the dose-response relationship was only based on six studies. Second, the strategies for choosing control groups varied between hospital- and community-based controls; this could lead some studies to include a healthier control group compared with others. Third, we were not able to take into account differences in laboratory methods for measuring Hcy levels, and in turn, differences in reference intervals between studies. Forth, Hcy levels are influenced by a vast array of environmental and genetic factors, but most studies only adjusted effect measures for the main known cardiovascular risk factors, age, sex, hypertension, diabetes, cholesterol, smoking status, and BMI. However, six studies adjusted for renal function[23] [106] [109] [113] [115] [117] and additional nutritional factors, such as folate and vitamin B12 levels, were adjusted in six studies.[21] [22] [23] [106] [108] [109] We were not able to further assess the possible differential impact of the etiology of elevated Hcy levels and the association with ischemic stroke. Furthermore, lipid-lowering medication, such as fibrates, commonly prescribed for patients in risk of CVD, might influence the Hcy levels.[127] Any potential influence of lipid-lowering drugs on the association between Hcy and ischemic stroke was not assessed.

Conclusion

The present review and meta-analysis indicate that a nonlinear association could exist between Hcy levels and the risk of ischemic stroke. This implies that the risk of ischemic stroke increases when Hcy exceeds a certain level. Identifying this cut-off point would be of strong clinical interest, as it could help distinguish which patients could benefit of Hcy-lowering treatment.

Conflict of Interest

M.H. has no conflicts of interest. A.M.H. has no conflicts of interest regarding the present paper but has the following general conflicts for interest: has received speaker's fees from CSL Behring, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, and Astellas, and unrestricted research support from Octapharma and CSL Behring.

J.F.H.A. has no conflicts of interest regarding the present paper but has the following conflicts of interest outside the present work: received a speaker's fee within the last 36 months from Siemens Healthineers, Denmark, and a speaker's fee within the last 36 months from Teva Denmark A/S.

• References

• 1 McCully KS. Atherogenesis and the chemical pathology of homocysteine. European Journal of Laboratory Medicine 1996; 4: 121-128
• 2 Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med 1998; 338 (15) 1042-1050
• 3 Ansari R, Mahta A, Mallack E, Luo JJ. Hyperhomocysteinemia and neurologic disorders: a review. J Clin Neurol 2014; 10 (04) 281-288
• 4 Refsum H, Ueland PM, Nygård O, Vollset SE. Homocysteine and cardiovascular disease. Annu Rev Med 1998; 49: 31-62
• 5 Faraci FM, Lentz SR. Hyperhomocysteinemia, oxidative stress, and cerebral vascular dysfunction. Stroke 2004; 35 (02) 345-347
• 6 Ungvari Z, Csiszar A, Edwards JG. et al. Increased superoxide production in coronary arteries in hyperhomocysteinemia: role of tumor necrosis factor-alpha, NAD(P)H oxidase, and inducible nitric oxide synthase. Arterioscler Thromb Vasc Biol 2003; 23 (03) 418-424
• 7 Eberhardt RT, Forgione MA, Cap A. et al. Endothelial dysfunction in a murine model of mild hyperhomocyst(e)inemia. J Clin Invest 2000; 106 (04) 483-491
• 8 Hankey GJ, Eikelboom JW. Homocysteine and vascular disease. Lancet 1999; 354 (9176): 407-413
• 9 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) 1924-1930
• 10 Alfthan G, Pekkanen J, Jauhiainen M. et al. Relation of serum homocysteine and lipoprotein(a) concentrations to atherosclerotic disease in a prospective Finnish population based study. Atherosclerosis 1994; 106 (01) 9-19
• 11 Ebbing M, Bønaa KH, Arnesen E. et al. Combined analyses and extended follow-up of two randomized controlled homocysteine-lowering B-vitamin trials. J Intern Med 2010; 268 (04) 367-382
• 12 Toole JF, Malinow MR, Chambless LE. et al. Lowering 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 2004; 291 (05) 565-575
• 13 Huo Y, Li J, Qin X. et al; CSPPT Investigators. 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) 1325-1335
• 14 Martí-Carvajal AJ, Solà I, Lathyris D, Dayer M. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev 2017; 8: CD006612
• 15 Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 2002; 325 (7374): 1202
• 16 Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009; 339: b2535
• 17 National Heart Lung, and Blood Institute. Study quality assessment tools. Accessed September 6, 2021 at: https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools
• 18 Iso H, Moriyama Y, Sato S. et al. Serum total homocysteine concentrations and risk of stroke and its subtypes in Japanese. Circulation 2004; 109 (22) 2766-2772
• 19 Cui R, Moriyama Y, Koike KA. et al; JACC Study group. Serum total homocysteine concentrations and risk of mortality from stroke and coronary heart disease in Japanese: the JACC study. Atherosclerosis 2008; 198 (02) 412-418
• 20 Haltmayer M, Mueller T, Lange W. et al. Relation between homocysteine and non-fatal stroke in peripheral arterial disease. Eur J Neurol 2002; 9 (06) 609-614
• 21 Fallon UB, Virtamo J, Young I. et al. Homocysteine and cerebral infarction in finnish male smokers. Stroke 2003; 34 (06) 1359-1363
• 22 Loffredo L, Violi F, Fimognari FL. et al. The association between hyperhomocysteinemia and ischemic stroke in patients with non-valvular atrial fibrillation. Haematologica 2005; 90 (09) 1205-1211
• 23 Eikelboom JW, Hankey GJ, Anand SS, Lofthouse E, Staples N, Baker RI. Association between high homocyst(e)ine and ischemic stroke due to large- and small-artery disease but not other etiologic subtypes of ischemic stroke. Stroke 2000; 31 (05) 1069-1075
• 24 Atanassova PA, Angelova E, Tzvetanov P, Semerdjieva M, Dimitrov BD. Modelling of increased homocysteine in ischaemic stroke: post-hoc cross-sectional matched case-control analysis in young patients. Arq Neuropsiquiatr 2007; 65 (01) 24-31
• 25 Bosco P, Guéant-Rodriguez RM, Anello G. et al. Association of homocysteine (but not of MTHFR 677 C>T, MTR 2756 A>G, MTRR 66 A>G and TCN2 776 C>G) with ischaemic cerebrovascular disease in Sicily. Thromb Haemost 2006; 96 (02) 154-159
• 26 Delport R, Ubbink JB, Vermaak WJ, Rossouw H, Becker PJ, Joubert J. Hyperhomocysteinaemia in black patients with cerebral thrombosis. QJM 1997; 90 (10) 635-639
• 27 Haapaniemi E, Helenius J, Soinne L, Syrjälä M, Kaste M, Tatlisumak T. Serial measurements of plasma homocysteine levels in early and late phases of ischemic stroke. Eur J Neurol 2007; 14 (01) 12-17
• 28 Hassan A, Hunt BJ, O'Sullivan M. et al. Homocysteine is a risk factor for cerebral small vessel disease, acting via endothelial dysfunction. Brain 2004; 127 (pt. 1): 212-219
• 29 Kara N, Senes M, Coskun O, Inan L, Saydam G, Yucel D. Urinary methylmalonic acid levels in patients with acute ischemic stroke. Clin Biochem 2009; 42 (7,8): 578-583
• 30 Kario K, Duell PB, Matsuo T. et al. High plasma homocyst(e)ine levels in elderly Japanese patients are associated with increased cardiovascular disease risk independently from markers of coagulation activation and endothelial cell damage. Atherosclerosis 2001; 157 (02) 441-449
• 31 Kelly PJ, Kistler JP, Shih VE. et al. Inflammation, homocysteine, and vitamin B6 status after ischemic stroke. Stroke 2004; 35 (01) 12-15
• 32 Kim MH, Moon JS, Park SY. et al. Different risk factor profiles between silent brain infarction and symptomatic lacunar infarction. Eur Neurol 2011; 65 (05) 250-256
• 33 Kim OJ, Hong SH, Oh SH. et al. Association between VEGF polymorphisms and homocysteine levels in patients with ischemic stroke and silent brain infarction. Stroke 2011; 42 (09) 2393-2402
• 34 Kristensen B, Malm J, Nilsson TK. et al. Hyperhomocysteinemia and hypofibrinolysis in young adults with ischemic stroke. Stroke 1999; 30 (05) 974-980
• 35 Kucukarabaci B, Gunes HV, Ozdemir G. et al. Investigation of association between plasminogen activator inhibitor type-1 (PAI-1) gene 4G/5G polymorphism frequency and plasma PAI-1 enzyme activity in patients with acute stroke. Genet Test 2008; 12 (03) 443-451
• 36 Lee JH, Kim OJ, Kim HS. et al. Polymorphisms of thymidylate synthase enhancer region (TSER) and upstream stimulatory factor 1 (USF1 306G > A) genes are associated with plasma homocysteine level and susceptibility to ischemic stroke in a Korean population. Genes Genomics 2008; 30: 563-570
• 37 Lehmann MF, Kallaur AP, Oliveira SR. et al. Inflammatory and metabolic markers and short-time outcome in patients with acute ischemic stroke in relation to TOAST subtypes. Metab Brain Dis 2015; 30 (06) 1417-1428
• 38 Li G, Liu Y, Li X. et al. Association of pai-1 4g/5g polymorphism with ischemic stroke in Chinese patients with type 2 diabetes mellitus. Genet Test Mol Biomarkers 2018; 22 (09) 554-560
• 39 Lindgren A, Brattström L, Norrving B, Hultberg B, Andersson A, Johansson BB. Plasma homocysteine in the acute and convalescent phases after stroke. Stroke 1995; 26 (05) 795-800
• 40 Lu SJ, Zhou XS, Zheng Q, Chen HL, Geng YL. Platelet membrane receptor P2Y12 H1/H2 polymorphism is highly associated with cerebral infarction: a case-control study. Neuropsychiatr Dis Treat 2018; 14: 2225-2231
• 41 Luo HC, Luo QS, Wang CF, Lei M, Li BL, Wei YS. Association of miR-146a, miR-149, miR-196a2, miR-499 gene polymorphisms with ischemic stroke in a Chinese people. Oncotarget 2017; 8 (46) 81295-81304
• 42 Ma L, Jiang Y, Kong X. et al. Synergistic effect of the MTHFR C677t and EPHX2 G860A polymorphism on the increased risk of ischemic stroke in Chinese type 2 diabetic patients. J Diabetes Res 2017; 2017: 6216205
• 43 Ma SG, Xu W, Wei CL. et al. Role of ischemia-modified albumin and total homocysteine in estimating symptomatic lacunar infarction in type 2 diabetic patients. Clin Biochem 2011; 44 (16) 1299-1303
• 44 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 (02) 242-247
• 45 Meiklejohn DJ, Vickers MA, Dijkhuisen R, Greaves M. Plasma homocysteine concentrations in the acute and convalescent periods of atherothrombotic stroke. Stroke 2001; 32 (01) 57-62
• 46 Mejia Mohamed EH, Tan KS, Ali JM, Mohamed Z. TT genotype of the methylenetetrahydrofolate reductase C677T polymorphism is an important determinant for homocysteine levels in multi-ethnic Malaysian ischaemic stroke patients. Ann Acad Med Singap 2011; 40 (04) 186-191
• 47 Modi M, Prabhakar S, Majumdar S, Khullar M, Lal V, Das CP. Hyperhomocysteinemia as a risk factor for ischemic stroke: an Indian scenario. Neurol India 2005; 53 (03) 297-301 , discussion 301–302
• 48 Moe KT, Woon FP, De Silva DA. et al. Association of acute ischemic stroke with the MTHFR C677T polymorphism but not with NOS3 gene polymorphisms in a Singapore population. Eur J Neurol 2008; 15 (12) 1309-1314
• 49 Mojiminiyi OA, Marouf R, Al Shayeb AR. et al. Determinants and associations of homocysteine and prothrombotic risk factors in Kuwaiti patients with cerebrovascular accident. Med Princ Pract 2008; 17 (02) 136-142
• 50 Parnetti L, Caso V, Santucci A. et al. Mild hyperhomocysteinemia is a risk-factor in all etiological subtypes of stroke. Neurol Sci 2004; 25 (01) 13-17
• 51 Perini F, Galloni E, Bolgan I. et al. Elevated plasma homocysteine in acute stroke was not associated with severity and outcome: stronger association with small artery disease. Neurol Sci 2005; 26 (05) 310-318
• 52 Pezzini A, Del Zotto E, Archetti S. et al. Plasma homocysteine concentration, C677T MTHFR genotype, and 844ins68bp CBS genotype in young adults with spontaneous cervical artery dissection and atherothrombotic stroke. Stroke 2002; 33 (03) 664-669
• 53 Press RD, Beamer N, Evans A, DeLoughery TG, Coull BM. Role of a common mutation in the homocysteine regulatory enzyme methylenetetrahydrofolate reductase in ischemic stroke. Diagn Mol Pathol 1999; 8 (01) 54-58
• 54 Rahman A, Gupta RD, Quraishi FA, Saha UK, Miah MNA, Ali Z. Relationship between homocysteine and ischemic stroke. Journal of Medicine (Bangladesh) 2013; 14: 47-51
• 55 Tantirittisak T, Sura T, Moleerergpoom W, Hanchaipiboolkul S. Plasma homocysteine and ischemic stroke patients in Thailand. J Med Assoc Thai 2007; 90 (06) 1183-1187
• 56 Ustundag M, Orak M, Guloglu C, Ozturk E, Tamam Y, Kale E. The role of serum ferritin, pro-brain natriuretic peptide and homocysteine levels in determining ischaemic stroke subtype, severity and mortality. Hong Kong J Emerg Med 2010; 17: 13-21
• 57 Vayá A, Ejarque I, Tembl J, Corella D, Laiz B. Hyperhomocysteinemia, obesity and cryptogenic stroke. Clin Hemorheol Microcirc 2011; 47 (01) 53-58
• 58 Wang C, Han L, Wu Q. et al. Association between homocysteine and incidence of ischemic stroke in subjects with essential hypertension: a matched case-control study. Clin Exp Hypertens 2015; 37 (07) 557-562
• 59 Wang CY, Chen ZW, Zhang T. et al. Elevated plasma homocysteine level is associated with ischemic stroke in Chinese hypertensive patients. Eur J Intern Med 2014; 25 (06) 538-544
• 60 Xia XS, Li X, Wang L, Wang JZ, Ma JP, Wu CJ. Supplementation of folic acid and vitamin B₁₂ reduces plasma levels of asymmetric dimethylarginine in patients with acute ischemic stroke. J Clin Neurosci 2014; 21 (09) 1586-1590
• 61 Yadav BK, Yadav R, Chang H. et al. Genetic polymorphisms rs699947, rs1570360, and rs3025039 on the VEGF gene are correlated with extracranial internal carotid artery stenosis and ischemic stroke. Ann Clin Lab Sci 2017; 47 (02) 144-155
• 62 Yang TH, Chang CY, Hu ML. Various forms of homocysteine and oxidative status in the plasma of ischemic-stroke patients as compared to healthy controls. Clin Biochem 2004; 37 (06) 494-499
• 63 Yang Z, Wang L, Zhang W, Wang X, Zhou S. Plasma homocysteine involved in methylation and expression of thrombomodulin in cerebral infarction. Biochem Biophys Res Commun 2016; 473 (04) 1218-1222
• 64 Yao Y, Gao LJ, Zhou Y. et al. Effect of advanced age on plasma homocysteine levels and its association with ischemic stroke in non-valvular atrial fibrillation. J Geriatr Cardiol 2017; 14 (12) 743-749
• 65 Yoo JH, Chung CS, Kang SS. Relation of plasma homocyst(e)ine to cerebral infarction and cerebral atherosclerosis. Stroke 1998; 29 (12) 2478-2483
• 66 Zhang F, Li X, Dong Q, Wang Y, Zhang H. Risk of acute cerebral infarction and plasma asymmetrical dimethylarginine and homocysteine levels: a clinical correlation analysis of Chinese population. J Stroke Cerebrovasc Dis 2014; 23 (09) 2225-2232
• 67 Zhang H, Zhao X, Wang C. et al. A preliminary study of the association between apolipoprotein e promoter methylation and atherosclerotic cerebral infarction. J Stroke Cerebrovasc Dis 2019; 28 (04) 1056-1061
• 68 Zhu F, Jin XP, Zhu M. et al. Matrix metalloproteinase 10 gene polymorphism and atherothrombotic cerebral infarction risk in a Han Chinese population. Int J Clin Exp Med 2013; 6 (07) 567-575
• 69 Adunsky A, Weitzman A, Fleissig Y. et al. The relation of plasma total homocysteine levels to prevalent cardiovascular disease in older patients with ischemic stroke. Aging (Milano) 2000; 12 (01) 48-52
• 70 Akpalu A, Nyame P. Plasma homocysteine as a risk factor for strokes in ghanaian adults. Ghana Med J 2009; 43 (04) 157-163
• 71 Al-Allawi NA, Avo AS, Jubrael JM. Methylenetetrahydrofolate reductase C677T polymorphism in Iraqi patients with ischemic stroke. Neurol India 2009; 57 (05) 631-635
• 72 Araki A, Sako Y, Fukushima Y, Matsumoto M, Asada T, Kita T. Plasma sulfhydryl-containing amino acids in patients with cerebral infarction and in hypertensive subjects. Atherosclerosis 1989; 79 (2,3): 139-146
• 73 Salem-Berrabah OB, Mrissa R, Machghoul S. et al. Hyperhomocysteinemia, C677T MTHFR polymorphism and ischemic stroke in Tunisian patients. Tunis Med 2010; 88 (09) 655-659
• 74 Brattström L, Lindgren A, Israelsson B. et al. Hyperhomocysteinaemia in stroke: prevalence, cause, and relationships to type of stroke and stroke risk factors. Eur J Clin Invest 1992; 22 (03) 214-221
• 75 Celikbilek A, Ismailogullari S, Zararsiz G. Neutrophil to lymphocyte ratio predicts poor prognosis in ischemic cerebrovascular disease. J Clin Lab Anal 2014; 28 (01) 27-31
• 76 Cingozbay BY, Yiginer O, Cebeci BS, Kardesoglu E, Demiralp E, Dincturk M. Role of homocysteine for thromboembolic complication in patients with non-valvular atrial fibrilation. Blood Coagul Fibrinolysis 2002; 13 (07) 609-613
• 77 Coull BM, Malinow MR, Beamer N, Sexton G, Nordt F, de Garmo P. Elevated plasma homocyst(e)ine concentration as a possible independent risk factor for stroke. Stroke 1990; 21 (04) 572-576
• 78 El Kossi MM, Zakhary MM. Oxidative stress in the context of acute cerebrovascular stroke. Stroke 2000; 31 (08) 1889-1892
• 79 Fatima S, Memon SF, Ansari AK, Baloch AH. Hyperhomocystenemia as a risk factor for ischemic stroke. J Liaquat Uni Med Health Sci 2012; 11: 158-161
• 80 Fekih-Mrissa N, Mrad M, Klai S. et al. Methylenetetrahydrofolate reductase (C677T and A1298C) polymorphisms, hyperhomocysteinemia, and ischemic stroke in Tunisian patients. J Stroke Cerebrovasc Dis 2013; 22 (04) 465-469
• 81 Karakurum Goksel B, Karatas M, Nebioglu A. et al. Subclinical hypothyroidism, hyperhomocysteinemia and dyslipidemia: investigating links with ischemic stroke in Turkish patients. Neurol Res 2007; 29 (08) 871-876
• 82 Han SC, Guo Y, Sun GJ, Gu YY. Relation of plasma homocysteine with folic acid and vitamine b12 in patients with cerebral infarction. Zhongguo Linchuang Kangfu 2002; 6: 2970-2971
• 83 Karabulut KU, Bayir A, Kara F, Ak A. The levels of serum b12, folic acid and homocysteine in the thromboembolic diseases. J Clin Anal Med 2017; 8: 130-133
• 84 Kokocińska D, Cierpka L, Chmiel B. et al. The usefulness of assessing the serum levels of homocysteine in diagnosis of atherosclerosis. Acta Angiologica 2005; 11: 114-120
• 85 Li FS, Luo XW, Jia LH. et al. Relativity of the type and grade of stroke with the serum homocysteine level. Zhongguo Linchuang Kangfu 2004; 8: 1974-1975
• 86 Liu JG, Zhang ZC, Gao HF, Liu HX, Tan XM. Relationship between hyperhomocysteinemia and cerebral stroke in young and middle-aged people. Zhongguo Linchuang Kangfu 2005; 9: 221-223
• 87 Moghaddasi M, Mamarabadi M, Mirzadeh S, Freydoonnejad AA, Razjouyan H. Homocysteine, vitamin B12 and folate levels in Iranian patients with ischemic stroke. Neurol Res 2010; 32 (09) 953-956
• 88 Mykhalojko OJ, Mykhalojko IJ. Some biochemical changes in patients with acute ischemic stroke. Ukr Biochem J 2017; 89: 31-35
• 89 Narang AP, Verma I, Kaur S, Narang A, Gupta S, Avasthi G. Homocysteine–risk factor for ischemic stroke?. Indian J Physiol Pharmacol 2009; 53 (01) 34-38
• 90 Omrani HQ, Shandiz EE, Qabai M, Chaman R, Fard HA, Qaffarpoor M. Hyperhomocysteinemia, folateo and B12 vitamin in Iranian patients with acute ischemic stroke. ARYA Atheroscler 2011; 7 (03) 97-101
• 91 Peng H, Huang Q, Li Y. et al. Study on the relationship between plasma homocysteine and acute cerebral vascular disease. J Tongji Med Univ 2000; 20 (04) 330-331
• 92 Sawuła W, Banecka-Majkutewicz Z, Kadziński L. et al. Homocysteine level and metabolism in ischemic stroke in the population of Northern Poland. Clin Biochem 2009; 42 (06) 442-447
• 93 Sönmezler A, Ulaş T, Dal MS, Demir ME, Karababa IF, Büyükhatipoǧlu H. Plasma homocysteine levels in patients with acute ischemic stroke: A cross-sectional study. Turkiye Klinikleri Journal of Medical Sciences 2013; 33: 384-388
• 94 Sun JZ, Xu Y, Lu H, Zhu Y. Polymorphism of the methylenetetrahydrofolate reductase gene association with homocysteine and ischemic stroke in type 2 diabetes. Neurol India 2009; 57 (05) 589-593
• 95 Sun WP, Zhao JX, Wan Q, Wei D, Yu YX. Association of hyperhomocysteinemia and methylenetetrahydrofolate reductase gene polymorphisms with ischemic stroke in northwest Chinese population. Zhongguo Linchuang Kangfu 2005; 9: 171-173
• 96 Tas A, Tas F, Candan F, Topaktas S. Association between homocysteine level and intima-media thickness in patients with first ischemic stroke. Neurol Psychiatry Brain Res 2005; 12: 53-58
• 97 Unal E, Mungan S, Bilen S. et al. The effects of lipoprotein(a) and homocysteine on prognosis and risk factors in acute ischemic stroke. Int J Neurosci 2013; 123 (08) 532-536
• 98 Urbańska EM, Luchowski P, Luchowska E. et al. Serum kynurenic acid positively correlates with cardiovascular disease risk factor, homocysteine: a study in stroke patients. Pharmacol Rep 2006; 58 (04) 507-511
• 99 Wei W, Chen X, Lin X. et al. Serum PPARγ level and PPARγ gene polymorphism as well as severity and prognosis of brain injury in patients with arteriosclotic cerebral infarction. Exp Ther Med 2018; 16 (05) 4058-4062
• 100 Wu GH, Kong FZ, Dong XF. et al. Association between hyperhomocysteinemia and stroke with atherosclerosis and small artery occlusion depends on homocysteine metabolism-related vitamin levels in Chinese patients with normal renal function. Metab Brain Dis 2017; 32 (03) 859-865
• 101 Yi L, Huang Y, Wu T, Wu J. A magnetic nanoparticles-based method for DNA extraction from the saliva of stroke patients. Neural Regen Res 2013; 8 (32) 3036-3046
• 102 Yingdong Z, Zhigang Z, Yang L. Association of plasma homocysteine level and N5,N10-methylenetetrahydrofolate reductase gene polymorphism with cerebral infarction. Chin Med Sci J 2002; 17 (04) 231-235
• 103 Zhang W, Zhang X. Correlation between the youth cerebral infarction in different TOAST classifications and high homocysteine. Cell Biochem Biophys 2015; 71 (01) 39-42
• 104 Zhou J, Zhang SZ, Zhang Y, Chen Z, Ding MP. Relationship between plasma homocysteine level and stroke. Zhongguo Linchuang Kangfu 2005; 9: 181-183
• 105 Tanne D, Haim M, Goldbourt U. et al. Prospective study of serum homocysteine and risk of ischemic stroke among patients with preexisting coronary heart disease. Stroke 2003; 34 (03) 632-636
• 106 Shimizu H, Kiyohara Y, Kato I. et al. Plasma homocyst(e)ine concentrations and the risk of subtypes of cerebral infarction. The Hisayama study. Cerebrovasc Dis 2002; 13 (01) 9-15
• 107 Tascilar N, Ekem S, Aciman E. et al. Hyperhomocysteinemia as an independent risk factor for cardioembolic stroke in the Turkish population. Tohoku J Exp Med 2009; 218 (04) 293-300
• 108 Tan NC, Venketasubramanian N, Saw SM, Tjia HT. Hyperhomocyst(e)inemia and risk of ischemic stroke among young Asian adults. Stroke 2002; 33 (08) 1956-1962
• 109 Khan U, Crossley C, Kalra L. et al. Homocysteine and its relationship to stroke subtypes in a UK black population: the south London ethnicity and stroke study. Stroke 2008; 39 (11) 2943-2949
• 110 Campbell DJ, Woodward M, Chalmers JP. et al. Soluble vascular cell adhesion molecule 1 and N-terminal pro-B-type natriuretic peptide in predicting ischemic stroke in patients with cerebrovascular disease. Arch Neurol 2006; 63 (01) 60-65
• 111 Hultdin J, Van Guelpen B, Winkvist A. 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 (09) 1555-1562
• 112 Kaplan RC, McGinn AP, Baird AE. et al. Inflammation and hemostasis biomarkers for predicting stroke in postmenopausal women: the Women's Health Initiative Observational Study. J Stroke Cerebrovasc Dis 2008; 17 (06) 344-355
• 113 Rueda-Clausen CF, Córdoba-Porras A, Bedoya G. et al. Increased plasma levels of total homocysteine but not asymmetric dimethylarginine in Hispanic subjects with ischemic stroke FREC-VI sub-study. Eur J Neurol 2012; 19 (03) 417-425
• 114 Liang Y, Chen P, Sun Y, Feng P, Huang B, Jiang T. Evaluation of laboratory parameters in predicting ischemic stroke in essential hypertension patients. Biomedical Research (India) 2017; 28: 4013-4019
• 115 Li Z, Sun L, Zhang H. et al; Multicenter Case-Control Study in China. Elevated plasma homocysteine was associated with hemorrhagic and ischemic stroke, but methylenetetrahydrofolate reductase gene C677T polymorphism was a risk factor for thrombotic stroke: a Multicenter Case-Control Study in China. Stroke 2003; 34 (09) 2085-2090
• 116 Shi Z, Liu S, Guan Y. et al. Changes in total homocysteine levels after acute stroke and recurrence of stroke. Sci Rep 2018; 8 (01) 6993
• 117 Petri M, Roubenoff R, Dallal GE, Nadeau MR, Selhub J, Rosenberg IH. Plasma homocysteine as a risk factor for atherothrombotic events in systemic lupus erythematosus. Lancet 1996; 348 (9035): 1120-1124
• 118 Bostom AG, Rosenberg IH, Silbershatz H. et al. Nonfasting plasma total homocysteine levels and stroke incidence in elderly persons: the Framingham Study. Ann Intern Med 1999; 131 (05) 352-355
• 119 Zee RY, Mora S, Cheng S. et al. Homocysteine, 5,10-methylenetetrahydrofolate reductase 677C>T polymorphism, nutrient intake, and incident cardiovascular disease in 24,968 initially healthy women. Clin Chem 2007; 53 (05) 845-851
• 120 Schindler K, Zauner C, Buchmayer H. et al. High prevalence of hyperhomocysteinemia in critically ill patients. Crit Care Med 2000; 28 (04) 991-995
• 121 Lonn E, Held C, Arnold JM. et al; HOPE-2 Investigators. 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. Can J Cardiol 2006; 22 (01) 47-53
• 122 Spence JD. Homocysteine-lowering therapy: a role in stroke prevention?. Lancet Neurol 2007; 6 (09) 830-838
• 123 Sterne JA, Sutton AJ, Ioannidis JP. et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ 2011; 343: d4002
• 124 Kong X, Huang X, Zhao M. et al. Platelet count affects efficacy of folic acid in preventing first stroke. J Am Coll Cardiol 2018; 71 (19) 2136-2146
• 125 Perry IJ, Refsum H, Morris RW, Ebrahim SB, Ueland PM, Shaper AG. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet 1995; 346 (8987): 1395-1398
• 126 Stehouwer CD, Weijenberg MP, van den Berg M, Jakobs C, Feskens EJ, Kromhout D. Serum homocysteine and risk of coronary heart disease and cerebrovascular disease in elderly men: a 10-year follow-up. Arterioscler Thromb Vasc Biol 1998; 18 (12) 1895-1901
• 127 Sahebkar A, Pirro M, Reiner Ž. et al. A systematic review and meta-analysis of controlled trials on the effects of statin and fibrate therapies on plasma homocysteine levels. Curr Med Chem 2016; 23 (39) 4490-4503
• 128 Cao L, Guo Y, Zhu Z. Study of the inflammatory mechanisms in hyperhomocysteinemia on large-artery atherosclerosis based on hypersensitive c-reactive protein-a study from southern china. J Stroke Cerebrovasc Dis 2019; 28 (07) 1816-1823
• 129 Dai Z, Jiao Y, Fan Q, Qi A, Xiao L, Li J. Homocysteine, interleukin-1β, and fasting blood glucose levels as prognostic markers for diabetes mellitus complicated with cerebral infarction and correlated with carotid intima-media thickness. Exp Ther Med 2020; 19 (02) 1167-1174
• 130 Wei GJ, Yuan MQ, Jiang LH. et al. A genetic variant of mir-34a contributes to susceptibility of ischemic stroke among Chinese population. Front Physiol 2019; 10: 432
• 131 Alkali NH, Watt H, Bwala SA, Gadzama A. Association of plasma homocysteine and ischaemic stroke in a nigerian population. Pakistan J Med Sci 2006; 22: 405-408

Publikationsverlauf

Eingereicht: 07. Mai 2021

Angenommen: 19. Juli 2021

Artikel online veröffentlicht:
24. September 2021