Study Of The Effect Of Homocysteine On The Prognosis Or Risk Of Cerebrovascular Diseases

Background:Homocysteine has been identified as a risk factor of cardio-cerebrovascular disease due to its effect on atherosclerosis and thrombosis. B vitamin supplement has been used for lowering homocysteine concentration as essential component during the metabolic pathway of homocysteine. However, the effect of B vitamin supplement for decreasing risk of cardio-cerebrovascular disease is not defined. Although the effect of elevated homocysteine level on prognosis of cardio-cerebrovascular disease has been noticed, inconsistent results were reported. Recently post-hoc analyses of several trials reported benefits of B vitamins supplementation in certain people, and reduced volume of infarction by homocysteine inhibitor was observed in animal experiments, which provide the basis for further study.Objectives:We aimed to evaluate the association between blood homocysteine level and ischemic stroke prognosis, and lowering homocysteine levels via B vitamin supplementation on cardio-cerebrovascular disease risk.Methods:This study was divided into two parts.In the first part we analyzed the data of acute ischemic stroke patients from the Henan Province Stroke Registry. Data of social characteristics, risk factors, clinical features and laboratory indexes were collected and patients were followed up for all-cause mortality, functional recovery and stroke recurrence. Logistic regression was performed to analyze the association between blood homocysteine level and stroke prognosis. Receiver operating characteristic (ROC) curve was used to analyze the cut-off point of homocysteine parameter for severe neurological impairment and poor prognosis.In the second part randomized controlled trials before August 2012 restricted to human beings were acquired through formal literature search for PubMed, Embase, the Cochrane library, CBM database and other Chinese database. After excluding most articles due to unclear design, inappropriate interventions or outcomes, short follow-up time, repeated reports, unfinished studies or incomplete data,20 randomized controlled trails and two post-hoc analyses of trials were retained. Data extracted in duplicate by two investigators independently were analyzed in Rev-Man 5.2 software. Subgroups analyses were introduced on existed diseases and the baseline of participant medication use, the baseline of blood homocysteine level and B12 concentration, intervention dose of B vitamin, lowered homocysteine concentration, follow-up time, background of cereal folate fortification, and primary or secondary prevention. Relative risk ratio (RR) with 95% CI was used as a measure of the association between B vitamin supplementation and risk of coronary artery disease and stroke diseases after pooling data from these trials using a fixed-effects or random-effects model. Heterogeneity testing was assessed by Chi square test and Ⅰ value.Results:In the first part 1460 eligible acute ischemic stroke patients were included in our study, including 991 (67.9%) men and 469 (32.1%) women. According to homocysteine level, age (P=0.022), the percentage of men (.P=0.000), complicated with hyperlipidemia rate (P=0.000), and the percentage of smoker (P=0.001) and alcoholic (P=0.016) increased in the higher quartile groups. According to NIHSS, age (P=0.020), plasma homocysteine level (P=0.009), complicated with diabetes rate (P=0.017) and atrial fibrillation rate (P=0.000) increased, and the percentage of smoker (P=0.007) decreased in the groups with NIHSS>16 point. Multivariate logistic regression showed that plasma homocysteine level (OR 1.02; 95%CI 1.01-1.04), complicated with diabetes (OR 1.75; 95%CI 1.14-2.69) and atrial fibrillation (OR 5.30; 95%CI 2.68-10.50) were independently associated with severe neurological impairment.1342(91.9%)were followed up at 12 month and 118(8.1%) were lost to the follow-up. According to mRS, age, plasma homocysteine level, complicated with diabetes rate and atrial fibrillation rate and stroke history rate increased, and the percentage of men and smoker decreased in the groups with mRS≥3. Multivariate logistic regression showed that age, blood homocysteine level, complicated with diabetes and stroke history were independently associated with poor prognosis. According to the end events, age (P=0.042), the percentage of alcoholic (P=0.001) and stroke history rate (P=0.000) increased in the particents with the recurrence of stroke, and age (P=0.000), complicated with diabetes rate (P=0.024) and coronary heart disease rate (P=0.001) and stroke history rate (P=0.005) increased, and the percentage of men decreased in the particents with all-cause death. Multivariate logistic regression showed that alcoholic (OR 2.02; 95%CI 1.31-3.12) and stroke history (OR2.14; 95%CI 1.47-3.25) were independently associated with the risk of recurrent stroke. Multivariate logistic regression showed that age (OR1.05; 95%CI 1.03-1.07) and coronary heart disease (OR 1.98; 95%CI 1.08-3.64) were independently associated with the mortality risk.In the second part 20 randomized controlled trials and two post-hoc trials with 52494 participants about the effect of B vitamin supplement on homocysteine level were assessed, in which cardio-cerebrovascular disease events were observed as clinical outcomes. We observed a reduction in overall stroke events resulting from reduction in homocysteine levels following B vitamin supplementation (RR 0.92, 95% CI,0.85-1.00; P=0.04) but not in subgroups according to ischemic vs hemorrhagic stroke (RR 0.98,95%CI 0.90-1.06; RR 0.76,95%CI 0.56-1.03, separately), or occurrence of fatal stroke. No significant results were observed in the effects of B vitamin supplementation for transient ischemic attack (TIA) events, myocardial infarction (MI) events, vascular mortality or total mortality.There were beneficial effects in reducing stroke events in subgroups with primary prevention (RR 0.84,95%CI 0.72-0.97), more than 3umol/L reduction of blood homocysteine concentration and 3 years or more follow-up time (RR 0.92, 95%CI 0.84-1.01; RR 0.91,95%CI 0.84-0.99, separately), without background of cereal folate fortification or chronic kidney disease (CKD) (RR 0.91,95%CI 0.83-1.00; RR 0.93,95%CI 0.85-1.00, separately). Some trials that included CKD patients reported decreased glomerular filtration rate with B vitamin supplementation.We also conducted detailed subgroup analyses for cyanocobalamin (vitamin B12) but did not find a significant benefit on reducing the risk of stroke regarding intervention dose of vitamin B12 or baseline blood B12 concentration. Stratified analysis for blood pressure and baseline participant medication use showed benefits with 130 mm Hg systolic blood pressure and lower anti-platelet drug use in reducing stroke risk.Conclusions:1. Elevated plasma homocysteine level was independently associated with severe neurological impairment and poor prognosis in acute ischemic stroke patients.2. The effects of elevated homocysteine level on risk of recurrent stroke and mortality were not defined due to the more complexed pathomechanisms of homocysteine on ischemic stroke.3. B vitamin supplementation for homocysteine reduction significantly reduced stroke events, especially in subjects who received appropriate intervention.4. In the future, more studies about chronic kidney diseases patient, malabsorption of vit B12 and Asian populations are needed.